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    Clinical Trial Results:
    Multicentre, double-blind, randomized, placebo-controlled, parallel-group, clinical trial to evaluates the clinical efficacy and safety of immunotherapy with purified major allergen Alt a 1 in patients with allergic rhinoconjunctivitis with or without mild to moderate asthma, sensitized the fungus Alternaria alternata

    Summary
    EudraCT number
    		 2010-024440-15
    Trial protocol
    		 ES  
    Global end of trial date
    19 Jul 2016

    Results information
    Results version number
    		 v1
    This version publication date
    04 Jan 2018
    First version publication date
    04 Jan 2018
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    DIA-ALT-0111
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    DIATER Laboratorio de Diagnostico y Aplicaciones Terapéuticas S.A.
    Sponsor organisation address
    Avda. Gregorio Peces Barba, 2 , Leganés, Madrid , Spain, 28918
    Public contact
    Silvia Fernándes Anaya, DIATER Laboratorio de Diagnostico y Aplicaciones Terapéuticas S.A., +34 91 496 60 13, s.fernandez@diater.com
    Scientific contact
    Silvia Fernándes Anaya, DIATER Laboratorio de Diagnostico y Aplicaciones Terapéuticas S.A., +34 91 496 60 13, s.fernandez@diater.com
    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
    16 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of specific immunotherapy with purified major allergen Alt a 1 of the fungus Alternaria alternata administered subcutaneously
    Protection of trial subjects
    After study inclusion, and throughout the study period, the following rescue medication was allowed for the control of the study disease Eye symptoms: Topical antihistamines (eye drops): levocabastine, at usual doses. Nasal symptoms: Antihistamines: loratadine. Topical nasal corticosteroids: nasal budesonide. Oral corticosteroids: deflazacort
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Sep 2011
    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
    Spain: 113
    Worldwide total number of subjects
    113
    EEA total number of subjects
    113
    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)
    48
    Adults (18-64 years)
    65
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Wash-out period for the following symptomatic medications: Loratadine: 7 days, Ketotifen: 7 days, other anti-histamininc medications: 7 days Short-acting beta-2 adrenergics: 4 hours, long-acting beta-2 adrenergics: 12 hours, antileukotrienes: 24 hours, inhaled corticosteroids: 12 hours, chromones: 24 hours

    Period 1
    Period 1 title
    First year
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer, Assessor
    Blinding implementation details
    To ensure adequate blinding of the investigational drug and preserve the blinded nature of the clinical trial, all treatments were packaged identically. The randomization and centre numbers were included in the label of each drug package and the labelling was done in such a way that neither the investigator nor the patient could identify the product administered. The blinded envelopes for each subject were safeguarded in the pharmacy service and by the Sponsor.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active-1, Year-1
    Arm description
    		 Concentration 0.25 µg/ml
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alt a 1 Active-1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Cluster dose schedule: 5 visits with escalation dose to the optimal dose for 5 weeks. Optimal dose schedule: 1 monthly optimal dose of 0.8 mL for 11 months.

    Arm title
    		 Active-2, Year-1
    Arm description
    		 Concentration 0.46 µg/ml
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alt a 1 Active-2
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Cluster dose schedule: 5 visits with escalation dose to the optimal dose for 5 weeks. Optimal dose schedule: 1 monthly optimal dose of 0.8 mL for 11 months.

    Arm title
    		 Placebo, Year-1
    Arm description
    		 Patients allocated to this arm received a matching Placebo and were switched to Active-2 in the second year of the study
    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
    Cluster dose schedule: 5 visits with escalation dose to the optimal dose for 5 weeks. Optimal dose schedule: 1 monthly optimal dose of 0.8 mL for 11 months.

    Number of subjects in period 1
    		Active-1, Year-1 Active-2, Year-1 Placebo, Year-1
    Started
    37
    46
    30
    Completed
    32
    40
    22
    Not completed
    5
    6
    8
         Physician decision
    -
    1
    -
         Adverse event, non-fatal
    1
    -
    -
         Lost to follow-up
    4
    4
    7
         Development of exclusion criteria
    -
    1
    -
         Protocol deviation
    -
    -
    1
    Period 2
    Period 2 title
    Second Year
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active 1, Year-2
    Arm description
    		 Concentration 0.25 µg/ml
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alt a 1 Active-1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 monthly dose of 0.8 mL for 12 months.

    Arm title
    		 Active-2, Year-2
    Arm description
    		 Concentration 0.46 µg/ml
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alt a 1 Active-2
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1 monthly dose of 0.8 mL for 12 months.

    Arm title
    		 Placebo in Year-1, Active-2 in Year-2
    Arm description
    		 Patients allocated to this arm received a matching Placebo in the first year of treatment and were switched to Active-2 (concentration 0.46 µg/ml) in the second year of the study
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo in Year-1, Active-2 in Year-2
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Cluster dose schedule: 5 visits with escalation dose of Active-2 to the optimal dose for 5 weeks. Optimal dose schedule: 1 monthly optimal dose of 0.8 mL for 11 months.

