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    Clinical Trial Results:
    Multicenter, randomized, parallel-group, double-blind, placebo-controlled clinical trial for evaluating the clinical efficacy and safety of intradermal immunotherapy with polimerised Phleum pratense, in patients with allergic rhino-conjunctivitis with or without mild to moderate asthma, sensitised to Phleum pratense pollen.

    Summary
    EudraCT number
    		 2014-000429-18
    Trial protocol
    		 ES  
    Global end of trial date
    28 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Oct 2018
    First version publication date
    14 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DIA-Phl-01-14
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    DIATER Laboratorio de Diagnóstico y Aplicaciones Terapéuticas, S.A.
    Sponsor organisation address
    Avda. Gregorio Peces Barba 2, Madrid, Spain, 28918
    Public contact
    Medical department, DIATER Laboratorio de Diagnóstico y Aplicaciones Terapéuticas, S.A., 0034 914966013, departamento.medico@diater.com
    Scientific contact
    Medical department, DIATER Laboratorio de Diagnóstico y Aplicaciones Terapéuticas, S.A., 0034 914966013, departamento.medico@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
    24 Aug 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Efficacy assessment of Polymerized Phleum pratense inmunotherapy administed intradermally
    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): nedocromil Nasal symptoms: Antihistamines: loratadine. Topical nasal corticosteroids: nasal budesonide. Oral corticosteroids: deflazacort
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Oct 2014
    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: 153
    Worldwide total number of subjects
    153
    EEA total number of subjects
    153
    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)
    15
    Adults (18-64 years)
    138
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitement period (from the date of the first site ready to recruit to the date for the last patient entered into the study): July 2015 to February 2016. FPFV: 08-OCT-2014; LPLV: 28-SEP-2017

    Pre-assignment
    Screening details
    		 Additionally to the 153 enrolled patients , 2 patients signing the Informed consent was screened but did not fullfill the selection criteria

    Pre-assignment period milestones
    Number of subjects started
    		 155 [1]
    Number of subjects completed
    		 153

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Not meeting selection criteria: 2
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects starting the pre-assignment period is the number of screened subjects signing informed consent The number of subjects reported as enrolled is the number of randomized subjects meeting the selection criteria.
    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, Monitor, 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
    		 Placebo- 1st year
    Arm description
    		 Placebo. First year of follow-up. first cycle of treatment
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    IMP was administered preseasonally and weekly during 6 weeks (0.1 ml of Placebo in each single volar forearm per visit: 0.2 ml total / treatment visit)

    Arm title
    		 Active 1-1st year
    Arm description
    		 Active IMP at low dose. First year of follow-up. first cycle of treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Polymerized Phleum pratense
    Investigational medicinal product code
    Phl p pol
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    IMP (0.3 microgram /ml) was administered preseasonally and weekly during 6 weeks (0.1 ml of IMP in one volar forearm and 0.1 ml of matching placebo in the other volar forearm in each single visit)

    Arm title
    		 Active 2- 1st year
    Arm description
    		 Active IMP at high dose. First year of follow-up. first cycle of treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Polymerized Phleum pratense
    Investigational medicinal product code
    Phl p pol
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    IMP (0.3 microgram /ml) was administered preseasonally and weekly during 6 weeks (0.1 ml of IMP in each volar forearm per visit. 0.2 ml total / treatment visit))

    Number of subjects in period 1
    		Placebo- 1st year Active 1-1st year Active 2- 1st year
    Started
    56
    44
    53
    Treated
    53
    42
    53
    Completed
    51
    38
    49
    Not completed
    5
    6
    4
         Consent withdrawn by subject
    5
    4
    -
         Physician decision
    -
    -
    1
         Adverse event, non-fatal
    -
    1
    2
         Lost to follow-up
    -
    1
    1
    Period 2
    Period 2 title
    Second year
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    As defined in the protocol, after the first year of follow-up, blinding was opened for the placebo group to receive during the second year of treatment the active treatment with the best efficacy/safety ratio . According to this, these patients were receiving the high dose of active treatment during the second period . the arms initally asigned to Active 1 and Active 2 remained blinded during the second year.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo-Active 2
    Arm description
    		 Active IMP at high doses during second year for patients initially receiving placebo during the first year
    Arm type
    		 Experimental

    Investigational medicinal product name
    Polymerized Phleum pratense
    Investigational medicinal product code
    Phl p pol
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    IMP (0.3 microgram /ml) was administered preseasonally and weekly during 6 weeks (0.1 ml of IMP in each volar forearm per visit. 0.2 ml total / treatment visit)

