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    Clinical Trial Results:
    Randomised double blind placebo controlled pivotal study to evaluate efficacy and safety of rPhleum in adult and adolescent patients suffering from rhinoconjunctivitis +/- controlled asthma

    Summary
    EudraCT number
    		 2009-011504-36
    Trial protocol
    		 DE   GB   PL   FR   ES  
    Global end of trial date
    09 Aug 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    AL0906rP
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ALLERGOPHARMA GMBH & CO. KG.
    Sponsor organisation address
    Hermann-Körner-Straße 52, Reinbek, Germany, 21465
    Public contact
    Department of Clinical Trials, ALLERGOPHARMA GMBH & CO. KG., 0049 40427650,
    Scientific contact
    Department of Clinical Trials, ALLERGOPHARMA GMBH & CO. KG., 0049 40427650,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Aug 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the hypothesis that the recombinant allergen preparation rPhleum is suitable for an efficacious SCIT in grass pollen allergic patients and that the trial product is sufficient to suppress allergic symptoms caused by natural grass pollen exposure. The trial medication was tested versus placebo. The trial population consisted of patients (with or without controlled asthma) who had rhinoconjunctivitis caused by grass pollen. At the onset of the grass pollen season in the baseline year of the trial, the patients started their documentation of allergic symptoms and use of rescue medication in a patient’s diary (nature and severity of symptoms, at the same time each day). This procedure was repeated during the following 2 seasons of the double-blind treatment period. Standardised diaries in local language were used, asking for details relevant for the statistical evaluation. SCIT =Subcutaneous immunotherapy
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki (October 2000 and following amendments), Good Clinical Practices guidelines, and local legal requirements. Other than routine care, no specific measures were implemented for the protection of trial subjects. Aluminium levels in plasma and urine were measured before treatment, after up-dosing, after 1 year of treatment, at the final visit, and the follow-up visit (6 months after individual subject's last dose administration). The cumulative amount of injected aluminium was calculated for each treatment year by summing up the aluminium dose [mg]. Aluminium values in blood plasma that were above 7.5 μg/L (International System of Units (SI): 0.278 μmol/L) were considered abnormal in this trial, based on the reference values from the study’s central laboratory. The median aluminium values plasma at baseline were: 5.85 μg/L active treatment group; 6.10 μg/L placebo group. During the up-titration a steady increase in plasma level for aluminium was seen, a steady-state was reached during the maintenance period; 6 months after discontinuation of the treatment, the aluminium levels returned to nearly the values observed at baseline. The aluminium analysis in urine did not yield any further clinically relevant data.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Feb 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 95
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    Germany: 76
    Worldwide total number of subjects
    195
    EEA total number of subjects
    195
    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)
    13
    Adults (18-64 years)
    182
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited in study centers in several countries in Europe. Overall, 806 subjects were screened for eligibility; of these, 195 subjects were randomised to treatment according to the exclusion and inclusion criteria.

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

    Period 1
    Period 1 title
    Double blind phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active treatment (rPhleum)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    rPhleum
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Strength 1 (0.78 μg/mL); Strength 2 (6.25 μg/mL); Strength 3 (50 μg/mL); Strength 4 (200 μg/mL). The investigational product (rPhleum), manufactured and supplied by Allergopharma, was a mixture of recombinant major allergens of Timothy Grass Pollen (Phleum pratense) adsorbed onto aluminium-hydroxide. During the clinical trial, vials with four different concentrations were used: At the beginning of the treatment, injections had to be administered in intervals of 7 (+ 7 days). The dose was increased progressively by one step at a time only, provided that the previous dose has been well tolerated. After the maximum individually tolerated dose (= maintenance dose) had been reached, the injection intervals were prolonged to 2, and finally 4 weeks (+ 2 weeks). During the grass pollen season the maintenance dose had to be reduced to 50% of the maximum individually tolerated dose. After the end of grass pollen season the dosage had to be re-adjusted again to 100%.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo in sterile suspension containing histamine dihydrochloride in 2 different strengths for subcutaneous injection in the upper arm. The placebo-preparation used was the verum-solution without any allergen active substance.

