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    Clinical Trial Results:
    Double-blind phase IV multicentre clinical trial to evaluate and compare specific and non specific effects of SCIT by use of an Environmental Challenge Chamber after treatment with Allergovit® grasses or Allergovit® birch in patients with grass and birch pollen allergy

    Summary
    EudraCT number
    		 2013-003095-12
    Trial protocol
    		 DE  
    Global end of trial date
    26 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Mar 2017
    First version publication date
    31 Mar 2017
    Other versions
    Summary report(s)
    		 AL1303AV_Lay Summary_final English
    AL1303AV_Lay Summary_final German

    Trial information

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    Trial identification
    Sponsor protocol code
    AL1303AV
    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
    Allergopharma GmbH & Co. KG, Allergopharma GmbH & Co. KG, 0049 40727650000,
    Scientific contact
    Allergopharma GmbH & Co. KG, Allergopharma GmbH & Co. KG, 0049 40727650000,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate a specific treatment effect of ALLERGOVIT® grasses and ALLERGOVIT® birch and to assess the superiority of their specific effects compared with their unspecific effects. The treatment groups received either ALLERGOVIT® grasses or ALLERGOVIT® birch, which mutually served as non-active comparator.
    Protection of trial subjects
    The study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practices guidelines, and local law requirements. Other than routine care, no specific measures for protection of trial subjects were implemented.
    Background therapy
    		 -
    Evidence for comparator
    		 The treatment groups received either ALLERGOVIT® grasses or ALLERGOVIT® birch, which mutually served as non-active comparator. In this trial, dual allergen sensitivity (birch as well as grass pollen) were treated with either the one or the other allergen. Each allergen treatment was acting as placebo for the other by evaluating the symptoms in the ECC after exposure to either of the allergens. ECC=Environmental Challenge Chamber
    Actual start date of recruitment
    03 Apr 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
    Germany: 95
    Worldwide total number of subjects
    95
    EEA total number of subjects
    95
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    93
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 For each of the 269 patients screened, the trial started with a Screening Visit and a telephone contact. The telephone contact (one week before pre-treatment ECC visits and before randomization) was done to confirm patient eligibility (laboratory report, new diseases or any concomitant medication changes). ECC=Environmental Challenge Chamber

    Pre-assignment
    Screening details
    		 At screening Visit (S1), a skin prick test (SPT), immunological profile assessment, and a lung function test (peak expiratory flow [PEF]) was performed. Relevant symptoms (adj. area under the curve (AUC) of Total Nasal Symptom Score (TNSS) of at least 10) documented during the pre-treatment exposure with birch or grass pollen allergens in the ECC.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    No placebo or other active comparator solution was used as comparator in this trial. The treatment groups received either ALLERGOVIT® grasses or ALLERGOVIT® birch, which mutually served as a comparator. Both active preparations used were identical in their outer appearance to ensure blinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ALLERGOVIT® grasses
    Arm description
    		 For each patient, the trial started with a screening Visit (S1, optional S2), a telephone contact, followed by a baseline period of at least 5 days. During this period, the baseline data for the calculation of the Primary Endpoint was surveyed in 2 ECC visits (pre-treatment ECC) with an interval of at least 5 days (ECCpre Birch and ECCpre Grass visits). Patients were randomized according to a 1:1 allocation sequence to receive either ALLERGOVIT® grasses or ALLERGOVIT® birch during the treatment period with up to 13 injections over 36 to 44 weeks. After the treatment period, all treated patients performed 2 distinct post-treatment ECC visits (ECCpost Birch and ECCpost Grass), again with an interval of at least 5 days. At least 5 days after the last post-treatment ECC visit, the final visit was scheduled.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALLERGOVIT® grasses
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ALLERGOVIT® grasses: 100% aluminium adsorbed allergoid preparation of pollen from Phleum pratense, Lolium perenne, Festuca pratensis, Holcus lanatus, Dactylis glomerata, and Poa pratensis at 1,000 and 10,000 TU/mL for subcut inject, in the upper arm by the investigator during the treatment visits. Dosing:2 phases: dose escalation (uptitration), maintenance. Dose escalation phase: injections with strength 1,000 TU/mL, using the dose steps: 0.1 mL, 0.2 mL, 0.4 mL and 0.8 mL, followed by injections with strength 10,000 TU/mL, using the dose steps: 0.15 mL, 0.3 mL, and 0.6 mL. At the beginning of the dose escalation phase, injections were admin at intervals of 7 d. Modifications to the dose escalation scheme were allowed when AEs occurred. Dose was increased progressively by 1 step, when that the previous dose was tolerated well. Maintenance phase: when max individually tolerated dose was reached, it was administered again after 2 wks, then after 4 wks, later after 6 to 8 wks.