    Arm title
    		 Active 1- 2nd year
    Arm description
    		 active IMP at low dose. Second year of follow-up. Second cycle of treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Polymerized Phleum pratense
    Investigational medicinal product code
    Phl p pol
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    IMP (0.3 microgram /ml) was administered preseasonally and weekly during 6 weeks (0.1 ml of IMP in one volar forearm and 0.1 ml of matching placebo in the other volar forearm in each single visit)

    Arm title
    		 Active 2- 2nd year
    Arm description
    		 Active IMP at high dose. Second year of follow-up. Second cycle of treatment
    Arm type
    		 Experimental

    Investigational medicinal product name
    Polymerized Phleum pratense
    Investigational medicinal product code
    Phl p pol
    Other name
    Pharmaceutical forms
    Powder and solvent for suspension for injection
    Routes of administration
    Intradermal use
    Dosage and administration details
    IMP (0.3 microgram /ml) was administered preseasonally and weekly during 6 weeks (0.1 ml of IMP in each volar forearm per visit) (0.2 ml total/ treatment visit)

    Number of subjects in period 2
    		Placebo-Active 2 Active 1- 2nd year Active 2- 2nd year
    Started
    51
    38
    49
    Treated
    51
    37
    47
    Completed
    49
    36
    45
    Not completed
    2
    2
    4
         Consent withdrawn by subject
    -
    2
    -
         Adverse event, non-fatal
    1
    -
    -
         Lost to follow-up
    1
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo- 1st year
    Reporting group description
    		 Placebo. First year of follow-up. first cycle of treatment

    Reporting group title
    Active 1-1st year
    Reporting group description
    		 Active IMP at low dose. First year of follow-up. first cycle of treatment

    Reporting group title
    Active 2- 1st year
    Reporting group description
    		 Active IMP at high dose. First year of follow-up. first cycle of treatment

    Reporting group values
    		 Placebo- 1st year Active 1-1st year Active 2- 1st year Total
    Number of subjects
    		 56 44 53 153
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 5 3 7 15
        Adults (18-64 years)
    		 51 41 46 138
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.7 ( 10.5 ) 33.5 ( 10.8 ) 30.6 ( 11.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 32 21 27 80
        Male
    		 24 23 26 73
    Subject analysis sets

    Subject analysis set title
    PP population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects completing the first year of follow-up according to protocol, no protocol violation related to the primary endpoint and a valid Symptom and medication questionaire registered during the first peak pollen season

    Subject analysis set title
    ITT Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    all randomized subjects receiving at least one dose of study drug

    Subject analysis sets values
    		 PP population ITT Population
    Number of subjects
    109
    148
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    12
    15
        Adults (18-64 years)
    97
    133
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    31.8 ( 11.1 )
    32.0 ( 10.9 )
    Gender categorical
    Units: Subjects
        Female
    60
    80
        Male
    49
    68

    End points

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    End points reporting groups
    Reporting group title
    Placebo- 1st year
    Reporting group description
    		 Placebo. First year of follow-up. first cycle of treatment

    Reporting group title
    Active 1-1st year
    Reporting group description
    		 Active IMP at low dose. First year of follow-up. first cycle of treatment

    Reporting group title
    Active 2- 1st year
    Reporting group description
    		 Active IMP at high dose. First year of follow-up. first cycle of treatment
    Reporting group title
    Placebo-Active 2
    Reporting group description
    		 Active IMP at high doses during second year for patients initially receiving placebo during the first year

    Reporting group title
    Active 1- 2nd year
    Reporting group description
    		 active IMP at low dose. Second year of follow-up. Second cycle of treatment

    Reporting group title
    Active 2- 2nd year
    Reporting group description
    		 Active IMP at high dose. Second year of follow-up. Second cycle of treatment

    Subject analysis set title
    PP population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Subjects completing the first year of follow-up according to protocol, no protocol violation related to the primary endpoint and a valid Symptom and medication questionaire registered during the first peak pollen season

    Subject analysis set title
    ITT Population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    all randomized subjects receiving at least one dose of study drug

