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    Clinical Trial Results:
    A multicentre randomised placebo-controlled double-blind clinical trial for evaluation of the optimal dose for safety and efficacy of specific immunotherapy with an aluminium hydroxide-adsorbed Allergoid preparation of house dust mite (Dermatophagoides pteronyssinus) in patients with controlled allergic bronchial asthma and rhinitis/rhinoconjunctivitis

    Summary
    EudraCT number
    		 2011-002248-29
    Trial protocol
    		 PL   ES  
    Global end of trial date
    02 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Nov 2017
    First version publication date
    29 Nov 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AL1009ac
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ALLERGOPHARMA GMBH & CO. KG.
    Sponsor organisation address
    Hermann-Körner-Straße 52, Reinbek, Germany, 21465
    Public contact
    Clinical Trials Information, Allergopharma GmbH & Co. KG, 0049 40427650,
    Scientific contact
    Clinical Trials Information, Allergopharma GmbH & Co. KG, 0049 40427650,
    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
    26 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluate the optimal dose for efficacy and tolerability of specific immunotherapy with an aluminium hydroxide-adsorbed allergoid preparation of major allergens of D. pteronyssinus in patients with controlled allergic asthma (acc. to GINA 2006) and allergic rhinoconjunctivitis, caused by house dust mite. This trial consisted of 2 parts: i) intracutaneous test (ICT), which is briefly summarized ii) dose range finding (DRF), which is presented in detail In the ICT part, patients (N=21 randomised, N=16 FAS) received an injection of 5000, 2500, and 500 SBE/mL of allergen extracts from D. pteronyssinus; each concentration was assessed after 2, 4, 6, and 8h to determine the appropriate wheal size swelling area and the read-off time for efficacy evaluation during the DRF part. For further investigations, the chosen concentration was 5000 SBE/mL, assessed after 6 h. ICT=Intracutaneous test DRF=Dose range finding FAS=Full analysis set SBE=Standardized biological unit
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki (October 2000 and following amendments), Good Clinical Practices guidelines, and local legal requirements. Other than routine care, no specific measures were implemented for the protection of trial subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 May 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 151
    Country: Number of subjects enrolled
    Spain: 16
    Worldwide total number of subjects
    167
    EEA total number of subjects
    167
    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)
    167
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Overall, 413 subjects were screened for eligibility. Of these, 167 subjects were randomised to treatment according to the exclusion and inclusion criteria: 21 patients were recruited into the ICT part and further 146 patients were recruited into the dose DRF part of the study; those participating in the ICT were not eligible for the DRF part.

    Pre-assignment
    Screening details
    		 Subjects were screened and randomised to treatment according to the exclusion and inclusion criteria.

    Period 1
    Period 1 title
    Dose range finding (DRF) (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
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo: solution containing aluminium hydroxide (Al(OH)3) in normal saline (9 g/L sodium chloride) was applied. Injection volume (0.1 mL at minimum 1.0 mL at maximum for matching Strength A placebo and 0.6 - 1.0 mL strength B placebo) was matching the volume of the corresponding active preparation. The injections were administered slowly, strictly subcutaneously, under sterile precautionary measures, on the extensor side of the upper arm, a hand’s breadth above the elbow, using a short-ground cannula. After each administration at the trial center, the patient was kept under close supervision for at least 30 minutes.

    Arm title
    		 600 PNU
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    D. pteronyssinus allergoid preparation 600 PNU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    D. pteronyssinus allergoid preparation 600 PNU For the injection volume and administration details of the active treatment, please see the description above for Placebo. PNU=Protein nitrogen unit

    Arm title
    		 1800 PNU
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    D. pteronyssinus allergoid preparation 1800 PNU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    D. pteronyssinus allergoid preparation 1800 PNU For the injection volume and administration details of the active treatment, please see the description above for Placebo. PNU=Protein nitrogen unit

    Arm title
    		 3000 PNU
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    D. pteronyssinus allergoid preparation 3000 PNU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    D. pteronyssinus allergoid preparation 3000 PNU For the injection volume and administration details of the active treatment, please see the description above for Placebo. PNU=Protein nitrogen unit

    Arm title
    		 5400 PNU
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    D. pteronyssinus allergoid preparation 5400 PNU
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    D. pteronyssinus allergoid preparation 5400 PNU For the injection volume and administration details of the active treatment, please see the description above for Placebo. PNU=Protein nitrogen unit

    Number of subjects in period 1 [1]
    		Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Started
    32
    24
    31
    28
    31
    Completed
    29
    24
    29
    25
    26
    Not completed
    3
    0
    2
    3
    5
         Consent withdrawn by subject
    1
    -
    2
    3
    1
         Adverse event, non-fatal
    1
    -
    -
    -
    -
         Pregnancy
    -
    -
    -
    -
    3
         Lost to follow-up
    1
    -
    -
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: This study was performed as 2 independent parts i.e. ICT and DRF. The number of randomised subjects was 21 in the ICT part and 146 in the DRF part. Subjects could participate either in the ICT or in the DRF part, but not both.

    Baseline characteristics

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

    Reporting group title
    600 PNU
    Reporting group description
    		 -

    Reporting group title
    1800 PNU
    Reporting group description
    		 -

    Reporting group title
    3000 PNU
    Reporting group description
    		 -

    Reporting group title
    5400 PNU
    Reporting group description
    		 -

    Reporting group values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU Total
    Number of subjects
    		 32 24 31 28 31 146
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 32 24 31 28 31 146
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 28.3 ± 7.5 25.4 ± 5 27.5 ± 7.3 27.9 ± 6.7 28 ± 7 -
    Gender categorical
    Units: Subjects
        Female
    		 21 12 14 12 11 70
        Male
    		 11 12 17 16 20 76
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 1 1
        Asian
    		 0 0 1 0 0 1
        White
    		 32 24 30 28 30 144

    End points

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

    Reporting group title
    600 PNU
    Reporting group description
    		 -

    Reporting group title
    1800 PNU
    Reporting group description
    		 -

    Reporting group title
    3000 PNU
    Reporting group description
    		 -

    Reporting group title
    5400 PNU
    Reporting group description
    		 -

    Primary: 1_Absolute change of the swelling area at 6h -- Late phase reaction (LPR)