    Number of subjects in period 2
    		Active 1, Year-2 Active-2, Year-2 Placebo in Year-1, Active-2 in Year-2
    Started
    32
    40
    22
    Completed
    30
    37
    21
    Not completed
    2
    3
    1
         Lost to follow-up
    1
    3
    1
         Concomitant disease / required other treatment
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active-1, Year-1
    Reporting group description
    		 Concentration 0.25 µg/ml

    Reporting group title
    Active-2, Year-1
    Reporting group description
    		 Concentration 0.46 µg/ml

    Reporting group title
    Placebo, Year-1
    Reporting group description
    		 Patients allocated to this arm received a matching Placebo and were switched to Active-2 in the second year of the study

    Reporting group values
    		 Active-1, Year-1 Active-2, Year-1 Placebo, Year-1 Total
    Number of subjects
    		 37 46 30 113
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 14 20 14 48
        Adults (18-64 years)
    		 23 26 16 65
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 22.2 ( 8.8 ) 20.2 ( 7.0 ) 21.0 ( 8.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 18 20 9 47
        Male
    		 19 26 21 66

    End points

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    End points reporting groups
    Reporting group title
    Active-1, Year-1
    Reporting group description
    		 Concentration 0.25 µg/ml

    Reporting group title
    Active-2, Year-1
    Reporting group description
    		 Concentration 0.46 µg/ml

    Reporting group title
    Placebo, Year-1
    Reporting group description
    		 Patients allocated to this arm received a matching Placebo and were switched to Active-2 in the second year of the study
    Reporting group title
    Active 1, Year-2
    Reporting group description
    		 Concentration 0.25 µg/ml

    Reporting group title
    Active-2, Year-2
    Reporting group description
    		 Concentration 0.46 µg/ml

    Reporting group title
    Placebo in Year-1, Active-2 in Year-2
    Reporting group description
    		 Patients allocated to this arm received a matching Placebo in the first year of treatment and were switched to Active-2 (concentration 0.46 µg/ml) in the second year of the study

    Primary: Combined symptom and medication score at 12 months - PP

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    End point title
    		 Combined symptom and medication score at 12 months - PP
    End point description
    The primary endpoint was calculated by (mean symptom score + mean symptomatic medication score)/2 Symptom score: registered by the patient for each of 8 symptoms evaluated on a 4-point Likert scale: 0 corresponds to “no” symptoms, 1: “mild symptoms”; 2: “moderate” symptoms, 3 “severe” symptoms. Symptomatic medication score (4-point Likert scale from 0 to 3): calculated individually according to type of rescue medication recorded by the patient. 0 corresponds to “No” medication, 1: local antihistamine; 2: local corticosteroid, 3: oral corticosteroid. The means and SD were calculated for each study group at the evaluable monitoring visit. The means obtained were compared two-by – two between groups using the bilateral T-test with 95% confidence intervals. Statistical significance was set at <0.05
    End point type
    Primary
    End point timeframe
    Assessed after 12 months at Visit 16 (V16)
    End point values
    		 Active-1, Year-1 Active-2, Year-1 Placebo, Year-1
    Number of subjects analysed
    20
    29
    15
    Units: Score
        arithmetic mean (standard deviation)
    0.46 ( 0.65 )
    0.23 ( 0.27 )
    0.62 ( 0.67 )
    Statistical analysis title
    		 Active-2 Vs. Placebo
    Statistical analysis description
    Combination of mean symptom score and mean symptomatic medication score
    Comparison groups
    Active-2, Year-1 v Placebo, Year-1
    Number of subjects included in analysis
    44
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [1] - The differences between groups were to be established by calculating the mean of the differences in the final-baseline score obtained individually (intrasubject) for each treatment group at 12 months (V16). However, many patients started with zero in the combined symptom and medication score, which does not allow any intrasubject clinical improvement. As there was no statistically significant difference in baseline values between groups, the mean scores at V16 between the groups were compared.
    Statistical analysis title
    		 Active-1 Vs. Placebo
    Statistical analysis description
    Combination of mean symptom score and mean symptomatic medication score
    Comparison groups
    Placebo, Year-1 v Active-1, Year-1
    Number of subjects included in analysis
    35
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.4885
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [2] - The differences between groups were to be established by calculating the mean of the differences in the final-baseline score obtained individually (intrasubject) for each treatment group at 12 months (V16). However, many patients started with zero in the combined symptom and medication score, which does not allow any intrasubject clinical improvement. As there was no statistically significant difference in baseline values between groups, the mean scores at V16 between the groups were compared.
    Statistical analysis title
    		 Active-1 Vs. Active-2
    Statistical analysis description
    Combination of mean symptom score and mean symptomatic medication score
    Comparison groups
    Active-1, Year-1 v Active-2, Year-1
    Number of subjects included in analysis
    49
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.1391
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [3] - The differences between groups were to be established by calculating the mean of the differences in the final-baseline score obtained individually (intrasubject) for each treatment group at 12 months (V16). However, many patients started with zero in the combined symptom and medication score, which does not allow any intrasubject clinical improvement. As there was no statistically significant difference in baseline values between groups, the mean scores at V16 between the groups were compared.