    Number of subjects in period 1
    		Active treatment (rPhleum) Placebo
    Started
    92
    103
    Completed
    78
    95
    Not completed
    14
    8
         Consent withdrawn by subject
    4
    2
         Adverse event, non-fatal
    8
    -
         Lost to follow-up
    2
    1
         In/exclusion criteria;
    -
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active treatment (rPhleum)
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Active treatment (rPhleum) Placebo Total
    Number of subjects
    		 92 103 195
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 6 7 13
        Adults (18-64 years)
    		 86 96 182
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 29.87 ± 11.02 31.41 ± 10.09 -
    Gender categorical
    Units: Subjects
        Female
    		 32 51 83
        Male
    		 60 52 112
    Race
    Units: Subjects
        African
    		 1 1 2
        Asian
    		 1 0 1
        Caucasian
    		 89 100 189
        Other
    		 1 2 3

    End points

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    End points reporting groups
    Reporting group title
    Active treatment (rPhleum)
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: 1_Change of the AUC of the ma-RC-SS; Change from baseline

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    End point title
    		 1_Change of the AUC of the ma-RC-SS; Change from baseline
    End point description
    Change of the AUC: ma-RC-SS from baseline season to season after 1 and 2 treatment years. AUC for each patient was calculated for the 42 day evaluation period (i.e. -10 days before peak pollen count until 31 days after peak pollen count). The peak pollen count for each centre was defined (BDRM), based on the actual pollen counts for the respective year. Symptoms: • Eyes (itching, tear flow, redness) • Nose (sneezing, itching, running, blockage) • Lungs (cough, wheezing, dyspnoea) Score intensity: 0 = absent symptoms (no sign/symptom evident) 1 = mild symptoms, minimal inconvenience 2 = moderate, bothersome but tolerable symptoms 3 = severe symptoms that interfered with daily living activities Daily medication scores: assigned as in AMS Scoring Conventions for Allergopharma clinical studies AMS=Advanced Medical Services GmbH (CRO) AUC=Area under the curve BDRM=Blind Data Review Meeting ma-RC-SS=Medication-adjusted rhinoconjunctivitis symptom score
    End point type
    Primary
    End point timeframe
    Baseline to 1 and 2 years after treatment.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    78 [1]
    95 [2]
    Units: score
    median (full range (min-max))
        1st year
    -188 (-660 to 402)
    -129 (-569 to 295)
        2nd year
    -232 (-724 to 181)
    -187.5 (-656 to 273)
    Notes
    [1] - Full analysis set; Change from baseline 1st year N=77 2nd year N=77
    [2] - Full analysis set; Change from baseline 1st year N=92 2nd year N=94
    Statistical analysis title
    		 Change from baseline (after 1 year of treatment)
    Statistical analysis description
    The difference between treatment groups in the median change of the AUC. The primary endpoint was tested in a confirmatory sense for the FAS using the 2-sided Wilcoxon Mann-Whitney U-Test at a significance level of alpha = 0.05. FAS=Full analysis set The number of subjects in this analysis is N=169; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Placebo v Active treatment (rPhleum)
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2918
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Change from baseline (after 2 years of treatment)
    Statistical analysis description
    The difference between treatment groups in the median change of the AUC The primary endpoint was tested in a confirmatory sense for the FAS using the 2-sided Wilcoxon Mann-Whitney U-Test at a significance level of alpha = 0.05. The number of subjects in this analysis is N=171; the number N=173 below is due to an innate error of the EudraCT database system. FAS=Full analysis set
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1124
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: 2_Change of the AUC of the ma-RC-SS: sensitivity analysis ('worst case'); Change from baseline