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    End point title
    		 1_Absolute change of the swelling area at 6h -- Late phase reaction (LPR)
    End point description
    Change to baseline: Final Visit - Baseline Swelling area (cm²) of the LPR (6h) including change of swelling area (cm²) of the LPR (6h) after ICT. Measurement of the absolute change of the swelling area (in cm2) of the LPR, 6 h after ICT with a solution of of placebo or the mite allergoid preparation of the major allergens of D. pteronyssinus, from baseline (Visit S4) to the measurement after 1 year of treatment (Visit T17). Data collected were recorded in an electronic case report form completed by the study sites staff. ICT data of Visit S4 and of Visit T17 (area and volume of the immediate reaction after 20 minutes and the LPR after 6 hours) were captured by using the optical device Primos 3D. For the quantitative evaluation of this data, a specific analytical software was used; the results of these evaluations were transferred to the clinical database. ICT=Intracutaneous testing LPR=Late phase reaction
    End point type
    Primary
    End point timeframe
    Baseline (S4), after 1 year of treatment (T17). S1 = Day 0 S4 = 32 weeks after S1 T1 (randomization) = 52 weeks (1 year) after S1 T17 =36 weeks after T1
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    27 [1]
    23
    27
    24
    27
    Units: cm2
        least squares mean (confidence interval 95%)
    -6.41 (-10.96 to -1.87)
    7.98 (3.17 to 12.8)
    6.3 (1.83 to 10.78)
    10.83 (6.04 to 15.61)
    8.64 (4.11 to 13.17)
    Notes
    [1] - Full analysis set, for all treatment groups
    Statistical analysis title
    		 1_Placebo vs 600 PNU
    Statistical analysis description
    To assess treatment differences, an analysis of covariance (ANCOVA) model was used with the change of the swelling area (visit S4 baseline – visit T17 end of treatment) as the dependent variable, treatment and center as fixed effect, and the size of the baseline swelling area (visit S4) as covariable.
    Comparison groups
    Placebo v 600 PNU
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001 [3]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -14.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.92
         upper limit
    		 -7.86
    Notes
    [2] - ANCOVA for change of the swelling area [cm2] of late phase reaction (after 6h), including variable center. LS Mean: least square mean estimated from analysis of covariance including the baseline value as covariate and treatment group as fixed effect.
    [3] - F-test
    Statistical analysis title
    		 2_Placebo vs 1800 PNU
    Statistical analysis description
    Please see description above for the statistical analysis item 1_Placebo vs 600 PNU.
    Comparison groups
    Placebo v 1800 PNU
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.0001 [5]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -12.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19
         upper limit
    		 -6.43
    Notes
    [4] - For the statistical analysis, please see description above item 1_Placebo vs 600 PNU.
    [5] - F-test
    Statistical analysis title
    		 3_Placebo vs 3000 PNU
    Statistical analysis description
    Please see description above for the statistical analysis item 1_Placebo vs 600 PNU.
    Comparison groups
    Placebo v 3000 PNU
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.0001 [7]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -17.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.69
         upper limit
    		 -10.8
    Notes
    [6] - For the statistical analysis, please see description above item 1_Placebo vs 600 PNU.
    [7] - F-test
    Statistical analysis title
    		 4_Placebo vs 5400 PNU
    Statistical analysis description
    Please see description above for the statistical analysis item 1_Placebo vs 600 PNU.
    Comparison groups
    Placebo v 5400 PNU
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 < 0.0001 [9]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -15.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.37
         upper limit
    		 -8.74
    Notes
    [8] - For the statistical analysis, please see description above item 1_Placebo vs 600 PNU.
    [9] - F-test
    Statistical analysis title
    		 5_600 PNU vs 5400 PNU
    Statistical analysis description
    Please see description above for the statistical analysis item 1_Placebo vs 600 PNU.
    Comparison groups
    600 PNU v 5400 PNU
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.8421 [11]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.21
         upper limit
    		 5.89
    Notes
    [10] - For the statistical analysis, please see description above item 1_Placebo vs 600 PNU.
    [11] - F-test
    Statistical analysis title
    		 6_600 PNU vs 3000 PNU
    Statistical analysis description
    600 PNU vs 3000 PNU To assess differences between treatment groups, an analysis of covariance (ANCOVA) model was used with the change of the swelling area (visit S4 baseline – visit T17 end of treatment), as the dependent variable, treatment and center as fixed effect, and the size of the baseline swelling area (visit S4) as covariable.
    Comparison groups
    600 PNU v 3000 PNU
    Number of subjects included in analysis
    47
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.4031 [13]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -2.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.57
         upper limit
    		 3.87
    Notes
    [12] - For the statistical analysis, please see description above item 1_Placebo vs 600 PNU.
    [13] - F-test
    Statistical analysis title
    		 7_600 PNU vs 1800 PNU
    Statistical analysis description
    600 PNU vs 1800 PNU Please see description above for the statistical analysis item 6_600 PNU vs 3000 PNU.
    Comparison groups
    600 PNU v 1800 PNU
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.6098 [15]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -1.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.81
         upper limit
    		 8.16
    Notes
    [14] - For the statistical analysis, please see description above item 1_Placebo vs 600 PNU.
    [15] - F-test
    Statistical analysis title
    		 8_1800 PNU vs 5400 PNU
    Statistical analysis description
    1800 PNU vs 5400 PNU Please see description above for the statistical analysis item 6_600 PNU vs 3000 PNU.
    Comparison groups
    1800 PNU v 5400 PNU
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.4648 [17]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -2.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.65
         upper limit
    		 3.97
    Notes
    [16] - For the statistical analysis, please see description above item 1_Placebo vs 600 PNU.
    [17] - F-test
    Statistical analysis title
    		 9_1800 PNU vs 3000 PNU
    Statistical analysis description
    1800 PNU vs 3000 PNU Please see description above for the statistical analysis item 6_600 PNU vs 3000 PNU.
    Comparison groups
    1800 PNU v 3000 PNU
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.1673 [19]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -4.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.97
         upper limit
    		 1.92
    Notes
    [18] - For the statistical analysis, please see description above item 1_Placebo vs 600 PNU.
    [19] - F-test
    Statistical analysis title
    		 10_3000 PNU vs 5400 PNU
    Statistical analysis description
    3000 PNU vs 5400 PNU Please see description above for the statistical analysis item 6_600 PNU vs 3000 PNU.
    Comparison groups
    3000 PNU v 5400 PNU
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.5124 [21]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    2.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.41
         upper limit
    		 8.78
    Notes
    [20] - For the statistical analysis, please see description above item 1_Placebo vs 600 PNU.
    [21] - F-test