    Secondary: Prick test with Alternaria alternata extract at 12 months

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    End point title
    		 Prick test with Alternaria alternata extract at 12 months
    End point description
    Area of the wheal.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Active-1, Year-1 Active-2, Year-1 Placebo, Year-1
    Number of subjects analysed
    32
    40
    22
    Units: mm2
        arithmetic mean (standard deviation)
    25.5 ( 19.6 )
    22.1 ( 16.4 )
    49.9 ( 44.9 )
    Statistical analysis title
    		 Active-2 Vs Placebo
    Comparison groups
    Active-2, Year-1 v Placebo, Year-1
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [4]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [4] -
    Statistical analysis title
    		 Active-1 Vs Placebo
    Comparison groups
    Placebo, Year-1 v Active-1, Year-1
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Active-1 Vs Active-2
    Comparison groups
    Active-1, Year-1 v Active-2, Year-1
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: IgG4 levels at 12 months

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    End point title
    		 IgG4 levels at 12 months
    End point description
    Serum levels of purified Alt a1 allergen specific IgG4 antibodies
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Active-1, Year-1 Active-2, Year-1 Placebo, Year-1
    Number of subjects analysed
    32
    39
    22
    Units: µg/L
        arithmetic mean (standard deviation)
    1099.0 ( 1768.0 )
    1578.0 ( 2198.0 )
    45.0 ( 49.6 )
    Statistical analysis title
    		 Active-2 Vs. Placebo
    Statistical analysis description
    The population evaluable by ITT was used: randomized patients who received at least one dose of the drug.
    Comparison groups
    Active-2, Year-1 v Placebo, Year-1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Active-1 Vs. Placebo
    Statistical analysis description
    The population evaluable by ITT was used: randomized patients who received at least one dose of the drug.
    Comparison groups
    Active-1, Year-1 v Placebo, Year-1
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Combined symptom and medication score at 12 months - ITT

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    End point title
    		 Combined symptom and medication score at 12 months - ITT
    End point description
    This endpoint was calculated by (mean symptom score + mean symptomatic medication score)/2 Symptom score: registered by the patient for each of 8 symptoms evaluated on a 4-point Likert scale: 0 corresponds to “no” symptoms, 1: “mild symptoms”; 2: “moderate” symptoms, 3 “severe” symptoms. Symptomatic medication score (4-point Likert scale from 0 to 3): calculated individually according to type of rescue medication recorded by the patient. 0 corresponds to “No” medication, 1: local antihistamine; 2: local corticosteroid, 3: oral corticosteroid. The means and SD were calculated for each study group at the evaluable monitoring visit. The means obtained were compared two-by – two between groups using the bilateral T-test with 95% confidence intervals. Statistical significance was set at <0.05
    End point type
    Secondary
    End point timeframe
    12 months (Visit 16)
    End point values
    		 Active-1, Year-1 Active-2, Year-1 Placebo, Year-1
    Number of subjects analysed
    21
    31
    20
    Units: Score
        arithmetic mean (standard deviation)
    0.44 ( 0.64 )
    0.29 ( 0.37 )
    0.47 ( 0.64 )
    Statistical analysis title
    		 Active-2 Vs Placebo
    Comparison groups
    Active-2, Year-1 v Placebo, Year-1
    Number of subjects included in analysis
    51
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.2719
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [5] - The differences between groups were to be established by calculating the mean of the differences in the final-baseline score obtained individually (intrasubject) for each treatment group at 12 months (V16). However, many patients started with zero in the combined symptom and medication score, which does not allow any intrasubject clinical improvement. As there was no statistically significant difference in baseline values between groups, the mean scores at V16 between the groups were compared.
    Statistical analysis title
    		 Active-1 Vs Placebo
    Comparison groups
    Placebo, Year-1 v Active-1, Year-1
    Number of subjects included in analysis
    41
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.8802
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [6] - The differences between groups were to be established by calculating the mean of the differences in the final-baseline score obtained individually (intrasubject) for each treatment group at 12 months (V16). However, many patients started with zero in the combined symptom and medication score, which does not allow any intrasubject clinical improvement. As there was no statistically significant difference in baseline values between groups, the mean scores at V16 between the groups were compared.