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    End point title
    		 2_Change of the AUC of the ma-RC-SS: sensitivity analysis ('worst case'); Change from baseline
    End point description
    Change of the AUC: ma-RC-SS from baseline season to season after 1 and 2 treatment years: sensitivity analysis ('worst case ma-RC-SS'). For sensitivity analyses ('worst case'), the missing score values were replaced by the patient’s highest value of the defined time period (if not more than 25% of the values were missing). The actual number of patients contributing data for this evaluation is shown under the results table. AUC=Area under the curve ma-RC-SS=Medication-adjusted rhinoconjunctivitis symptom score
    End point type
    Secondary
    End point timeframe
    Baseline to 1 and 2 years after treatment.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    78 [3]
    95 [4]
    Units: score
    median (full range (min-max))
        1st year
    -188 (-660 to 402)
    -131 (-559 to 295)
        2nd year
    -230 (-724 to 181)
    -163 (-656 to 273)
    Notes
    [3] - Full analysis set; Change from baseline 1st year N=77 2nd year N=77
    [4] - Full analysis set; Change from baseline 1st year N=92 2nd year N=94
    Statistical analysis title
    		 Change from baseline (after 1 year of treatment)
    Statistical analysis description
    The difference between treatment groups in the median change of the AUC. The number of subjects in this analysis is N=169; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3378
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Change from baseline (after 2 years of treatment)
    Statistical analysis description
    The difference between treatment groups in the median change of the AUC. The number of subjects in this analysis is N=171; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1392
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: 3_Change of the AUC of the RC-SMS; Change from baseline

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    End point title
    		 3_Change of the AUC of the RC-SMS; Change from baseline
    End point description
    Change of the AUC: RC-SMS from baseline season to season after 1 and 2 treatment years. The actual number of patients contributing data for this evaluation is shown under the results table. AUC=Area under the curve RC=Rhinoconjunctivitis SMS=Symptom and medication score
    End point type
    Secondary
    End point timeframe
    Baseline to 1 and 2 years after treatment.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    78 [5]
    95 [6]
    Units: score
    median (full range (min-max))
        1st year
    -159 (-800 to 380)
    -129.5 (-717 to 325)
        2nd year
    -271 (-838 to 556)
    -215.5 (-844 to 398)
    Notes
    [5] - Full analysis set; Change from baseline 1st year N=77 2nd year N=77
    [6] - Full analysis set; Change from baseline 1st year N=92 2nd year N=94
    Statistical analysis title
    		 Change from baseline (after 1 year of treatment)
    Statistical analysis description
    The difference between treatment groups in the median change of the AUC. The number of subjects in this analysis is N=169; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Placebo v Active treatment (rPhleum)
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.1805
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [7] - Wilcoxon-Mann-Whitney-U-Test, Active vs. Placebo
    Statistical analysis title
    		 Change from baseline (after 2 years of treatment)
    Statistical analysis description
    The difference between treatment groups in the median change of the AUC. The number of subjects in this analysis is N=171; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.0723
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [8] - Wilcoxon-Mann-Whitney-U-Test, Active vs. Placebo

    Secondary: 4a_AUC of RC-symptom score; Change from baseline

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    End point title
    		 4a_AUC of RC-symptom score; Change from baseline
    End point description
    Change of the AUC:RC-symptom score from baseline season to season after 1 and 2 treatment years. The actual number of patients contributing data for this evaluation is shown under the results table. AUC=Area under the curve RC=Rhinoconjunctivitis
    End point type
    Secondary
    End point timeframe
    Baseline to 1 and 2 years after treatment.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    78 [9]
    95 [10]
    Units: score
    median (full range (min-max))
        1st year
    -131 (-499 to 231)
    -102.5 (-439 to 255)
        2nd year
    -175.5 (-534 to 429)
    -133.5 (-527 to 176)
    Notes
    [9] - Full analysis set; Change from baseline 1st year N=77 2nd year N=77
    [10] - Full analysis set; Change from baseline 1st year N=92 2nd year N=94
    Statistical analysis title
    		 Change from baseline (after 1 year of treatment)
    Statistical analysis description
    The number of subjects in this analysis is N=169; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2085
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Change from baseline (after 2 years of treatment)
    Statistical analysis description
    The number of subjects in this analysis is N=171; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0683
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: 4b_AUC of RC-medication score; Change from baseline