    Primary: 2_Responder analysis for the primary endpoint

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    End point title
    		 2_Responder analysis for the primary endpoint
    End point description
    Change to baseline: Final Visit - Baseline Two criteria for responder analysis were evaluated: • Patients were defined as responders if the LPR (area in cm2) at 6 h for ICT was reduced by at least 50% between baseline and after treatment. • Patients were defined as responders if the LPR (area in cm2) at 6 h for ICT was reduced by at least 30% between baseline and after treatment. Statistical analysis is shown below for the comparison of placebo vs active dose treatment group. For the comparisons between active dose treatment groups, no statistically significant results were observed (data are not shown). LPR=Late phase reaction
    End point type
    Primary
    End point timeframe
    Baseline (S4), after 1 year of treatment (T17). S1=Day 0 S4 (baseline)=32 weeks after S1. T1 (randomisation)=52 weeks (1 year) after S1 T17=36 weeks after T1
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    27 [22]
    23
    27
    24
    27
    Units: subject
        Improvement at least 50%
    2
    10
    7
    11
    10
        Improvement at least 30%
    4
    13
    15
    16
    17
    Notes
    [22] - Full analysis set for all treatment groups
    Statistical analysis title
    		 1_Placebo vs 600 PNU - reduction of 50 %
    Comparison groups
    Placebo v 600 PNU
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0029
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 2_Placebo vs 1800 PNU - reduction of 50 %
    Comparison groups
    Placebo v 1800 PNU
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0679
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 3_Placebo vs 3000 PNU - reduction of 50 %
    Comparison groups
    Placebo v 3000 PNU
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0017
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 4_Placebo vs 5400 PNU - reduction of 50 %
    Comparison groups
    Placebo v 5400 PNU
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0088
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 5_Placebo vs 600 PNU - reduction of 30 %
    Comparison groups
    Placebo v 600 PNU
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0019
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 6_Placebo vs 1800 PNU - reduction of 30 %
    Comparison groups
    Placebo v 1800 PNU
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0017
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 7_Placebo vs 3000 PNU - reduction of 30 %
    Comparison groups
    Placebo v 3000 PNU
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 8_Placebo vs 5400 PNU - reduction of 30 %
    Comparison groups
    Placebo v 5400 PNU
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 Chi-squared
    Confidence interval

    Secondary: 3_Absolute change of the swelling volume at 6h -- Late phase reaction (LPR)

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    End point title
    		 3_Absolute change of the swelling volume at 6h -- Late phase reaction (LPR)
    End point description
    Volume (mL) of the LPR (6 h after ICT), including change of volume (mL) of the LPR (6 h after ICT). LS Mean: least square mean estimated from analysis of covariance including the baseline value as covariate and center and treatment group as fixed effects. Data recording and measuring are described in the endpoint 1 above. Statistical analysis is shown below for the comparison of placebo vs active dose treatment group. For the comparisons between active dose treatment groups, no statistically significant results were observed (data are not shown). LPR=Late phase reaction
    End point type
    Secondary
    End point timeframe
    Baseline (S4), after 1 year of treatment (T17). S1=Day 0 S4 (baseline)=32 weeks after S1. T1 (randomisation)=52 weeks (1 year) after S1 T17=36 weeks after T1
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    27 [23]
    23
    27
    24
    27
    Units: mL
        least squares mean (confidence interval 95%)
    -0.98 (-1.79 to -0.17)
    1.63 (0.76 to 2.5)
    1.72 (0.92 to 2.53)
    2.13 (1.28 to 2.98)
    2.03 (1.22 to 2.84)
    Notes
    [23] - Full analysis set for all treatment groups
    Statistical analysis title
    		 1_Placebo vs 600 PNU
    Comparison groups
    Placebo v 600 PNU
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 < 0.0001 [25]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -2.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 -1.41
    Notes
    [24] - ANCOVA for change of the swelling volume [mL] of late phase reaction (after 6h), including variable center. LS Mean: least square mean estimated from analysis of covariance including the baseline value as covariate and treatment group as fixed effect.
    [25] - F-test
    Statistical analysis title
    		 2_Placebo vs 1800 PNU
    Comparison groups
    1800 PNU v Placebo
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 < 0.0001 [27]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.84
         upper limit
    		 -1.56
    Notes
    [26] - ANCOVA for change of the swelling volume [mL] of late phase reaction (after 6h), including variable center. LS Mean: least square mean estimated from analysis of covariance including the baseline value as covariate and treatment group as fixed effect.
    [27] - F-test
    Statistical analysis title
    		 3_Placebo vs 3000 PNU
    Comparison groups
    Placebo v 3000 PNU
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 < 0.0001 [29]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -3.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.28
         upper limit
    		 -1.94
    Notes
    [28] - ANCOVA for change of the swelling volume [mL] of late phase reaction (after 6h), including variable center. LS Mean: least square mean estimated from analysis of covariance including the baseline value as covariate and treatment group as fixed effect.
    [29] - F-test
    Statistical analysis title
    		 4_Placebo vs 5400 PNU
    Comparison groups
    Placebo v 5400 PNU
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 < 0.0001 [31]
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -3.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.16
         upper limit
    		 -1.86
    Notes
    [30] - ANCOVA for change of the swelling volume [mL] of late phase reaction (after 6h), including variable center. LS Mean: least square mean estimated from analysis of covariance including the baseline value as covariate and treatment group as fixed effect.
    [31] - F-test

    Secondary: 4_Absolute change of the swelling area at 20min -- Early phase reaction (EPR)