    Secondary: Prick test with purified allergen Alt a1 at 12 months

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    End point title
    		 Prick test with purified allergen Alt a1 at 12 months
    End point description
    Area of the wheal
    End point type
    Secondary
    End point timeframe
    12 months (Visit 16)
    End point values
    		 Active-1, Year-1 Active-2, Year-1 Placebo, Year-1
    Number of subjects analysed
    32
    40
    22
    Units: mm2
        arithmetic mean (standard deviation)
    22.7 ( 14.9 )
    18.7 ( 10.7 )
    50.3 ( 50.8 )
    Statistical analysis title
    		 Active-2 Vs. Placebo
    Statistical analysis description
    ITT population
    Comparison groups
    Active-2, Year-1 v Placebo, Year-1
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Active-1 Vs. Placebo
    Statistical analysis description
    ITT population
    Comparison groups
    Placebo, Year-1 v Active-1, Year-1
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Symptom score at 12 months

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    End point title
    		 Symptom score at 12 months
    End point description
    Symptom score: registered by the patient for each of 8 symptoms evaluated on a 4-point Likert scale: 0 corresponds to “no” symptoms, 1: “mild symptoms”; 2: “moderate” symptoms, 3 “severe” symptoms. Symptomatic medication score (4-point Likert scale from 0 to 3): calculated individually according to type of rescue medication recorded by the patient. 0 corresponds to “No” medication, 1: local antihistamine; 2: local corticosteroid, 3: oral corticosteroid The population evaluable by ITT was used: randomized patients who received at least one dose of the drug.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Active-1, Year-1 Active-2, Year-1 Placebo, Year-1
    Number of subjects analysed
    21
    31
    20
    Units: score
        arithmetic mean (standard deviation)
    0.40 ( 0.46 )
    0.43 ( 0.43 )
    0.44 ( 0.50 )
    Statistical analysis title
    		 Active-2 Vs. Placebo
    Statistical analysis description
    ITT population
    Comparison groups
    Active-2, Year-1 v Placebo, Year-1
    Number of subjects included in analysis
    51
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.9112
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [7] - The differences between groups were to be established by calculating the mean of the differences in the final-baseline score obtained individually (intrasubject) for each treatment group at 12 months (V16). However, many patients started with zero in the combined symptom and medication score, which does not allow any intrasubject clinical improvement. As there was no statistically significant difference in baseline values between groups, the mean scores at V16 between the groups were compared.
    Statistical analysis title
    		 Active-1 Vs. Placebo
    Statistical analysis description
    ITT population
    Comparison groups
    Active-2, Year-1 v Placebo, Year-1
    Number of subjects included in analysis
    51
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.8069
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [8] - The differences between groups were to be established by calculating the mean of the differences in the final-baseline score obtained individually (intrasubject) for each treatment group at 12 months (V16). However, many patients started with zero in the combined symptom and medication score, which does not allow any intrasubject clinical improvement. As there was no statistically significant difference in baseline values between groups, the mean scores at V16 between the groups were compared.

    Secondary: IgE levels at 12 months

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    End point title
    		 IgE levels at 12 months
    End point description
    Serum levels of purified Alt a 1 allergen specific IgE antibodies
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Active-1, Year-1 Active-2, Year-1 Placebo, Year-1
    Number of subjects analysed
    32
    39
    22
    Units: kU/l
        arithmetic mean (standard deviation)
    18.9 ( 22.7 )
    17.5 ( 17.9 )
    10.8 ( 10.8 )
    Statistical analysis title
    		 Active-2 Vs. Placebo
    Statistical analysis description
    ITT population
    Comparison groups
    Active-2, Year-1 v Placebo, Year-1
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Statistical analysis title
    		 Active-1 Vs. Placebo
    Statistical analysis description
    ITT population
    Comparison groups
    Placebo, Year-1 v Active-1, Year-1
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Secondary: Medication score at 12 months

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    End point title
    		 Medication score at 12 months
    End point description
    Symptomatic medication score (4-point Likert scale from 0 to 3): calculated individually according to type of rescue medication recorded by the patient. 0 corresponds to “No” medication, 1: local antihistamine; 2: local corticosteroid, 3: oral corticosteroid
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Active-1, Year-1 Active-2, Year-1 Placebo, Year-1
    Number of subjects analysed
    22
    33
    20
    Units: Score
        arithmetic mean (standard deviation)
    0.45 ( 0.96 )
    0.24 ( 0.56 )
    0.50 ( 1.00 )
    Statistical analysis title
    		 Active-2 Vs. Placebo
    Statistical analysis description
    ITT population
    Comparison groups
    Active-2, Year-1 v Placebo, Year-1
    Number of subjects included in analysis
    53
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [9]
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [9] - The differences between groups were to be established by calculating the mean of the differences in the final-baseline score obtained individually (intrasubject) for each treatment group at 12 months (V16). However, many patients started with zero in the combined symptom and medication score, which does not allow any intrasubject clinical improvement. As there was no statistically significant difference in baseline values between groups, the mean scores at V16 between the groups were compared.
    Statistical analysis title
    		 Active-1 Vs. Placebo
    Statistical analysis description
    ITT population
    Comparison groups
    Placebo, Year-1 v Active-1, Year-1
    Number of subjects included in analysis
    42
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [10]
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [10] - The differences between groups were to be established by calculating the mean of the differences in the final-baseline score obtained individually (intrasubject) for each treatment group at 12 months (V16). However, many patients started with zero in the combined symptom and medication score, which does not allow any intrasubject clinical improvement. As there was no statistically significant difference in baseline values between groups, the mean scores at V16 between the groups were compared.