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    End point title
    		 4b_AUC of RC-medication score; Change from baseline
    End point description
    Change of the AUC:RC-medication score from baseline season to season after 1 and 2 treatment years. The actual number of patients contributing data for this evaluation is shown under the results table. AUC=Area under the curve RC=Rhinoconjunctivitis
    End point type
    Secondary
    End point timeframe
    Baseline to 1 and 2 years after treatment.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    78 [11]
    95 [12]
    Units: score
    median (full range (min-max))
        1st year
    -57 (-404 to 153)
    -57.3 (-291 to 230)
        2nd year
    -96.5 (-371 to 127)
    -88.5 (-384 to 300)
    Notes
    [11] - Full analysis set; Change from baseline 1st year N=77 2nd year N=77
    [12] - Full analysis set; Change from baseline 1st year N=92 2nd year N=94
    Statistical analysis title
    		 Change from baseline (after 1 year of treatment)
    Statistical analysis description
    The number of subjects in this analysis is N=169; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3539
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Change from baseline (after 2 years of treatment)
    Statistical analysis description
    The number of subjects in this analysis is N=171; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0922
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: 5a_AUC of SMS; Change from baseline

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    End point title
    		 5a_AUC of SMS; Change from baseline
    End point description
    Change of the AUC: SMS change from baseline season to season after 1 and 2 treatment years. The actual number of patients contributing data for this evaluation is shown under the results table. AUC=Area under the curve SMS=Symptom and medication score
    End point type
    Secondary
    End point timeframe
    Baseline to 1 and 2 years after treatment.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    78 [13]
    95 [14]
    Units: score
    median (full range (min-max))
        1st year
    -165 (-832 to 381)
    -125.8 (-931 to 325)
        2nd year
    -274 (-904 to 649)
    -229 (-956 to 458)
    Notes
    [13] - Full analysis set; Change from baseline 1st year N=77 2nd year N=77
    [14] - Full analysis set; Change from baseline 1st year N=92 2nd year N=94
    Statistical analysis title
    		 Change from baseline (after 1 year of treatment)
    Statistical analysis description
    The number of subjects in this analysis is N=169; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2107
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Change from baseline (after 2 years of treatment)
    Statistical analysis description
    The number of subjects in this analysis is N=171; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1421
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: 5b_AUC of symptom score; Change from baseline

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    End point title
    		 5b_AUC of symptom score; Change from baseline
    End point description
    Change of the AUC: symptom score (SS) from baseline season to season after 1 and 2 treatment years. The actual number of patients contributing data for this evaluation is shown under the results table. AUC=Area under the curve SS=Symptom score
    End point type
    Secondary
    End point timeframe
    Baseline to 1 and 2 years after treatment.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    78 [15]
    95 [16]
    Units: score
    median (full range (min-max))
        1st year
    -141 (-566 to 260)
    -122 (-612 to 361)
        2nd year
    -176.5 (-572 to 522)
    -136.5 (-636 to 285)
    Notes
    [15] - Full analysis set; Change from baseline 1st year N=77 2nd year N=77
    [16] - Full analysis set; Change from baseline 1st year N=92 2nd year N=94
    Statistical analysis title
    		 Change from baseline (after 1 year of treatment)
    Statistical analysis description
    The number of subjects in this analysis is N=169; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2401
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Change from baseline (after 2 years of treatment)
    Statistical analysis description
    The number of subjects in this analysis is N=171; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1148
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: 5c_AUC of medication score; Change from baseline

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    End point title
    		 5c_AUC of medication score; Change from baseline
    End point description
    Change of the AUC: medication score from baseline season to season after 1 and 2 treatment years. The actual number of patients contributing data for this evaluation is shown under the results table. AUC=Area under the curve
    End point type
    Secondary
    End point timeframe
    Baseline to 1 and 2 years after treatment.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    78 [17]
    95 [18]
    Units: score
    median (full range (min-max))
        1st year
    -56.5 (-404 to 205)
    -53.3 (-319 to 230)
        2nd year
    -99.5 (-371 to 210)
    -88.5 (-384 to 304)
    Notes
    [17] - Full analysis set; Change from baseline 1st year N=77 2nd year N=77
    [18] - Full analysis set; Change from baseline 1st year N=92 2nd year N=94
    Statistical analysis title
    		 Change from baseline (after 1 year of treatment)
    Statistical analysis description
    The number of subjects in this analysis is N=169; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4854
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Change from baseline (after 2 years of treatment)
    Statistical analysis description
    The number of subjects in this analysis is N=171; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.156
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: 6_Immunological profile: IgG (specific total) and IgG4 to Phleum pratense; Change from baseline