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    End point title
    		 4_Absolute change of the swelling area at 20min -- Early phase reaction (EPR)
    End point description
    Change to baseline: Final Visit - Baseline Swelling area (cm²) of the early phase (20 min) reaction including change of swelling area (cm²) of the EPR (20 min after ICT). LS Mean: least square mean estimated from analysis of covariance including the baseline value as covariate and center and treatment group as fixed effects. Data recording and measuring are described in the endpoint 1 above. Statistical analysis is shown below for the comparison of placebo vs active dose treatment group. For the comparisons between active dose treatment groups, no statistically significant results were observed (data are not shown). EPR=Early phase reaction
    End point type
    Secondary
    End point timeframe
    Baseline (S4), after 1 year of treatment (T17). S1=Day 0 S4 (baseline)=32 weeks after S1. T1 (randomisation)=52 weeks (1 year) after S1 T17=36 weeks after T1
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    27 [32]
    24
    28
    24
    27
    Units: cm2
        least squares mean (confidence interval 95%)
    0.79 (-0.29 to 1.87)
    1.15 (0 to 2.3)
    1.99 (0.92 to 3.05)
    3.01 (1.86 to 4.16)
    0.91 (-0.18 to 1.99)
    Notes
    [32] - Full analysis set for all treatment groups
    Statistical analysis title
    		 1_Placebo vs 600 PNU
    Statistical analysis description
    ANCOVA for change of the swelling area [cm2] of EPR EPR=early phase reaction
    Comparison groups
    Placebo v 600 PNU
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6522
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.94
         upper limit
    		 1.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8
    Statistical analysis title
    		 2_Placebo vs 1800 PNU
    Statistical analysis description
    ANCOVA for change of the swelling area [cm2] of EPR EPR=early phase reaction
    Comparison groups
    1800 PNU v Placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1213
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.72
         upper limit
    		 0.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.77
    Statistical analysis title
    		 3_Placebo vs 3000 PNU
    Statistical analysis description
    ANCOVA for change of the swelling area [cm2] of EPR EPR=early phase reaction
    Comparison groups
    Placebo v 3000 PNU
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0063
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -2.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.79
         upper limit
    		 -0.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8
    Statistical analysis title
    		 4_Placebo vs 5400 PNU
    Statistical analysis description
    ANCOVA for change of the swelling area [cm2] of EPR EPR=early phase reaction
    Comparison groups
    Placebo v 5400 PNU
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8788
    Method
    		 ANCOVA
    Parameter type
    		 LS mean
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.65
         upper limit
    		 1.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.77

    Secondary: 5_Absolute change of the swelling volume at 20min -- Early phase reaction (EPR)

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    End point title
    		 5_Absolute change of the swelling volume at 20min -- Early phase reaction (EPR)
    End point description
    Volume (mL) of the EPR (20 min after ICT) including change of volume (mL) of the EPR (20 min after ICT). LS Mean: least square mean estimated from analysis of covariance including the baseline value as covariate and center and treatment group as fixed effects. Data recording and measuring are described in the endpoint 1 above. Statistical analysis is shown below for the comparison of placebo vs active dose treatment group. For the comparisons between active dose treatment groups, no statistically significant results were observed (data are not shown). EPR=Early phase reaction
    End point type
    Secondary
    End point timeframe
    Baseline (S4), after 1 year of treatment (T17). S1=Day 0 S4 (baseline)=32 weeks after S1. T1 (randomisation)=52 weeks (1 year) after S1 T17=36 weeks after T1
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    27 [33]
    24
    28
    24
    27
    Units: mL
        least squares mean (confidence interval 95%)
    0.13 (-0.02 to 0.29)
    0.19 (0.03 to 0.35)
    0.36 (0.21 to 0.51)
    0.48 (0.31 to 0.64)
    0.21 (0.05 to 0.36)
    Notes
    [33] - Full analysis set for all treatment groups
    Statistical analysis title
    		 1_Placebo vs 600 PNU
    Comparison groups
    Placebo v 600 PNU
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6065 [34]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [34] - F-test
    Statistical analysis title
    		 2_Placebo vs 1800 PNU
    Comparison groups
    1800 PNU v Placebo
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.041 [35]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    -0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.44
         upper limit
    		 -0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [35] - F-test
    Statistical analysis title
    		 3_Placebo vs 3000 PNU
    Comparison groups
    Placebo v 3000 PNU
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0028 [36]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    -0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.57
         upper limit
    		 -0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [36] - F-test
    Statistical analysis title
    		 4_Placebo vs 5400 PNU
    Comparison groups
    Placebo v 5400 PNU
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4876 [37]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [37] - F-test

    Secondary: 6_Changes in specific IgE to D. pteronyssinus (IU/mL)

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    End point title
    		 6_Changes in specific IgE to D. pteronyssinus (IU/mL)
    End point description
    Determination of specific IgE to D. pteronyssinus - a of major allergen of house dust mites. The amino acid sequences of D. pteronyssinus and D. farinae allergens can have about 80% sequence identity; therefore both cross reactivity and species specificity would be expected. LS Mean: least square mean was estimated from the analysis of covariance, including the baseline value as covariate and treatment group as fixed effect. Statistical analysis is shown below for the comparison of placebo group vs active dose treatment group. For the comparisons between active dose treatment groups, no statistically significant results were observed (data are not shown).
    End point type
    Secondary
    End point timeframe
    Baseline (visit S1), after 1 year of treatment (visit T16). S1=Day 0 S4 (baseline)=32 weeks after S1. T1 (randomisation)=52 weeks (1 year) after S1 T16=35 weeks after T1
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    28 [38]
    23
    30
    25
    28
    Units: IU/mL
        least squares mean (confidence interval 95%)
    2.43 (-1.43 to 6.29)
    -2.32 (-6.54 to 1.91)
    -3.93 (-7.64 to -0.22)
    -4.41 (-8.46 to -0.35)
    -1.31 (-5.17 to 2.55)
    Notes
    [38] - Full analysis set for all treatment groups
    Statistical analysis title
    		 1_Placebo vs 600 PNU
    Comparison groups
    Placebo v 600 PNU
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1021 [39]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    4.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.96
         upper limit
    		 10.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.88
    Notes
    [39] - (F-test)
    Statistical analysis title
    		 2_Placebo vs 1800 PNU
    Comparison groups
    Placebo v 1800 PNU
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0208 [40]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    6.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.98
         upper limit
    		 11.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.72
    Notes
    [40] - (F-test)
    Statistical analysis title
    		 3_Placebo vs 3000 PNU
    Comparison groups
    Placebo v 3000 PNU
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0167 [41]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    6.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.26
         upper limit
    		 12.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.82
    Notes
    [41] - (F-test)
    Statistical analysis title
    		 4_Placebo vs 5400 PNU
    Comparison groups
    Placebo v 5400 PNU
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1804 [42]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    3.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.76
         upper limit
    		 9.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.78
    Notes
    [42] - (F-test)

    Secondary: 7_Changes in specific IgE to D. farinae (IU/mL)