    Secondary: Combined symptom and medication score at 24 months - ITT

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    End point title
    		 Combined symptom and medication score at 24 months - ITT
    End point description
    This endpoint was calculated by (mean symptom score + mean symptomatic medication score)/2 Symptom score: registered by the patient for each of 8 symptoms evaluated on a 4-point Likert scale: 0 corresponds to “no” symptoms, 1: “mild symptoms”; 2: “moderate” symptoms, 3 “severe” symptoms. Symptomatic medication score (4-point Likert scale from 0 to 3): calculated individually according to type of rescue medication recorded by the patient. 0 corresponds to “No” medication, 1: local antihistamine; 2: local corticosteroid, 3: oral corticosteroid. the means and SD were calculated for each study group at the evaluable monitoring visit. The means obtained were compared two-by – two between groups using the bilateral T-test with 95% confidence intervals. Statistical significance was set at <0.05
    End point type
    Secondary
    End point timeframe
    24 months (Visit 29)
    End point values
    		 Active 1, Year-2 Active-2, Year-2
    Number of subjects analysed
    13
    18
    Units: Score
        arithmetic mean (standard deviation)
    0.50 ( 0.65 )
    0.28 ( 0.34 )
    Statistical analysis title
    		 Active-2 Vs. Active-1
    Comparison groups
    Active 1, Year-2 v Active-2, Year-2
    Number of subjects included in analysis
    31
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.2859
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [11] - The differences between groups were to be established by calculating the mean of the differences in the final-baseline score obtained individually (intrasubject) for each treatment group. However, many patients started with zero in the combined symptom and medication score, which does not allow any intrasubject clinical improvement. As there was no statistically significant difference in baseline values between groups, the mean scores at V29 (24 months) between the groups were compared.

    Secondary: Prick test with Alternaria alternata extract at 24 months

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    End point title
    		 Prick test with Alternaria alternata extract at 24 months
    End point description
    Area of the wheal
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Active 1, Year-2 Active-2, Year-2 Placebo in Year-1, Active-2 in Year-2
    Number of subjects analysed
    30
    36
    21
    Units: mm2
        arithmetic mean (standard deviation)
    20 ( 16.3 )
    19 ( 15.9 )
    21.6 ( 20.2 )
    Statistical analysis title
    		 Placebo in Year-1, Active-2 in Year-2 Vs. Placebo
    Comparison groups
    Placebo in Year-1, Active-2 in Year-2
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [12]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [12] - Placebo in Year-1, Active-2 in Year-2 vs Placebo in Year-1

    Secondary: IgG4 levels at 24 months

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    End point title
    		 IgG4 levels at 24 months
    End point description
    Serum level of purified Alt a1 allergen specific IgG4 antibodies
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Active 1, Year-2 Active-2, Year-2 Placebo in Year-1, Active-2 in Year-2
    Number of subjects analysed
    30
    36
    21
    Units: µg/ml
        arithmetic mean (standard deviation)
    1917.0 ( 3422.0 )
    2088.0 ( 1978.0 )
    1230.0 ( 984.6 )
    Statistical analysis title
    		 Placebo in Year-1, Active-2 in Year-2 Vs. Placebo
    Comparison groups
    Placebo in Year-1, Active-2 in Year-2
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [13]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [13] - Placebo in Year-1, Active-2 in Year-2 vs Placebo in Year-1

    Secondary: Prick test with purified allergen Alt a1 at 24 months

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    End point title
    		 Prick test with purified allergen Alt a1 at 24 months
    End point description
    Area of the wheal
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Active 1, Year-2 Active-2, Year-2 Placebo in Year-1, Active-2 in Year-2
    Number of subjects analysed
    30
    36
    21
    Units: mm2
        arithmetic mean (standard deviation)
    16.8 ( 11.9 )
    13.2 ( 12.3 )
    18.1 ( 14.2 )
    Statistical analysis title
    		 Placebo in Year-1, Active-2 in Year-2 Vs. Placebo
    Comparison groups
    Placebo in Year-1, Active-2 in Year-2
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.05 [14]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [14] - Placebo in Year-1, Active-2 in Year-2 vs Placeb in Year-1 o