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    End point title
    		 6_Immunological profile: IgG (specific total) and IgG4 to Phleum pratense; Change from baseline
    End point description
    At screening visit as well as at final visit of the double blind phase, the following immunological assessments were performed: specific total IgG to Phleum pratense and specific IgG4 to Phleum pratense. The actual number of patients contributing data for this evaluation is shown under the results table.
    End point type
    Secondary
    End point timeframe
    Baseline to 2 years after treatment.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    78 [19]
    95 [20]
    Units: mg/L
    median (full range (min-max))
        IgG
    38.1 (-2 to 171)
    -0.4 (-8 to 6)
        IgG4
    29.4 (0 to 30)
    0 (-3 to 2)
    Notes
    [19] - Full analysis set; Change from baseline IgG (total specific) N=71 IgG4 N=71
    [20] - Full analysis set; Change from baseline IgG (total specific) N=82 IgG4 N=82
    Statistical analysis title
    		 Change from baseline (2 years of treatment) IgG
    Statistical analysis description
    Change from baseline (after 2 years of treatment) IgG (specific, total). The number of subjects in this analysis is N=152; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 Change from baseline (2 years of treatment); IgG4
    Statistical analysis description
    Change from baseline (after 2 year of treatment) IgG4 The number of subjects in this analysis is N=153; the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: 7_Number of RC well days overall; Change from baseline

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    End point title
    		 7_Number of RC well days overall; Change from baseline
    End point description
    The number of RC 'well days' within the 42 day evaluation period, defined as the number of days with RC symptom score ≤ 2 and RC medication score = 0 (as summarized for the endpoint 1). Change from baseline. The actual number of patients contributing data for this evaluation is shown under the results table. RC=Rhinoconjunctivitis
    End point type
    Secondary
    End point timeframe
    Baseline to 2 years after treatment.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    70 [21]
    85 [22]
    Units: day
        median (full range (min-max))
    4 (-7 to 42)
    5 (-23 to 39)
    Notes
    [21] - Full analysis set; Change from baseline
    [22] - Full analysis set; Change from baseline
    Statistical analysis title
    		 Change from baseline (after 2 years of treatment)
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2831
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: 8_Responder analysis overall

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    End point title
    		 8_Responder analysis overall
    End point description
    Patient’s response to the trial medication was defined as an at least 40% decrease of the AUC of ma-RC-SS from baseline to end of each treatment year. Shown are patients who were responders by treatment year. The number of subjects 'Missing' for a particular evaluation time point are shown under the results table. ma-RC-SS=Medication-adjusted rhinoconjunctivitis symptom score
    End point type
    Secondary
    End point timeframe
    Baseline to 1 and 2 years after treatment.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    78 [23]
    95 [24]
    Units: subject
        Responders after 1st year
    33
    40
        Responders after 2nd year
    43
    46
    Notes
    [23] - Missing N=1 N=1 Non responders N=44 N=34
    [24] - Missing N=3 N=1 Non responders N=52 N=48
    Statistical analysis title
    		 Change from baseline (after 1 year of treatment)
    Statistical analysis description
    The number of subjects in this analysis is N=73 (responders with at least 40% decrease of AUC of ma-RC-SS from baseline); the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Change from baseline (after 2 years of treatment)
    Statistical analysis description
    The number of subjects in this analysis is N=89 (responders with at least 40% decrease of AUC of ma-RC-SS from baseline); the number N=173 below is due to an innate error of the EudraCT database system.
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.442
    Method
    		 Fisher exact
    Confidence interval