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    End point title
    		 7_Changes in specific IgE to D. farinae (IU/mL)
    End point description
    Determination of specific IgE to D. farinae - a major allergen of house dust mites. Please refer to the description shown in endpoint 6.
    End point type
    Secondary
    End point timeframe
    Baseline (visit S1), after 1 year of treatment (visit T16). S1=Day 0 S4 (baseline)=32 weeks after S1. T1 (randomisation)=52 weeks (1 year) after S1 T16=35 weeks after T1
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    28 [43]
    23
    30
    25
    28
    Units: IU/mL
        least squares mean (confidence interval 95%)
    6.05 (3.17 to 8.93)
    3.62 (0.47 to 6.78)
    1.29 (-1.49 to 4.06)
    2.85 (-0.19 to 5.9)
    3.18 (0.28 to 6.07)
    Notes
    [43] - Full analysis set for all treatment groups
    Statistical analysis title
    		 1_Placebo vs 600 PNU
    Comparison groups
    Placebo v 600 PNU
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2616 [44]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    2.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.83
         upper limit
    		 6.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.15
    Notes
    [44] - F-test
    Statistical analysis title
    		 2_Placebo vs 1800 PNU
    Comparison groups
    1800 PNU v Placebo
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0209 [45]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    4.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 8.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.04
    Notes
    [45] - F-test
    Statistical analysis title
    		 3_Placebo vs 3000 PNU
    Comparison groups
    Placebo v 3000 PNU
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1307 [46]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.96
         upper limit
    		 7.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1
    Notes
    [46] - F-test
    Statistical analysis title
    		 4_Placebo vs 5400 PNU
    Comparison groups
    Placebo v 5400 PNU
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1704 [47]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    2.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.25
         upper limit
    		 7
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.09
    Notes
    [47] - F-test

    Secondary: 8_Changes in specific IgG D. pteronyssinus (mg/L)

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    End point title
    		 8_Changes in specific IgG D. pteronyssinus (mg/L)
    End point description
    Determination of specific IgG D. pteronyssinus - a major allergen of house dust mites. Please refer to the description shown in endpoint 6.
    End point type
    Secondary
    End point timeframe
    Baseline (visit S1), after 1 year of treatment (visit T16). S1=Day 0 S4 (baseline)=32 weeks after S1. T1 (randomisation)=52 weeks (1 year) after S1 T16=35 weeks after T1
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    28 [48]
    24
    30
    25
    28
    Units: mg/L
        least squares mean (confidence interval 95%)
    -0.54 (-2.73 to 1.65)
    -4.02 (-6.38 to -1.66)
    -6.47 (-8.58 to -4.36)
    -7.56 (-9.88 to -5.24)
    -9.38 (-11.57 to -7.2)
    Notes
    [48] - Full analysis set for all treatment groups
    Statistical analysis title
    		 1_Placebo vs 600 PNU
    Comparison groups
    Placebo v 600 PNU
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0346 [49]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    3.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 6.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.63
    Notes
    [49] - F-test
    Statistical analysis title
    		 2_Placebo vs 1800 PNU
    Comparison groups
    Placebo v 1800 PNU
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [50]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    5.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.89
         upper limit
    		 8.97
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.53
    Notes
    [50] - F-test
    Statistical analysis title
    		 3_Placebo vs 3000 PNU
    Comparison groups
    Placebo v 3000 PNU
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [51]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    7.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.81
         upper limit
    		 10.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.62
    Notes
    [51] - F-test
    Statistical analysis title
    		 4_Placebo vs 5400 PNU
    Comparison groups
    Placebo v 5400 PNU
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [52]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    8.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.75
         upper limit
    		 11.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.56
    Notes
    [52] - F-test

    Secondary: 9_Changes in specific IgG D. farinae (mg/L)

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    End point title
    		 9_Changes in specific IgG D. farinae (mg/L)
    End point description
    Determination of specific IgG D. farinae - a major allergen of house dust mites. Please refer to the description shown in endpoint 6.
    End point type
    Secondary
    End point timeframe
    Baseline (visit S1), after 1 year of treatment (visit T16). S1=Day 0 S4 (baseline)=32 weeks after S1. T1 (randomisation)=52 weeks (1 year) after S1 T16=35 weeks after T1
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    28 [53]
    24
    30
    25
    28
    Units: mg/L
        least squares mean (confidence interval 95%)
    -0.96 (-3.18 to 1.25)
    -4.85 (-7.24 to -2.45)
    -6.92 (-9.06 to -4.78)
    -7.6 (-9.95 to -5.25)
    -7.45 (-9.67 to -5.24)
    Notes
    [53] - Full analysis set for all treatment groups
    Statistical analysis title
    		 1_Placebo vs 600 PNU
    Comparison groups
    Placebo v 600 PNU
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0202 [54]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    3.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 7.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.65
    Notes
    [54] - F-test
    Statistical analysis title
    		 2_Placebo vs 1800 PNU
    Comparison groups
    Placebo v 1800 PNU
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002 [55]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    5.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.88
         upper limit
    		 9.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.56
    Notes
    [55] - F-test
    Statistical analysis title
    		 3_Placebo vs 3000 PNU
    Comparison groups
    Placebo v 3000 PNU
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [56]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    6.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.39
         upper limit
    		 9.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.64
    Notes
    [56] - F-test
    Statistical analysis title
    		 4_Placebo vs 5400 PNU
    Comparison groups
    Placebo v 5400 PNU
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [57]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    6.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.35
         upper limit
    		 9.62
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.58
    Notes
    [57] - F-test

    Secondary: 10_Changes in specific IgG4 D. pteronyssinus (mg/L)