    Secondary: Symptom score at 24 months

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    End point title
    		 Symptom score at 24 months
    End point description
    Symptom score: registered by the patient for each of 8 symptoms evaluated on a 4-point Likert scale: 0 corresponds to “no” symptoms, 1: “mild symptoms”; 2: “moderate” symptoms, 3 “severe” symptoms. Symptomatic medication score (4-point Likert scale from 0 to 3): calculated individually according to type of rescue medication recorded by the patient. 0 corresponds to “No” medication, 1: local antihistamine; 2: local corticosteroid, 3: oral corticosteroid The population evaluable by ITT was used: randomized patients who received at least one dose of the drug.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Active 1, Year-2 Active-2, Year-2
    Number of subjects analysed
    13
    18
    Units: Score
        arithmetic mean (standard deviation)
    0.62 ( 0.61 )
    0.46 ( 0.56 )
    Statistical analysis title
    		 Active-1 Year-2 Vs. Active-2 Year-2
    Comparison groups
    Active 1, Year-2 v Active-2, Year-2
    Number of subjects included in analysis
    31
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [15]
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [15] - The differences between groups were to be established by calculating the mean of the differences in the final-baseline score obtained individually (intrasubject) for each treatment group. However, many patients started with zero in the combined symptom and medication score, which does not allow any intrasubject clinical improvement. As there was no statistically significant difference in baseline values between groups, the mean scores at V29 (24 months) between the groups were compared.

    Secondary: IgE levels at 24 months

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    End point title
    		 IgE levels at 24 months
    End point description
    Serum levels of purified Alt a1 allergen specific IgE antibodies
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Active 1, Year-2 Active-2, Year-2 Placebo in Year-1, Active-2 in Year-2
    Number of subjects analysed
    30
    36
    21
    Units: kU/l
        arithmetic mean (standard deviation)
    17.3 ( 24.8 )
    12.9 ( 11.8 )
    15.6 ( 16.0 )
    Statistical analysis title
    		 Placebo in Year-1, Active-2 in Year-2 Vs. Placebo
    Comparison groups
    Placebo in Year-1, Active-2 in Year-2
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [16]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation
    Notes
    [16] - Placebo in Year-1, Active-2 in Year-2 vs Placebo in Year-1

    Secondary: Medication score at 24 months

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    End point title
    		 Medication score at 24 months
    End point description
    Symptomatic medication score (4-point Likert scale from 0 to 3): calculated individually according to type of rescue medication recorded by the patient. 0 corresponds to “No” medication, 1: local antihistamine; 2: local corticosteroid, 3: oral corticosteroid
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Active 1, Year-2 Active-2, Year-2
    Number of subjects analysed
    14
    19
    Units: Score
        arithmetic mean (standard deviation)
    0.36 ( 0.93 )
    0.16 ( 0.50 )
    Statistical analysis title
    		 Active-1 Year-2 Vs. Active-2 Year-2
    Comparison groups
    Active 1, Year-2 v Active-2, Year-2
    Number of subjects included in analysis
    33
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.4755
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [17] - The differences between groups were to be established by calculating the mean of the differences in the final-baseline score obtained individually (intrasubject) for each treatment group. However, many patients started with zero in the combined symptom and medication score, which does not allow any intrasubject clinical improvement. As there was no statistically significant difference in baseline values between groups, the mean scores at V29 (24 months) between the groups were compared.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Two years of treatment
    Adverse event reporting additional description
    The occurrence of adverse events was to be sought by non-directive questionning of the patient at each visit during the clinical trial. Adverse events also could have been detected when they were volunteered by the patient during or between visits or through physical examination or other assessments.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Active-1, Year-1
    Reporting group description
    		 Alt a1 - Active 1, adverse events reported during the first year of treatment

    Reporting group title
    Active-2, Year-1
    Reporting group description
    		 Alt a 1 - Active 2; adverse events reported during the first year of treatment

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo treatment, adverse events reported during the first year of treatment

    Reporting group title
    Active-1, Year-2
    Reporting group description
    		 Adverse events reported during the second year of treatment with Active-1

    Reporting group title
    Active-2, Year-2
    Reporting group description
    		 Adverse events reported during the second year of treatment with Active-2

    Reporting group title
    Placebo in Year-1, Active-2 in Year-2
    Reporting group description
    		 Adverse events reported during 1 year of treatment with Active-2 in patients who were treated with placebo in the first year of the study.