    Primary: Combined symptom and medication score - First year- PP

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    End point title
    		 Combined symptom and medication score - First year- PP
    End point description
    The primary endpoint was calculated by (mean symptom score + mean symptomatic medication score) /2. Scale range: 0-3 Symptom score (ocular/nasal) registered during the pollen season by the patient for each of 7 symptoms evaluated on a 4-point scale: 0 corresponds to “no” symptoms, 1:“mild symptoms”; 2:“moderate” symptoms, 3:“severe” symptoms. Symptomatic medication score calculated individually according to type and doses of rescue medication recorded by the patient and ranging from 0 (no medication) to 24 (ocular and oral antihistamine + nasal and oral corticosteroid, all at maximum doses) and converted into a 0-3 scale range. PP population
    End point type
    Primary
    End point timeframe
    Registered during the first pollen season (May-June) after the first year of treatment
    End point values
    		 Placebo- 1st year Active 1-1st year Active 2- 1st year
    Number of subjects analysed
    42
    32
    35
    Units: score
        arithmetic mean (standard deviation)
    0.65 ( 0.31 )
    0.69 ( 0.37 )
    0.50 ( 0.26 )
    Statistical analysis title
    		 combined score- first year- PP
    Statistical analysis description
    PP population
    Comparison groups
    Active 2- 1st year v Placebo- 1st year
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.0203
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 -0.02
    Variability estimate
    Standard deviation
    Notes
    [1] - The difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference
    Statistical analysis title
    		 combined score- first year- PP
    Statistical analysis description
    PP population
    Comparison groups
    Active 1-1st year v Placebo- 1st year
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.6407
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.19
    Variability estimate
    Standard deviation
    Notes
    [2] - The difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference
    Statistical analysis title
    		 Combined score First year-PP
    Statistical analysis description
    PP population
    Comparison groups
    Active 1-1st year v Active 2- 1st year
    Number of subjects included in analysis
    67
    Analysis specification
    Post-hoc
    Analysis type
    		 other [3]
    P-value
    		 = 0.0174
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.35
    Variability estimate
    Standard deviation
    Notes
    [3] - The difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference Difference between both active treatments was not prespecified in the protocol but defined and analysed before unblinding.

    Secondary: Combined symptom and medication score - First year- ITT

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    End point title
    		 Combined symptom and medication score - First year- ITT
    End point description
    The primary endpoint was calculated by (mean symptom score + mean symptomatic medication score) /2. Scale range: 0-3 Symptom score (ocular/nasal) registered during the pollen season by the patient for each of 7 symptoms evaluated on a 4-point scale: 0 corresponds to “no” symptoms, 1:“mild symptoms”; 2:“moderate” symptoms, 3:“severe” symptoms. Symptomatic medication score (4-point scale from 0 to 3) calculated individually according to type and doses of rescue medication recorded by the patient and ranging from 0 (no medication) to 24 (ocular and oral antihistamine + nasal and oral corticosteroid, all at maximum doses) and converted into a 0-3 scale. ITT population
    End point type
    Secondary
    End point timeframe
    Registered during the first pollen season (May-June) after the first year of treatment
    End point values
    		 Placebo- 1st year Active 1-1st year Active 2- 1st year
    Number of subjects analysed
    42
    32
    37
    Units: score
        arithmetic mean (standard deviation)
    0.65 ( 0.31 )
    0.69 ( 0.37 )
    0.57 ( 0.42 )
    Statistical analysis title
    		 Combined score 1st year-ITT
    Statistical analysis description
    ITT population
    Comparison groups
    Active 2- 1st year v Placebo- 1st year
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.3083
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.25
         upper limit
    		 0.08
    Variability estimate
    Standard deviation
    Notes
    [4] - The difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference
    Statistical analysis title
    		 combined score- 1st year- ITT
    Comparison groups
    Active 1-1st year v Placebo- 1st year
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.6407
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.19
    Variability estimate
    Standard deviation
    Notes
    [5] - The difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference
    Statistical analysis title
    		 Combined score 1st year-ITT
    Statistical analysis description
    ITT population
    Comparison groups
    Active 1-1st year v Active 2- 1st year
    Number of subjects included in analysis
    69
    Analysis specification
    Post-hoc
    Analysis type
    		 other [6]
    P-value
    		 = 0.2101
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.31
    Variability estimate
    Standard deviation
    Notes
    [6] - Analysis of the difference between active treatments was not predefined in the protocol but defined and analyzed before unblinding. The difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference