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    End point title
    		 10_Changes in specific IgG4 D. pteronyssinus (mg/L)
    End point description
    Determination of specific IgG4 D. pteronyssinus - a major allergen of house dust mites. Please refer to the description shown in endpoint 6.
    End point type
    Secondary
    End point timeframe
    Baseline (visit S1), after 1 year of treatment (visit T16). S1=Day 0 S4 (baseline)=32 weeks after S1. T1 (randomisation)=52 weeks (1 year) after S1 T16=35 weeks after T1
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    28 [58]
    24
    30
    25
    28
    Units: mg/L
        least squares mean (confidence interval 95%)
    -0.03 (-0.68 to 0.62)
    -1.07 (-1.78 to -0.37)
    -2.44 (-3.07 to -1.82)
    -2.16 (-2.85 to -1.47)
    -3.04 (-3.7 to -2.38)
    Notes
    [58] - Full analysis set for all treatment groups
    Statistical analysis title
    		 1_Placebo vs 600 PNU
    Comparison groups
    Placebo v 600 PNU
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.033 [59]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.48
    Notes
    [59] - F-test
    Statistical analysis title
    		 2_Placebo vs 1800 PNU
    Comparison groups
    Placebo v 1800 PNU
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [60]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    2.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.51
         upper limit
    		 3.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.46
    Notes
    [60] - F-test
    Statistical analysis title
    		 3_Placebo vs 3000 PNU
    Comparison groups
    Placebo v 3000 PNU
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [61]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    2.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.18
         upper limit
    		 3.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.48
    Notes
    [61] - F-test
    Statistical analysis title
    		 4_Placebo vs 5400 PNU
    Comparison groups
    Placebo v 5400 PNU
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [62]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    3.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.08
         upper limit
    		 3.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.47
    Notes
    [62] - F-test

    Secondary: 11_Changes in specific IgG4 D. farinae (mg/L)

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    End point title
    		 11_Changes in specific IgG4 D. farinae (mg/L)
    End point description
    Determination of specific IgG4 D. farinae - a major allergen of house dust mites. Please refer to the description shown in endpoint 6.
    End point type
    Secondary
    End point timeframe
    Baseline (visit S1), after 1 year of treatment (visit T16). S1=Day 0 S4 (baseline)=32 weeks after S1. T1 (randomisation)=52 weeks (1 year) after S1 T16=35 weeks after T1
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    28 [63]
    24
    30
    25
    28
    Units: mg/L
        least squares mean (confidence interval 95%)
    0.11 (-0.46 to 0.68)
    -0.68 (-1.3 to -0.06)
    -1.81 (-2.37 to -1.26)
    -1.37 (-1.98 to -0.77)
    -1.95 (-2.53 to -1.37)
    Notes
    [63] - Full analysis set for all treatment groups
    Statistical analysis title
    		 1_Placebo vs 600 PNU
    Comparison groups
    Placebo v 600 PNU
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0654 [64]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 1.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.43
    Notes
    [64] - F-test
    Statistical analysis title
    		 2_Placebo vs 1800 PNU
    Comparison groups
    Placebo v 1800 PNU
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [65]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    1.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.13
         upper limit
    		 2.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4
    Notes
    [65] - F-test
    Statistical analysis title
    		 3_Placebo vs 3000 PNU
    Comparison groups
    Placebo v 3000 PNU
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0006 [66]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 2.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.42
    Notes
    [66] - F-test
    Statistical analysis title
    		 4_Placebo vs 5400 PNU
    Comparison groups
    Placebo v 5400 PNU
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [67]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    2.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.25
         upper limit
    		 2.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.41
    Notes
    [67] - F-test

    Secondary: 12_Change of minimal asthma control dose

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    End point title
    		 12_Change of minimal asthma control dose
    End point description
    The change of minimal asthma control dose as assessed by the Asthma Control Test (ACT). This endpoint was analyzed for the subset of patients who had asthma control only under Fluticasone treatment of either 500 μg/day or 200 μg/day; patients with controlled asthma without Fluticasone were excluded from this analysis. Asthma control was defined by a sum score of at least 20 points in the ACT. Asthma Control Test and Score Each of the 5 questions regarding asthma symptoms or medication use, had a score 1 (worst score) to 5 (best score). Refr. Kosinski M, Bayliss MS, Turner-Bowker DM, Fortin EW. Asthma Control Test™: A User’s Guide. Lincoln (RI): QualityMetric Incorporated, 2004.
    End point type
    Secondary
    End point timeframe
    Baseline, post treatment (T18 and/or T19). S1=Day 0 S4 (baseline)=32 weeks after S1. T1 (randomisation)=52 weeks (1 year) after S1 T17=36 weeks after T1 T18=42 weeks after T1 T19=50 weeks after T1
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    15 [68]
    12
    13
    8
    13
    Units: score
        arithmetic mean (standard deviation)
    -100 ± 352.5
    -175 ± 283.2
    -246.2 ± 166.4
    -187.5 ± 258.8
    -376.9 ± 200.6
    Notes
    [68] - Full analysis set for all treatment groups
    No statistical analyses for this end point

    Secondary: 13_Changes in asthma control test score between baseline and post-treatment

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    End point title
    		 13_Changes in asthma control test score between baseline and post-treatment
    End point description
    Please refer to the description for endpoint 12.
    End point type
    Secondary
    End point timeframe
    Baseline, post treatment (T18 and/or T19). S1=Day 0 S4 (baseline)=32 weeks after S1. T1 (randomisation)=52 weeks (1 year) after S1 T17=36 weeks after T1 T18=42 weeks after T1 T19=50 weeks after T1
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    13 [69]
    7
    9
    6
    12
    Units: score
        least squares mean (confidence interval 95%)
    -1.77 (-3.97 to 0.42)
    -4.33 (-6.87 to 1.8)
    -4.83 (-7.31 to -2.36)
    -3.63 (-6.37 to -0.88)
    -4.00 (-6.18 to -1.83)
    Notes
    [69] - Full analysis set for all treatment groups
    Statistical analysis title
    		 1_Placebo vs 600 PNU
    Comparison groups
    Placebo v 600 PNU
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0963 [70]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    2.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 5.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.49
    Notes
    [70] - F-test
    Statistical analysis title
    		 2_Placebo vs 1800 PNU
    Comparison groups
    Placebo v 1800 PNU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0432 [71]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    3.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 6.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.45
    Notes
    [71] - F-test
    Statistical analysis title
    		 3_Placebo vs 3000 PNU
    Comparison groups
    Placebo v 3000 PNU
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2662 [72]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    1.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.48
         upper limit
    		 5.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.64
    Notes
    [72] - F-test
    Statistical analysis title
    		 4_Placebo vs 5400 PNU
    Comparison groups
    Placebo v 5400 PNU
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0816 [73]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    2.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 4.75
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.24
    Notes
    [73] - F-test

    Secondary: 14_Changes in morning PEF (L/min)