    Secondary: 9_Conjunctival provocation test

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    End point title
    		 9_Conjunctival provocation test
    End point description
    Conjunctival provocation test CPT reproduces the events occurring by instilling an allergen on the ocular surface. A lyophilised 6 grass pollen allergen cocktail with a standardised activity to be reconstituted and diluted for the provocation test was supplied by Allergopharma. At the performance of the first test the initial concentration was 5 SBU/ml. After having applied the initial concentration a titration with increasing concentrations was done until a positive test result was achieved. The highest possible concentration was 5000 SBU/ml. CPT=Conjunctival provocation test
    End point type
    Secondary
    End point timeframe
    Baseline to 2 years after treatment.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    78 [25]
    95 [26]
    Units: subject
        Missing
    8
    6
        Unchanged
    14
    37
        Partly improved
    9
    12
        Improved
    47
    40
    Notes
    [25] - Full analysis set; Change from baseline
    [26] - Full analysis set; Change from baseline
    Statistical analysis title
    		 Change from baseline (after 2 years of treatment)
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0025 [27]
    Method
    		 Mantel-Haenszel
    Confidence interval
    Notes
    [27] - The difference in improvement in conjunctival provocation test results between the active treatment group and placebo group was statistically significant.

    Secondary: 10_European Quality of Life Questionnaire (EQ-5D) score; Change from baseline

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    End point title
    		 10_European Quality of Life Questionnaire (EQ-5D) score; Change from baseline
    End point description
    European Quality of Life Questionnaire (EQ-5D) score; Change from baseline . The scores from the EQ-5D were used with the patient’s time from first treatment to end of trial as a measure of disease burden. The EQ-5D score was derived from the answers to the five questions using the utility (value set) of the UK population. Questions for EQ-5D were: Mobility, Self-care, Usual activity, Pain/discomfort, Anxiety/Depression The score scale was from 1 to 3 (For full health i.e. health state 11111, the EQ-5D score was 1). The actual number of patients contributing data for this evaluation is shown within the results table.
    End point type
    Secondary
    End point timeframe
    Start of treatment (Baseline) to the end of the trial.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    72 [28]
    85 [29]
    Units: score
        median (full range (min-max))
    0.00 (-0.3 to 0.2)
    0.00 (-0.3 to 0.3)
    Notes
    [28] - Full analysis set
    [29] - Full analysis set
    Statistical analysis title
    		 Change from baseline to end of treatment
    Comparison groups
    Placebo v Active treatment (rPhleum)
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.507 [30]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [30] - The median overall EQ-5D scores did not change from baseline to final visit and at each time point the median score value was 1, reflecting full health in both treatment groups.

    Secondary: 11_European Quality of Life Questionnaire (EQ-5D) score/QALY; Change from baseline

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    End point title
    		 11_European Quality of Life Questionnaire (EQ-5D) score/QALY; Change from baseline
    End point description
    European Quality of Life Questionnaire (EQ-5D) score/QALY; Change from baseline. The scores from the EQ-5D were used with the patient’s time from first treatment to end of trial in years to calculate QALYs as a measure of disease burden. QALY was derived by multiplying the EQ-5D score with the patient’s time from first treatment to end of trial in years: QALY = EQ-5D Score * (Date of last patient’s visit – Date of patient’s first treatment + 1)/365. The actual number of patients contributing data for this evaluation is shown within the results table. EQ-5D=European Quality of Life Questionnaire QALY=Quality Adjusted Life Year
    End point type
    Secondary
    End point timeframe
    Start of treatment (Baseline) to the end of trial.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    74 [31]
    86 [32]
    Units: score
        median (full range (min-max))
    1.65 (0.4 to 1.7)
    1.65 (0.3 to 1.7)
    Notes
    [31] - Full analysis set
    [32] - Full analysis set
    Statistical analysis title
    		 Change from baseline to end of treatment
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8791 [33]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [33] - The median value for quality adjusted life years (QALYs) was 1.65 in both treatment groups indicating no difference between groups in disease burden.