    Secondary: Combined symptom and medication score - 2nd year v 1st year- ITT

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    End point title
    		 Combined symptom and medication score - 2nd year v 1st year- ITT
    End point description
    evolution of the score over time was obtained by means of intragroup comparison. ITT population
    End point type
    Secondary
    End point timeframe
    Symptoms and medication score was registered during the first and second pollen season after entering into the study
    End point values
    		 Placebo- 1st year Active 1-1st year Active 2- 1st year Placebo-Active 2 Active 1- 2nd year Active 2- 2nd year
    Number of subjects analysed
    42
    32
    37
    40
    32
    37
    Units: score
        arithmetic mean (standard deviation)
    0.65 ( 0.31 )
    0.69 ( 0.37 )
    0.57 ( 0.42 )
    0.46 ( 0.3 )
    0.54 ( 0.29 )
    0.61 ( 0.47 )
    Statistical analysis title
    		 combined score- 2nd year vs first year
    Comparison groups
    Placebo-Active 2 v Placebo- 1st year
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.0003
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 -0.09
    Variability estimate
    Standard deviation
    Notes
    [7] - Difference in means between first and second period was tested using a two-sided paired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference
    Statistical analysis title
    		 Combined score 2nd years v first year
    Comparison groups
    Active 1- 2nd year v Active 1-1st year
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.0083
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 -0.04
    Variability estimate
    Standard deviation
    Notes
    [8] - Difference in means between periods was tested using a two-sided paired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference
    Statistical analysis title
    		 combined score- 2nd year vs first year
    Statistical analysis description
    ITT population
    Comparison groups
    Active 2- 2nd year v Active 2- 1st year
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.9532
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.12
    Variability estimate
    Standard deviation
    Notes
    [9] - Difference in means between periods was tested using a two-sided paired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference

    Secondary: Allergen concentration eliciting a positive Conjuntival challenge test: change from baseline

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    End point title
    		 Allergen concentration eliciting a positive Conjuntival challenge test: change from baseline
    End point description
    The test was performed by applying a single drop of allergen solution directly into the conjunctival sac of the eye followed by observation for allergic symptomas (i.e. redness, itchiness). The allergen was applied at increasing concentrations administered at 10-minute intervals until reaching the maximum concentration or a positive result , whatever happened first. An increase in the concentration eliciting a positive result indicates a better tolerance to the allergen exposure.
    End point type
    Secondary
    End point timeframe
    at baseline and after the first and second pollen seasson
    End point values
    		 Placebo- 1st year Active 1-1st year Active 2- 1st year Placebo-Active 2 Active 1- 2nd year Active 2- 2nd year
    Number of subjects analysed
    51
    37
    48
    48
    35
    43
    Units: µg/ml
        arithmetic mean (standard deviation)
    17.14 ( 56.79 )
    152.59 ( 494.59 )
    269.91 ( 674.96 )
    365.52 ( 770.75 )
    318.84 ( 720.23 )
    404.75 ( 758.16 )
    Statistical analysis title
    		 conjuctival challenge test- first year
    Statistical analysis description
    ITT population. Change from baseline after first year of treatment
    Comparison groups
    Active 1-1st year v Placebo- 1st year
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.1058
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    135.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.13
         upper limit
    		 301.04
    Variability estimate
    Standard deviation
    Notes
    [10] - Mean difference between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference an increase in the concentration eliciting a positive test indicates a better tolerance to the allergen exposure
    Statistical analysis title
    		 conjuctival challenge test- first year
    Statistical analysis description
    ITT population. Change from baseline after first year of treatment.
    Comparison groups
    Active 2- 1st year v Placebo- 1st year
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.0128
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    252.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 56.19
         upper limit
    		 449.34
    Variability estimate
    Standard deviation
    Notes
    [11] - Mean difference between 2 groups was tested using a two-sided unpairedt-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference an increase in the concentration eliciting a positive test indicates a better tolerance to the allergen exposure
    Statistical analysis title
    		 conjuctival challenge test- first year
    Statistical analysis description
    ITT population. Change from baseline after the first year of treatment
    Comparison groups
    Active 1-1st year v Active 2- 1st year
    Number of subjects included in analysis
    85
    Analysis specification
    Post-hoc
    Analysis type
    		 other [12]
    P-value
    		 = 0.3767
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -117.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -379.86
         upper limit
    		 145.24
    Variability estimate
    Standard deviation
    Notes
    [12] - Mean difference between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference Difference between both active treatment was not pre-especified in the protocol but it was analysed before unblinding. An increase in the concentration eliciting a positive test indicates a better tolerance to the allergen exposure
    Statistical analysis title
    		 conjuctival challenge test- second year
    Statistical analysis description
    ITT population. Change from baseline after second year of treatment
    Comparison groups
    Active 1- 2nd year v Active 2- 2nd year
    Number of subjects included in analysis
    78
    Analysis specification
    Post-hoc
    Analysis type
    		 other [13]
    P-value
    		 = 0.6123
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -85.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -422.08
         upper limit
    		 250.27
    Variability estimate
    Standard deviation
    Notes
    [13] - Mean difference between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference Difference between both active treatment was not pre-especified in the protocol but defined and analysed before unblinding an increase in the concentration eliciting a positive test indicates a better tolerance to the allergen exposure
    Statistical analysis title
    		 conjuctival challenge test- second year
    Statistical analysis description
    ITT population. Change from baseline after second year of treatment. Placebo group was receiving active treatment during the 2nd year. This is an intragroup comparison. Change from baseline after first (placebo period) and second year(Active treatment) of follow-up was compaired.
    Comparison groups
    Placebo-Active 2 v Placebo- 1st year
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.0019
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    365.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 141.72
         upper limit
    		 589.32
    Variability estimate
    Standard deviation
    Notes
    [14] - Difference in means between 2 periods of the placebo group was tested using a two-sided paired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference an increase in the concentration eliciting a positive test indicates a better tolerance to the allergen exposure