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    End point title
    		 14_Changes in morning PEF (L/min)
    End point description
    Only morning PEF after treatment, that had been measured at the same corticoid dose as the before treatment PEF were used for comparison.
    End point type
    Secondary
    End point timeframe
    Baseline, post treatment (T18 and/or T19). S1=Day 0 S4 (baseline)=32 weeks after S1. T1 (randomisation)=52 weeks (1 year) after S1 T17=36 weeks after T1 T18=42 weeks after T1 T19=50 weeks after T1
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    13 [74]
    7
    9
    6
    11
    Units: L/min
        least squares mean (confidence interval 95%)
    4.1 (-38.14 to 46.34)
    -52.09 (-108.98 to 4.79)
    -41.99 (-92.04 to 8.06)
    -87.56 (-150.2 to -24.92)
    -22.49 (-68.41 to 23.44)
    Notes
    [74] - Full analysis set for all treatment groups
    Statistical analysis title
    		 1_Placebo vs 600 PNU
    Comparison groups
    Placebo v 600 PNU
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1208 [75]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    56.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.46
         upper limit
    		 127.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    35.45
    Notes
    [75] - F-test
    Statistical analysis title
    		 2_Placebo vs 1800 PNU
    Comparison groups
    Placebo v 1800 PNU
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1666 [76]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    46.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.03
         upper limit
    		 112.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    32.72
    Notes
    [76] - F-test
    Statistical analysis title
    		 3_Placebo vs 3000 PNU
    Comparison groups
    Placebo v 3000 PNU
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0165 [77]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    91.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 17.68
         upper limit
    		 165.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    36.6
    Notes
    [77] - F-test
    Statistical analysis title
    		 4_Placebo vs 5400 PNU
    Comparison groups
    Placebo v 5400 PNU
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.403 [78]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    26.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.97
         upper limit
    		 90.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    31.45
    Notes
    [78] - F-test

    Secondary: 15_Changes in morning PEF in relation to predicted value (%)

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    End point title
    		 15_Changes in morning PEF in relation to predicted value (%)
    End point description
    The change of the morning PEF before and after treatment was analyzed in the same way as the change in the ACT score. Only morning PEF after treatment, that had been measured at the same corticoid dose as the before treatment PEF were used for comparison. Lung function tests were assessed as PEF relative to the expected normal value. Percentages were analyzed as smallest values post injection and post ICT and as highest decrease of PEF between pre and post injection and between pre and post ICT at each visit. Mean values of minimal values at each visit did not change substantially over time. No relevant differences between the treatment groups were observed, especially not at doses 3000 or 5400 PNU vs with placebo group. All 5 treatment groups were similar in their mean highest decrease of PEF in (% ) between pre and 30 min post injection over all visits. Pre and post ICT measurements did not show any substantial changes on average wrt. to PEF values.
    End point type
    Secondary
    End point timeframe
    Baseline, post treatment (T18 and/or T19). S1=Day 0 S4 (baseline)=32 weeks after S1. T1 (randomisation)=52 weeks (1 year) after S1 T17=36 weeks after T1 T18=42 weeks after T1 T19=50 weeks after T1
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    13 [79]
    7
    9
    6
    11
    Units: percent
        least squares mean (confidence interval 95%)
    -3.51 (-10.01 to 2.99)
    -8.91 (-17.76 to -0.06)
    -7.82 (-15.63 to -0.01)
    -12.71 (-22.79 to -2.63)
    -4.29 (-11.4 to 2.83)
    Notes
    [79] - Full analysis set for all treatment groups
    Statistical analysis title
    		 1_Placebo vs 600 PNU
    Comparison groups
    Placebo v 600 PNU
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3264 [80]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    5.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.58
         upper limit
    		 16.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.43
    Notes
    [80] - F-test
    Statistical analysis title
    		 2_Placebo vs 1800 PNU
    Comparison groups
    1800 PNU v Placebo
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3957 [81]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    4.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.84
         upper limit
    		 14.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.02
    Notes
    [81] - F-test
    Statistical analysis title
    		 3_Placebo vs 3000 PNU
    Comparison groups
    Placebo v 3000 PNU
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.132 [82]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    9.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.89
         upper limit
    		 21.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.98
    Notes
    [82] - F-test
    Statistical analysis title
    		 4_Placebo vs 5400 PNU
    Comparison groups
    5400 PNU v Placebo
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8709 [83]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.83
         upper limit
    		 10.38
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.75
    Notes
    [83] - F-test

    Secondary: 16_Vital signs: Systolic blood pressure (SBP); Diastolic blood pressure (DBP)

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    End point title
    		 16_Vital signs: Systolic blood pressure (SBP); Diastolic blood pressure (DBP)
    End point description
    Vital signs: systolic blood pressure, diastolic blood pressure, pulse rate, and respiratory rate were measured for all patients. The mean changes in all treatment groups were marginal and similar over time. Mean changes within the screening period from screening visit S1 to Visit T1 and from T1 to the final Visit T19 were very similar, indicating no effect of the treatment with study medication on these mean values. Prior to each injections, vital sign measurements were performed as well. From Visit T9 onward vital signs were assessed post injection: at visits T9 to T12 at 10 minutes, 20, 30 , 60 , 180, and 360 min after the injection and at visits T13 to T16 at 30 minutes after the injection in order capture any possible systemic reaction. Individual smallest values post-injection at each visit and the highest decreases from pre- to post injection at each visit in each single parameter were analyzed. The 4 active treatment groups showed no stat significant difference vs placebo.
    End point type
    Secondary
    End point timeframe
    Screening (S1), during treatment (T1-T16), final visit (T19). Results for SBP and DBP are shown only for the difference between screening visit (S1), prior to the first injection of study medication on Visit T1, and at the final Visit (T19).
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    30 [84]
    24
    29
    25
    29
    Units: mmHg
    arithmetic mean (standard deviation)
        Systolic blood pressure
    -1.7 ± 9.69
    -0.46 ± 11.31
    2.21 ± 10.88
    1.28 ± 8.06
    -1.17 ± 11.91
        Diastolic blood pressure
    -4.53 ± 7.95
    1.67 ± 8.61
    -0.83 ± 11.73
    0.36 ± 8.93
    -1.14 ± 9.04
    Notes
    [84] - Safety set for all treatment groups
    No statistical analyses for this end point