    Secondary: 12_European Quality of Life Questionnaire (EQ-5D): General Health; Visual Analogue Scale (VAS); Change from baseline

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    End point title
    		 12_European Quality of Life Questionnaire (EQ-5D): General Health; Visual Analogue Scale (VAS); Change from baseline
    End point description
    European Quality of Life Questionnaire (EQ-5D): General Health; Visual Analogue Scale (VAS); Change from baseline. Patients were asked to assess their general health status by marking on a VAS from 0 (worst) to 100 (best) to rate their general health at baseline and at final visit. The actual number of patients contributing data for this evaluation is shown within the results table. EQ-5D=European Quality of Life Questionnaire VAS=Visual Analogue Scale
    End point type
    Secondary
    End point timeframe
    Start of treatment (Baseline) to the end of the trial.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    72 [34]
    84 [35]
    Units: score
        median (full range (min-max))
    0 (-35 to 25)
    0 (-30 to 45)
    Notes
    [34] - Full analysis set
    [35] - Full analysis set
    Statistical analysis title
    		 Change from baseline to end of treatment
    Comparison groups
    Active treatment (rPhleum) v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3924 [36]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [36] - The median score was 90 in both treatment groups and at both time points indicating an assessment of good health in both groups and at both time points.

    Secondary: 13a_Vital signs: Systolic blood pressure

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    End point title
    		 13a_Vital signs: Systolic blood pressure
    End point description
    Vital signs: Systolic blood pressure Change from baseline visit to the last visit of double-blind phase and end of entire trial were evaluated to obtain further data for the safety evaluation. The actual number of patients contributing data for this evaluation is shown under the results table.
    End point type
    Secondary
    End point timeframe
    Baseline to the end of 2nd year of treatment (end of the double-blind treatment phase) and to the end of the follow-up phase.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    90 [37]
    102 [38]
    Units: mmHg
    median (full range (min-max))
        End of 2nd year of treatment
    0 (-20 to 30)
    0 (-40 to 45)
        End of 6 month (follow-up)
    0 (-30 to 28)
    0 (-42 to 30)
    Notes
    [37] - Safety set End of 2nd year of treatment N=69 Follow-up N=57
    [38] - Safety set End of 2nd year of treatment N=80 Follow-up N=64
    No statistical analyses for this end point

    Secondary: 13b_Vital signs: Diastolic blood pressure

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    End point title
    		 13b_Vital signs: Diastolic blood pressure
    End point description
    Vital signs: Diastolic blood pressure Change from baseline visit to the last visit of double-blind phase and end of entire trial were evaluated to obtain further data for the safety evaluation. The actual number of patients contributing data for this evaluation is shown under the results table.
    End point type
    Secondary
    End point timeframe
    Baseline to the end of 2nd year of treatment (end of the double-blind treatment phase) and to the end of the follow-up phase.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    90 [39]
    102 [40]
    Units: mmHg
    median (full range (min-max))
        End of 2nd year of treatment
    0 (-18 to 18)
    0 (-20 to 30)
        End of 6 month (follow-up
    0 (-19 to 20)
    0 (-30 to 20)
    Notes
    [39] - Safety set End of 2nd year of treatment N=69 Follow-up N=57
    [40] - Safety set End of 2nd year of treatment N=80 Follow-up N=64
    No statistical analyses for this end point

    Secondary: 13c_Vital signs: Heart rate

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    End point title
    		 13c_Vital signs: Heart rate
    End point description
    Vital signs: Heart rate Change from baseline visit to the last visit of double-blind phase and end of entire trial were evaluated to obtain further data for the safety evaluation. The actual number of patients contributing data for this evaluation is shown under the results table. bmp=Beats per min
    End point type
    Secondary
    End point timeframe
    Baseline to the end of 2nd year of treatment (end of the double-blind treatment phase) and to the end of the follow-up phase.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    90 [41]
    102 [42]
    Units: bmp
    median (full range (min-max))
        End of 2nd year of treatment
    1 (-23 to 25)
    2 (-38 to 34)
        End of 6 month (follow-up)
    0 (-29 to 45)
    0 (-38 to 22)
    Notes
    [41] - Safety set End of 2nd year of treatment N=69 Follow-up N=57
    [42] - Safety set End of 2nd year of treatment N=80 Follow-up N=64
    No statistical analyses for this end point