    Secondary: Rhinoconjuctivitis symptoms score- PP

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    End point title
    		 Rhinoconjuctivitis symptoms score- PP
    End point description
    End point type
    Secondary
    End point timeframe
    measured during the first and second pollen season (May-June) after starting IT with the IMP.
    End point values
    		 Placebo- 1st year Active 1-1st year Active 2- 1st year Placebo-Active 2 Active 1- 2nd year Active 2- 2nd year
    Number of subjects analysed
    42
    32
    35
    37
    28
    30
    Units: score
        arithmetic mean (standard deviation)
    0.85 ( 0.43 )
    0.90 ( 0.49 )
    0.75 ( 0.43 )
    0.63 ( 0.40 )
    0.82 ( 0.45 )
    0.81 ( 0.53 )
    Statistical analysis title
    		 Symptoms score- intergroup-first year-PP
    Statistical analysis description
    PP population
    Comparison groups
    Active 1-1st year v Placebo- 1st year
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.6772
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.26
    Variability estimate
    Standard deviation
    Notes
    [15] - The difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference
    Statistical analysis title
    		 Symptoms score- intergroup- first year PP
    Statistical analysis description
    PP population
    Comparison groups
    Active 2- 1st year v Placebo- 1st year
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.2867
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.09
    Variability estimate
    Standard deviation
    Notes
    [16] - The difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference
    Statistical analysis title
    		 Symptoms score- intergroup-first year-PP
    Statistical analysis description
    PP population
    Comparison groups
    Active 2- 1st year v Active 1-1st year
    Number of subjects included in analysis
    67
    Analysis specification
    Post-hoc
    Analysis type
    		 other [17]
    P-value
    		 = 0.1876
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.38
    Variability estimate
    Standard deviation
    Notes
    [17] - The difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference. Difference between active treatments was not pre-specified in the protocol but was defined and analysed before unblinding
    Statistical analysis title
    		 Symptoms score- intragroup-PP
    Statistical analysis description
    Follow-up PP population: Second year v First year
    Comparison groups
    Active 1- 2nd year v Active 1-1st year
    Number of subjects included in analysis
    60
    Analysis specification
    Post-hoc
    Analysis type
    		 other [18]
    P-value
    		 = 0.1404
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.03
    Variability estimate
    Standard deviation
    Notes
    [18] - Difference in means between two periods was tested using a two-sided paired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference.
    Statistical analysis title
    		 Symptoms score- intragroup-PP
    Statistical analysis description
    Follow-up PP population: Second year v First year
    Comparison groups
    Active 2- 2nd year v Active 2- 1st year
    Number of subjects included in analysis
    65
    Analysis specification
    Post-hoc
    Analysis type
    		 other [19]
    P-value
    		 = 0.6265
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.24
    Variability estimate
    Standard deviation
    Notes
    [19] - Difference in means between two periods was tested using a two-sided paired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference.
    Statistical analysis title
    		 Symptoms score- intragroup-PP
    Statistical analysis description
    Follow-up PP population: Second year v First year
    Comparison groups
    Placebo-Active 2 v Placebo- 1st year
    Number of subjects included in analysis
    79
    Analysis specification
    Post-hoc
    Analysis type
    		 other [20]
    P-value
    		 = 0.0016
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 -0.09
    Variability estimate
    Standard deviation
    Notes
    [20] - Difference in means between periods was tested using a two-sided paired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference.