    Secondary: 17_Vital signs: Respiratory rate

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    End point title
    		 17_Vital signs: Respiratory rate
    End point description
    Please refer to the description shown for endpoint 16.
    End point type
    Secondary
    End point timeframe
    Screening (S1), during treatment (T1-T16), final visit (T19). Results for respiratory rate are shown only for the difference between screening visit (S1), prior to the first injection of study medication on Visit T1, and at the final Visit (T19).
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    30 [85]
    24
    29
    25
    29
    Units: breaths/min
        arithmetic mean (standard deviation)
    -0.6 ± 2.79
    0.04 ± 1.63
    -0.97 ± 2.85
    0.44 ± 1.66
    -0.41 ± 1.8
    Notes
    [85] - Safety set for all treatment groups
    No statistical analyses for this end point

    Secondary: 18_Vital signs: Heart rate

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    End point title
    		 18_Vital signs: Heart rate
    End point description
    Please refer to the description shown for endpoint 16.
    End point type
    Secondary
    End point timeframe
    Screening (S1), during treatment (T1-T16), final visit (T19). Results for the heart rate are shown only for the difference between screening visit (S1), prior to the first injection of study medication on Visit T1, and at the final Visit (T19).
    End point values
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Number of subjects analysed
    30 [86]
    24
    29
    25
    29
    Units: bpm
        arithmetic mean (standard deviation)
    0.8 ± 10.36
    1.38 ± 10.68
    3 ± 9.59
    -1 ± 9.04
    1.03 ± 7.98
    Notes
    [86] - Safety set for all treatment groups
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of the study (signing of the informed consent) until the end of the study (last study visit i.e. 144.6 weeks after study start).
    Adverse event reporting additional description
    Data shown represent the 'Safety analysis set'. AEs and SAEs shown below are from the DRF part of the study. During the ICT part of the study, 3 non serious AEs were reported (cough, decrease value of PEF, itching edema 20 cm diameter after ICT).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    600 PNU
    Reporting group description
    		 -

    Reporting group title
    1800 PNU
    Reporting group description
    		 -

    Reporting group title
    3000 PNU
    Reporting group description
    		 -

    Reporting group title
    5400 PNU
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 24 (4.17%)
    1 / 31 (3.23%)
    0 / 28 (0.00%)
    3 / 31 (9.68%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Scar hernia-post operative
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 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
    Vascular disorders
    Varices of lower legs
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    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
    Immune system disorders
    Anaphylactic reaction grade II
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Umbilical hernia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    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
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 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
    Respiratory, thoracic and mediastinal disorders
    Asthma exacerbation
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 24 (4.17%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    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
    Infections and infestations
    Viral meningitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    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
    Appendicitis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 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
    Acute appendicitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 24 (0.00%)
    1 / 31 (3.23%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo 600 PNU 1800 PNU 3000 PNU 5400 PNU
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 32 (46.88%)
    13 / 24 (54.17%)
    13 / 31 (41.94%)
    11 / 28 (39.29%)
    19 / 31 (61.29%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 24 (4.17%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Allergy test
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Peak expiratory flow rate decreased
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Joint injury
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Ligament sprain
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 24 (4.17%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Surgical and medical procedures
    Nasal polypectomy
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
         occurrences all number
    3
    0
    0
    1
    0
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 24 (4.17%)
    3 / 31 (9.68%)
    4 / 28 (14.29%)
    4 / 31 (12.90%)
         occurrences all number
    0
    1
    6
    13
    9
    Injection site oedema
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 24 (4.17%)
    0 / 31 (0.00%)
    1 / 28 (3.57%)
    3 / 31 (9.68%)
         occurrences all number
    0
    2
    0
    2
    5
    Injection site papule
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 24 (4.17%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Injection site pruritus
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 24 (4.17%)
    1 / 31 (3.23%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    1
    2
    0
    2
    Injection site swelling
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 24 (8.33%)
    2 / 31 (6.45%)
    1 / 28 (3.57%)
    5 / 31 (16.13%)
         occurrences all number
    0
    2
    3
    3
    10
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 24 (0.00%)
    2 / 31 (6.45%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    2
    0
    2
    0
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 24 (4.17%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    0
    1
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    4 / 32 (12.50%)
    1 / 24 (4.17%)
    3 / 31 (9.68%)
    4 / 28 (14.29%)
    1 / 31 (3.23%)
         occurrences all number
    4
    2
    3
    4
    1
    Dyspnoea
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 24 (4.17%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Dermatitis atopic
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 24 (4.17%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 24 (4.17%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 24 (8.33%)
    2 / 31 (6.45%)
    0 / 28 (0.00%)
    1 / 31 (3.23%)
         occurrences all number
    1
    2
    2
    0
    1
    Influenza
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 24 (4.17%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 32 (6.25%)
    4 / 24 (16.67%)
    3 / 31 (9.68%)
    3 / 28 (10.71%)
    7 / 31 (22.58%)
         occurrences all number
    2
    4
    3
    3
    9
    Otitis externa
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 24 (4.17%)
    0 / 31 (0.00%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    3 / 32 (9.38%)
    2 / 24 (8.33%)
    1 / 31 (3.23%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    3
    2
    1
    0
    2
    Respiratory tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 24 (0.00%)
    0 / 31 (0.00%)
    1 / 28 (3.57%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Rhinovirus infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 24 (0.00%)
    1 / 31 (3.23%)
    0 / 28 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 24 (0.00%)
    2 / 31 (6.45%)
    0 / 28 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    2
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Feb 2012
    Changes of the trial schedule, implementation of the lung function test before and after ICT, change in the point of times to be investigated in the ICT trial part, implementation of an optical device for the assessment of the ICT reaction (wheal or swelling).
    05 Jun 2012
    Changes of the trial schedule, of exclusion criteria and clarification for the use of asthma medication.
    20 Sep 2012
    This amendment concerned the prolongation of the trial to implement a second screening period and change of 1 exclusion criterion.
    11 Jan 2013
    Spain only: This amendment concerned the clarification of 1 exclusion criterion, the submission of additional sites in Poland and Spain. Further the amendment concerned changes of the administrative structure and assessment of additional allergens for Spanish patients. Poland only: Implementation of a possible second check of inclusion and exclusion criteria for patients, which dropped out in the first screening phase according to the 2 changed exclusion criteria.
    11 Sep 2013
    Spain only: prolongation of the screening period.

    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.
    Rudert, M; Tribanek, M; Karjalainen, M; Haefner, D; Narkus, A; New objective method to measure skin test results within clinical trials; Allergy; 2013; 68 (Suppl. 97), 1–104.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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