    Serious adverse events
    		 Active-1, Year-1 Active-2, Year-1 Placebo Active-1, Year-2 Active-2, Year-2 Placebo in Year-1, Active-2 in Year-2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    1 / 32 (3.13%)
    0 / 40 (0.00%)
    2 / 22 (9.09%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 32 (0.00%)
    0 / 40 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delivery
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 32 (0.00%)
    0 / 40 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    1 / 32 (3.13%)
    0 / 40 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Meniscus injury
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 32 (0.00%)
    0 / 40 (0.00%)
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Meningitis virica
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 32 (0.00%)
    0 / 40 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Active-1, Year-1 Active-2, Year-1 Placebo Active-1, Year-2 Active-2, Year-2 Placebo in Year-1, Active-2 in Year-2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 37 (78.38%)
    39 / 45 (86.67%)
    20 / 29 (68.97%)
    24 / 32 (75.00%)
    32 / 40 (80.00%)
    13 / 22 (59.09%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 37 (32.43%)
    17 / 45 (37.78%)
    9 / 29 (31.03%)
    6 / 32 (18.75%)
    12 / 40 (30.00%)
    4 / 22 (18.18%)
         occurrences all number
    39
    85
    15
    21
    52
    14
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    3 / 37 (8.11%)
    3 / 45 (6.67%)
    4 / 29 (13.79%)
    0 / 32 (0.00%)
    2 / 40 (5.00%)
    0 / 22 (0.00%)
         occurrences all number
    10
    4
    9
    0
    5
    0
    Injection site pruritus
         subjects affected / exposed
    6 / 37 (16.22%)
    10 / 45 (22.22%)
    2 / 29 (6.90%)
    1 / 32 (3.13%)
    2 / 40 (5.00%)
    1 / 22 (4.55%)
         occurrences all number
    14
    26
    4
    1
    2
    1
    Injection site oedema
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 45 (6.67%)
    1 / 29 (3.45%)
    0 / 32 (0.00%)
    2 / 40 (5.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    7
    2
    0
    5
    0
    Injection site reaction
         subjects affected / exposed
    6 / 37 (16.22%)
    9 / 45 (20.00%)
    4 / 29 (13.79%)
    2 / 32 (6.25%)
    1 / 40 (2.50%)
    3 / 22 (13.64%)
         occurrences all number
    12
    11
    5
    6
    1
    6
    Asthenia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 45 (0.00%)
    2 / 29 (6.90%)
    0 / 32 (0.00%)
    0 / 40 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    2
    0
    0
    0
    Injection site inflammation
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 45 (4.44%)
    2 / 29 (6.90%)
    0 / 32 (0.00%)
    2 / 40 (5.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    6
    4
    0
    4
    0
    Injection site pain
         subjects affected / exposed
    5 / 37 (13.51%)
    0 / 45 (0.00%)
    4 / 29 (13.79%)
    1 / 32 (3.13%)
    3 / 40 (7.50%)
    0 / 22 (0.00%)
         occurrences all number
    9
    0
    10
    6
    5
    0
    Discomfort
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 45 (2.22%)
    1 / 29 (3.45%)
    1 / 32 (3.13%)
    3 / 40 (7.50%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    1
    2
    3
    0
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 45 (2.22%)
    2 / 29 (6.90%)
    2 / 32 (6.25%)
    3 / 40 (7.50%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    2
    2
    3
    0
    Odynophagia
         subjects affected / exposed
    2 / 37 (5.41%)
    4 / 45 (8.89%)
    2 / 29 (6.90%)
    1 / 32 (3.13%)
    5 / 40 (12.50%)
    2 / 22 (9.09%)
         occurrences all number
    2
    5
    2
    1
    5
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 45 (2.22%)
    0 / 29 (0.00%)
    2 / 32 (6.25%)
    0 / 40 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    3
    0
    5
    0
    1
    Dental discomfort
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 45 (6.67%)
    1 / 29 (3.45%)
    2 / 32 (6.25%)
    1 / 40 (2.50%)
    1 / 22 (4.55%)
         occurrences all number
    0
    5
    2
    2
    1
    2
    Vomiting
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 32 (0.00%)
    4 / 40 (10.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    6
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    4 / 37 (10.81%)
    6 / 45 (13.33%)
    0 / 29 (0.00%)
    2 / 32 (6.25%)
    2 / 40 (5.00%)
    0 / 22 (0.00%)
         occurrences all number
    14
    15
    0
    18
    5
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    3 / 37 (8.11%)
    4 / 45 (8.89%)
    3 / 29 (10.34%)
    3 / 32 (9.38%)
    4 / 40 (10.00%)
    2 / 22 (9.09%)
         occurrences all number
    5
    17
    5
    7
    13
    2
    Cough
         subjects affected / exposed
    2 / 37 (5.41%)
    6 / 45 (13.33%)
    3 / 29 (10.34%)
    1 / 32 (3.13%)
    4 / 40 (10.00%)
    1 / 22 (4.55%)
         occurrences all number
    2
    7
    7
    1
    5
    1
    Nasal congestion
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    0 / 32 (0.00%)