    Secondary: Medication consumption score-PP

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    End point title
    		 Medication consumption score-PP
    End point description
    End point type
    Secondary
    End point timeframe
    measured during the first and second pollen season (May-June) after starting IT with the IMP.
    End point values
    		 Placebo- 1st year Active 1-1st year Active 2- 1st year Placebo-Active 2 Active 1- 2nd year Active 2- 2nd year
    Number of subjects analysed
    42
    32
    35
    37
    28
    30
    Units: score
        arithmetic mean (standard deviation)
    0.45 ( 0.34 )
    0.48 ( 0.41 )
    0.24 ( 0.21 )
    0.28 ( 0.25 )
    0.26 ( 0.25 )
    0.24 ( 0.24 )
    Statistical analysis title
    		 Medication score- Intergroup-PP
    Statistical analysis description
    PP population first year
    Comparison groups
    Active 1-1st year v Placebo- 1st year
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 = 0.7411
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.2
    Variability estimate
    Standard deviation
    Notes
    [21] - Difference in mean between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference.
    Statistical analysis title
    		 Medication score- Intergroup-PP
    Statistical analysis description
    PP population first year
    Comparison groups
    Active 2- 1st year v Placebo- 1st year
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 other [22]
    P-value
    		 = 0.0018
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 -0.08
    Variability estimate
    Standard deviation
    Notes
    [22] - Difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference.
    Statistical analysis title
    		 Medication score- Intergroup-PP
    Statistical analysis description
    PP populatin first year
    Comparison groups
    Active 2- 1st year v Active 1-1st year
    Number of subjects included in analysis
    67
    Analysis specification
    Post-hoc
    Analysis type
    		 other [23]
    P-value
    		 = 0.0058
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 0.4
    Variability estimate
    Standard deviation
    Notes
    [23] - Difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference. Difference between active treatments was no pre-specified in the protocol but defined and analysed unblinding
    Statistical analysis title
    		 Medication score- Intragroup-PP
    Statistical analysis description
    Follow-up PP population: second year v First year
    Comparison groups
    Active 1- 2nd year v Active 1-1st year
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other [24]
    P-value
    		 = 0.0009
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 -0.08
    Variability estimate
    Standard deviation
    Notes
    [24] - Difference in means between two periods was tested using a two-sided paired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference.
    Statistical analysis title
    		 Medication score- Intragroup-PP
    Statistical analysis description
    Follow-up PP population: second year v First year
    Comparison groups
    Active 2- 2nd year v Active 2- 1st year
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 0.8967
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.1
    Variability estimate
    Standard deviation
    Notes
    [25] - Difference in means between two periods was tested using a two-sided paired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference.
    Statistical analysis title
    		 Medication score- Intragroup-PP
    Statistical analysis description
    Follow-up PP population: second year v First year
    Comparison groups
    Placebo-Active 2 v Placebo- 1st year
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    P-value
    		 = 0.0111
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 -0.03
    Variability estimate
    Standard deviation
    Notes
    [26] - Difference in means between two periods was tested using a two-sided paired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference.

    Secondary: Serum Specific IgE antibodies- Phleum Pratense- Change from baseline

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    End point title
    		 Serum Specific IgE antibodies- Phleum Pratense- Change from baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, preseasonally after first year of IMP administration and preseasonally after second year of IMP administration
    End point values
    		 Placebo- 1st year Active 1-1st year Active 2- 1st year Placebo-Active 2 Active 1- 2nd year Active 2- 2nd year
    Number of subjects analysed
    49
    38
    48
    47
    36
    46
    Units: kU/L
        arithmetic mean (standard deviation)
    2.38 ( 12.72 )
    2.37 ( 10.46 )
    2.01 ( 10.43 )
    -1.78 ( 15.89 )
    -2.29 ( 6.96 )
    -2.89 ( 8.98 )
    Statistical analysis title
    		 sIgE-Phleum pratense- first year
    Statistical analysis description
    ITT population. Change from baseline after first year of treatment.
    Comparison groups
    Active 1-1st year v Placebo- 1st year
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.9948
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.08
         upper limit
    		 5.05
    Variability estimate
    Standard deviation
    Notes
    [27] - Difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference
    Statistical analysis title
    		 sIgE-Phleum pratense- first year-
    Statistical analysis description
    ITT population. Change from baseline after first year of treatment.
    Comparison groups
    Active 2- 1st year v Placebo- 1st year
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 other [28]
    P-value
    		 = 0.8752
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.07
         upper limit
    		 4.32
    Variability estimate
    Standard deviation
    Notes
    [28] - Difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference
    Statistical analysis title
    		 sIgE-Phleum pratense- first year
    Statistical analysis description
    ITT population. Change from baseline after first year of treatment.
    Comparison groups
    Active 1-1st year v Active 2- 1st year
    Number of subjects included in analysis
    86
    Analysis specification
    Post-hoc
    Analysis type
    		 other [29]
    P-value
    		 = 0.36
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.15
         upper limit
    		 4.87
    Variability estimate
    Standard deviation
    Notes
    [29] - Difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference Difference between both active treatments was not pre-especified in the protocol but it was analysed before unblinding.
    Statistical analysis title
    		 sIgE-Phleum pratense- 2nd year
    Statistical analysis description
    ITT population. Change from baseline after second year of treatment. Placebo group was receiving active treatment during the 2nd year. Placebo group was receiving active treatment during the 2nd year. This is an intragroup comparison. Change from baseline after first (placebo period) and second year(Active treatment) of follow-up was compaired.
    Comparison groups
    Placebo-Active 2 v Placebo- 1st year
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 other [30]
    P-value
    		 = 0.4476
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.44
         upper limit
    		 2.89
    Variability estimate
    Standard deviation
    Notes
    [30] - Difference in meansbetween 2 periods of the placebo group was tested using a two-sided paired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference
    Statistical analysis title
    		 sIgE-Phleum pratense- 2nd year
    Statistical analysis description
    ITT population. Change from baseline after second year of treatment.
    Comparison groups
    Active 1- 2nd year v Active 2- 2nd year
    Number of subjects included in analysis
    82
    Analysis specification
    Post-hoc
    Analysis type
    		 other [31]
    P-value
    		 = 0.7448
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.02
         upper limit
    		 4.21
    Variability estimate
    Standard deviation
    Notes
    [31] - Difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference Difference between both active treatments was not pre-especified in the protocol but it was defined and analysed before unblinding.