    Secondary: 13d_Vital signs: Respiratory rate

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    End point title
    		 13d_Vital signs: Respiratory rate
    End point description
    Changes in vital signs: Respiratory rate Change from baseline visit to the last visit of double-blind phase and end of entire trial were evaluated to obtain further data for the safety evaluation. The actual number of patients contributing data for this evaluation is shown under the results table.
    End point type
    Secondary
    End point timeframe
    Baseline to the end of 2nd year of treatment (end of the double-blind treatment phase) and to the end of the follow-up phase.
    End point values
    		 Active treatment (rPhleum) Placebo
    Number of subjects analysed
    90 [43]
    102 [44]
    Units: breaths per min
    median (full range (min-max))
        End of 2nd year of treatment
    0 (-12 to 4)
    0 (-8 to 8)
        End of 6 month (follow-up
    0 (-12 to 6)
    0 (-6 to 7)
    Notes
    [43] - Safety set End of 2nd year of treatment N=68 Follow-up N=56
    [44] - Safety set End of 2nd year of treatment N=78 Follow-up N=62
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 3 years from the start of the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Active treatment (rPhleum)
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Active treatment (rPhleum) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 90 (10.00%)
    6 / 102 (5.88%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Endoscopy upper gastrointestinal tract
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon neoplasm
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Electric shock
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal abscess
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Active treatment (rPhleum) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 90 (75.56%)
    75 / 102 (73.53%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 90 (8.89%)
    10 / 102 (9.80%)
         occurrences all number
    10
    18
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    8 / 90 (8.89%)
    5 / 102 (4.90%)
         occurrences all number
    25
    28
    Injection site oedema
         subjects affected / exposed
    10 / 90 (11.11%)
    5 / 102 (4.90%)
         occurrences all number
    22
    8
    Injection site pain
         subjects affected / exposed
    5 / 90 (5.56%)
    13 / 102 (12.75%)
         occurrences all number
    7
    23
    Injection site pruritus
         subjects affected / exposed
    10 / 90 (11.11%)
    4 / 102 (3.92%)
         occurrences all number
    18
    4
    Injection site swelling
         subjects affected / exposed
    17 / 90 (18.89%)
    13 / 102 (12.75%)
         occurrences all number
    49
    20
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    4 / 90 (4.44%)
    6 / 102 (5.88%)
         occurrences all number
    5
    7
    Cough
         subjects affected / exposed
    6 / 90 (6.67%)
    2 / 102 (1.96%)
         occurrences all number
    7
    2
    Dyspnoea
         subjects affected / exposed
    8 / 90 (8.89%)
    1 / 102 (0.98%)
         occurrences all number
    9
    1
    Oropharyngeal pain
         subjects affected / exposed
    3 / 90 (3.33%)
    9 / 102 (8.82%)
         occurrences all number
    5
    14
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    9 / 90 (10.00%)
    1 / 102 (0.98%)
         occurrences all number
    10
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 90 (3.33%)
    6 / 102 (5.88%)
         occurrences all number
    4
    7
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 90 (5.56%)
    11 / 102 (10.78%)
         occurrences all number
    7
    11
    Nasopharyngitis
         subjects affected / exposed
    23 / 90 (25.56%)
    36 / 102 (35.29%)
         occurrences all number
    36
    62
    Pharyngitis
         subjects affected / exposed
    2 / 90 (2.22%)
    8 / 102 (7.84%)
         occurrences all number
    2
    9
    Sinusitis
         subjects affected / exposed
    0 / 90 (0.00%)
    6 / 102 (5.88%)
         occurrences all number
    0
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Aug 2012
    • Altered the primary endpoint to change of the area under the curve (AUC) of the medication-adjusted Rhinoconjunctivitis Symptom Score (ma-RC-SS) from the baseline season to the season after 2 years of treatment. The former primary endpoint (change of AUC of the Rhinoconjunctivitis Symptom-Medication-Score [RC-SMS] after 2 years) became an additional secondary endpoint. • Added additional safety laboratory assessments for aluminium, at the final visit of the treatment phase as well as 6 months after the last individual application of trial medication. • Specified parameters: IgE and IgG. • Added as secondary endpoints: changes of rhinoconjunctivitis symptom score, rhinoconjunctivitis medication score, symptom score and medication score after 1, 2, and 3 years. • Added as a secondary endpoint: change of AUC of the medication-adjusted Rhinoconjunctivitis Symptom Score (ma-RC-SS) after 1 and 3 years.

    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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