    1 / 40 (2.50%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    4 / 37 (10.81%)
    7 / 45 (15.56%)
    0 / 29 (0.00%)
    4 / 32 (12.50%)
    4 / 40 (10.00%)
    2 / 22 (9.09%)
         occurrences all number
    7
    11
    0
    8
    8
    2
    Bronchospasm
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 45 (6.67%)
    2 / 29 (6.90%)
    1 / 32 (3.13%)
    1 / 40 (2.50%)
    1 / 22 (4.55%)
         occurrences all number
    1
    4
    2
    5
    1
    1
    Dyspnoea
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 45 (4.44%)
    2 / 29 (6.90%)
    2 / 32 (6.25%)
    3 / 40 (7.50%)
    1 / 22 (4.55%)
         occurrences all number
    0
    2
    4
    6
    4
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    1 / 32 (3.13%)
    0 / 40 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    6
    0
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    3 / 37 (8.11%)
    5 / 45 (11.11%)
    2 / 29 (6.90%)
    0 / 32 (0.00%)
    1 / 40 (2.50%)
    1 / 22 (4.55%)
         occurrences all number
    4
    6
    4
    0
    2
    1
    Musculoskeletal and connective tissue disorders
    Contusion
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 45 (2.22%)
    1 / 29 (3.45%)
    0 / 32 (0.00%)
    2 / 40 (5.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    1
    1
    0
    3
    0
    Back pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 45 (2.22%)
    1 / 29 (3.45%)
    2 / 32 (6.25%)
    3 / 40 (7.50%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    2
    3
    4
    0
    Muscle contracture
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 45 (4.44%)
    1 / 29 (3.45%)
    1 / 32 (3.13%)
    3 / 40 (7.50%)
    0 / 22 (0.00%)
         occurrences all number
    0
    4
    1
    1
    4
    0
    Pain in extremity
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 45 (2.22%)
    0 / 29 (0.00%)
    2 / 32 (6.25%)
    2 / 40 (5.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    0
    3
    2
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 37 (8.11%)
    0 / 45 (0.00%)
    2 / 29 (6.90%)
    0 / 32 (0.00%)
    3 / 40 (7.50%)
    0 / 22 (0.00%)
         occurrences all number
    4
    0
    2
    0
    3
    0
    Conjunctivitis
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 45 (0.00%)
    1 / 29 (3.45%)
    1 / 32 (3.13%)
    3 / 40 (7.50%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    1
    2
    4
    0
    Influenza
         subjects affected / exposed
    2 / 37 (5.41%)
    4 / 45 (8.89%)
    2 / 29 (6.90%)
    3 / 32 (9.38%)
    4 / 40 (10.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    5
    3
    4
    5
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 37 (8.11%)
    7 / 45 (15.56%)
    3 / 29 (10.34%)
    6 / 32 (18.75%)
    8 / 40 (20.00%)
    6 / 22 (27.27%)
         occurrences all number
    4
    9
    3
    9
    11
    9
    Pharyngitis
         subjects affected / exposed
    4 / 37 (10.81%)
    1 / 45 (2.22%)
    3 / 29 (10.34%)
    1 / 32 (3.13%)
    3 / 40 (7.50%)
    3 / 22 (13.64%)
         occurrences all number
    5
    2
    4
    1
    3
    4
    Pharyngotonsillitis
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    1 / 32 (3.13%)
    0 / 40 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    0
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    4 / 37 (10.81%)
    8 / 45 (17.78%)
    3 / 29 (10.34%)
    4 / 32 (12.50%)
    5 / 40 (12.50%)
    3 / 22 (13.64%)
         occurrences all number
    6
    10
    4
    8
    6
    5
    Sinusitis
         subjects affected / exposed
    4 / 37 (10.81%)
    0 / 45 (0.00%)
    1 / 29 (3.45%)
    3 / 32 (9.38%)
    0 / 40 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    5
    0
    1
    4
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 45 (2.22%)
    1 / 29 (3.45%)
    2 / 32 (6.25%)
    3 / 40 (7.50%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    1
    2
    4
    1
    Hordeolum
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 45 (6.67%)
    0 / 29 (0.00%)
    1 / 32 (3.13%)
    0 / 40 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 37 (2.70%)
    5 / 45 (11.11%)
    0 / 29 (0.00%)
    2 / 32 (6.25%)
    1 / 40 (2.50%)
    0 / 22 (0.00%)
         occurrences all number
    1
    6
    0
    2
    1
    0
    Ear infection
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 45 (0.00%)
    0 / 29 (0.00%)
    2 / 32 (6.25%)
    0 / 40 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    0
    0
    2
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Nov 2012
    Increase in the number of participant sites due to low recruitment rate.
    13 May 2013
    Increase in the number of participant sites due to low recruitment rate.
    15 Jul 2013
    Change of the Principal Investigator for the “Hospital del Sureste” , Madrid

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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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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