    Secondary: Serum specific IgG4-Phleum pratense- change from baseline

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    End point title
    		 Serum specific IgG4-Phleum pratense- change from baseline
    End point description
    ITT population
    End point type
    Secondary
    End point timeframe
    Baseline, preseasonally after firt year of IMP administration and preseasonally after second year of IMP administration
    End point values
    		 Placebo- 1st year Active 1-1st year Active 2- 1st year Placebo-Active 2 Active 1- 2nd year Active 2- 2nd year
    Number of subjects analysed
    49
    38
    48
    47
    36
    46
    Units: µg/ml
        arithmetic mean (standard deviation)
    0.03 ( 0.11 )
    0.01 ( 0.09 )
    -0.00 ( 0.11 )
    0.01 ( 0.25 )
    -0.02 ( 0.17 )
    -0.05 ( 0.19 )
    Statistical analysis title
    		 sIgG4-Phleum pratense- first year
    Statistical analysis description
    ITT population. Change from baseline after first year of treatment.
    Comparison groups
    Placebo- 1st year v Active 1-1st year
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 other [32]
    P-value
    		 = 0.448
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.03
    Variability estimate
    Standard deviation
    Notes
    [32] - Difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference
    Statistical analysis title
    		 sIgG4-Phleum pratense- first year
    Statistical analysis description
    ITT population. Change from baseline after first year of treatment.
    Comparison groups
    Active 2- 1st year v Placebo- 1st year
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    P-value
    		 = 0.1566
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.01
    Variability estimate
    Standard deviation
    Notes
    [33] - Difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference
    Statistical analysis title
    		 sIgG4-Phleum pratense- first year
    Statistical analysis description
    ITT population. Change from baseline after first year of treatment.
    Comparison groups
    Active 2- 1st year v Active 1-1st year
    Number of subjects included in analysis
    86
    Analysis specification
    Post-hoc
    Analysis type
    		 other [34]
    P-value
    		 = 0.5068
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.06
    Variability estimate
    Standard deviation
    Notes
    [34] - Difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference Difference between both active treatments was not pre-especified in the protocol but it was analysed before unblinding.
    Statistical analysis title
    		 sIgG4-Phleum pratense- 2nd year
    Statistical analysis description
    ITT population. Change from baseline after second year of treatment. Placebo group was receiving active treatment during the 2nd year. Change from baseline after first (placebo period) and second year(Active treatment) of follow-up was compaired.
    Comparison groups
    Placebo-Active 2 v Placebo- 1st year
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 = 0.8443
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.08
    Variability estimate
    Standard deviation
    Notes
    [35] - Difference in means between both periods of the placebo group was tested using a two-sided paired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference
    Statistical analysis title
    		 sIgG4-Phleum pratense- 2nd year
    Statistical analysis description
    ITT population. Change from baseline after second year of treatment.
    Comparison groups
    Active 1- 2nd year v Active 2- 2nd year
    Number of subjects included in analysis
    82
    Analysis specification
    Post-hoc
    Analysis type
    		 other [36]
    P-value
    		 = 0.4724
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.11
    Variability estimate
    Standard deviation
    Notes
    [36] - Difference in means between 2 groups was tested using a two-sided unpaired t-test. The test was performed at a significance level of 5% for the null-hypothesis of no difference Difference between both active treatments was not pre-especified in the protocol but it was analysed before unblinding.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Although IMP was administered preseasonally for 6 weeks in each period (total IMP exposure 12 weeks during the study), advese events were reported during the whole study period until last assessment visit (around 20 months from the firt treatment visit)
    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
    17.0
    Reporting groups
    Reporting group title
    Active 1- Year 1
    Reporting group description
    		 Low dose of Active IMP during the first period of assessment

    Reporting group title
    Active 2- year 1
    Reporting group description
    		 High dose of Active IMP during the first period of assessment

    Reporting group title
    Placebo - year 1
    Reporting group description
    		 -

    Reporting group title
    Active 1- Year 2
    Reporting group description
    		 low dose of active IMP during the second year of assessment

    Reporting group title
    Active 2- year 2
    Reporting group description
    		 High dose of active IMP during the second year of asssessment

    Reporting group title
    Placebo-Active 2- year 2
    Reporting group description
    		 Group initially assigned to placebo arm for the first year but switching to Active 2 (high dose of active IMP) for the second year

    Serious adverse events
    		 Active 1- Year 1 Active 2- year 1 Placebo - year 1 Active 1- Year 2 Active 2- year 2 Placebo-Active 2- year 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 37 (0.00%)
    0 / 47 (0.00%)
    0 / 51 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Urticaria
    Additional description: mild urticaria resolved spontaneouly in less than 2 days. this SAE was not related to the study drug
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 37 (0.00%)
    0 / 47 (0.00%)
    0 / 51 (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 - year 1 Active 1- Year 2 Active 2- year 2 Placebo-Active 2- year 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 42 (30.95%)
    19 / 53 (35.85%)
    15 / 53 (28.30%)
    13 / 37 (35.14%)
    20 / 47 (42.55%)
    24 / 51 (47.06%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    3 / 37 (8.11%)
    1 / 47 (2.13%)
    4 / 51 (7.84%)
         occurrences all number
    0
    1
    0
    3
    2
    6
    General disorders and administration site conditions
    Administration site pruritus
         subjects affected / exposed
    3 / 42 (7.14%)
    6 / 53 (11.32%)
    0 / 53 (0.00%)
    3 / 37 (8.11%)
    7 / 47 (14.89%)
    6 / 51 (11.76%)
         occurrences all number
    3
    7
    0
    6
    12
    16
    Administration site erythema
         subjects affected / exposed
    2 / 42 (4.76%)
    3 / 53 (5.66%)
    0 / 53 (0.00%)
    3 / 37 (8.11%)
    2 / 47 (4.26%)
    1 / 51 (1.96%)
         occurrences all number
    2
    3
    0
    5
    2
    1
    Local reaction
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    2 / 37 (5.41%)
    2 / 47 (4.26%)
    1 / 51 (1.96%)
         occurrences all number
    1
    0
    0
    3
    2
    1
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 53 (0.00%)
    2 / 53 (3.77%)
    0 / 37 (0.00%)
    0 / 47 (0.00%)
    5 / 51 (9.80%)
         occurrences all number
    0
    0
    2
    0
    0
    5
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    1 / 37 (2.70%)
    1 / 47 (2.13%)
    3 / 51 (5.88%)
         occurrences all number
    1
    1
    0
    1
    1
    3
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 53 (1.89%)
    5 / 53 (9.43%)
    0 / 37 (0.00%)
    0 / 47 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    5
    0
    0
    1
    Nasal pruritus
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 53 (0.00%)
    2 / 53 (3.77%)
    0 / 37 (0.00%)
    0 / 47 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    0
    2
    0
    0
    3
    Catarrh
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    2 / 37 (5.41%)
    3 / 47 (6.38%)
    5 / 51 (9.80%)
         occurrences all number
    1
    0
    1
    3
    3
    5
    Sneezing
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 53 (1.89%)
    2 / 53 (3.77%)
    0 / 37 (0.00%)
    0 / 47 (0.00%)
    4 / 51 (7.84%)
         occurrences all number
    0
    1
    2
    0
    0
    4
    Nasal congestion
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    0 / 37 (0.00%)
    0 / 47 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    2 / 37 (5.41%)
    1 / 47 (2.13%)
    4 / 51 (7.84%)
         occurrences all number
    5
    0
    0
    3
    1
    5
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 42 (2.38%)
    4 / 53 (7.55%)
    2 / 53 (3.77%)
    0 / 37 (0.00%)
    0 / 47 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    1
    5
    2
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jun 2015
    Increase in the number of participant sites

    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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