    Arm title
    		 ALLERGOVIT® birch
    Arm description
    		 For each patient, the trial started with a screening Visit (S1, optional S2), a telephone contact, followed by a baseline period of at least 5 days. During this period, the baseline data for the calculation of the Primary Endpoint was surveyed in 2 ECC visits (pre-treatment ECC) with an interval of at least 5 days (ECCpre Birch and ECCpre Grass visits). Patients were randomized according to a 1:1 allocation sequence to receive either ALLERGOVIT® grasses or ALLERGOVIT® birch during the treatment period with up to 13 injections over 36 to 44 weeks. After the treatment period, all treated patients performed 2 distinct post-treatment ECC visits (ECCpost Birch and ECCpost Grass), again with an interval of at least 5 days. At least 5 days after the last post-treatment ECC visit, the final visit was scheduled.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALLERGOVIT® birch
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    ALLERGOVIT® birch: 100% aluminium adsorbed allergoid preparation - pollen from birch (Betula verrucosa) at 1 000 and 10 000 TU/mL for subcut. injection, admin. in the upper arm by the investigator during the treatment visits. Dosing:2 phases: dose escalation (uptitration), maintenance. Dose escalation phase: injections with strength 1,000 TU/mL, using the dose steps: 0.1 mL, 0.2 mL, 0.4 mL and 0.8 mL, followed by injections with strength 10,000 TU/mL, using the dose steps: 0.15 mL, 0.3 mL, and 0.6 mL. At the beginning of the dose escalation phase, injections were admin at intervals of 7 d. Modifications to the dose escalation scheme were allowed when AEs occurred. Dose was increased progressively by 1 step, when that the previous dose was tolerated well. Maintenance phase: when max individually tolerated dose was reached, it was administered again after 2 wks, then after 4 wks, later after 6 to 8 wks.

    Number of subjects in period 1
    		ALLERGOVIT® grasses ALLERGOVIT® birch
    Started
    47
    48
    Completed
    42
    45
    Not completed
    5
    3
         Consent withdrawn by subject
    2
    -
         Adverse event, non-fatal
    1
    1
         Pregnancy
    1
    2
         Other, not further specified
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ALLERGOVIT® grasses
    Reporting group description
    		 For each patient, the trial started with a screening Visit (S1, optional S2), a telephone contact, followed by a baseline period of at least 5 days. During this period, the baseline data for the calculation of the Primary Endpoint was surveyed in 2 ECC visits (pre-treatment ECC) with an interval of at least 5 days (ECCpre Birch and ECCpre Grass visits). Patients were randomized according to a 1:1 allocation sequence to receive either ALLERGOVIT® grasses or ALLERGOVIT® birch during the treatment period with up to 13 injections over 36 to 44 weeks. After the treatment period, all treated patients performed 2 distinct post-treatment ECC visits (ECCpost Birch and ECCpost Grass), again with an interval of at least 5 days. At least 5 days after the last post-treatment ECC visit, the final visit was scheduled.

    Reporting group title
    ALLERGOVIT® birch
    Reporting group description
    		 For each patient, the trial started with a screening Visit (S1, optional S2), a telephone contact, followed by a baseline period of at least 5 days. During this period, the baseline data for the calculation of the Primary Endpoint was surveyed in 2 ECC visits (pre-treatment ECC) with an interval of at least 5 days (ECCpre Birch and ECCpre Grass visits). Patients were randomized according to a 1:1 allocation sequence to receive either ALLERGOVIT® grasses or ALLERGOVIT® birch during the treatment period with up to 13 injections over 36 to 44 weeks. After the treatment period, all treated patients performed 2 distinct post-treatment ECC visits (ECCpost Birch and ECCpost Grass), again with an interval of at least 5 days. At least 5 days after the last post-treatment ECC visit, the final visit was scheduled.

    Reporting group values
    		 ALLERGOVIT® grasses ALLERGOVIT® birch Total
    Number of subjects
    		 47 48 95
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 47 46 93
        From 65-84 years
    		 0 2 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.2 ± 9.8 33 ± 11.2 -
    Gender categorical
    Units: Subjects
        Female
    		 25 28 53
        Male
    		 22 20 42
    Race
    Units: Subjects
        Asian
    		 3 1 4
        White
    		 42 45 87
        Other
    		 2 2 4

    End points

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    End points reporting groups
    Reporting group title
    ALLERGOVIT® grasses
    Reporting group description
    		 For each patient, the trial started with a screening Visit (S1, optional S2), a telephone contact, followed by a baseline period of at least 5 days. During this period, the baseline data for the calculation of the Primary Endpoint was surveyed in 2 ECC visits (pre-treatment ECC) with an interval of at least 5 days (ECCpre Birch and ECCpre Grass visits). Patients were randomized according to a 1:1 allocation sequence to receive either ALLERGOVIT® grasses or ALLERGOVIT® birch during the treatment period with up to 13 injections over 36 to 44 weeks. After the treatment period, all treated patients performed 2 distinct post-treatment ECC visits (ECCpost Birch and ECCpost Grass), again with an interval of at least 5 days. At least 5 days after the last post-treatment ECC visit, the final visit was scheduled.

    Reporting group title
    ALLERGOVIT® birch
    Reporting group description
    		 For each patient, the trial started with a screening Visit (S1, optional S2), a telephone contact, followed by a baseline period of at least 5 days. During this period, the baseline data for the calculation of the Primary Endpoint was surveyed in 2 ECC visits (pre-treatment ECC) with an interval of at least 5 days (ECCpre Birch and ECCpre Grass visits). Patients were randomized according to a 1:1 allocation sequence to receive either ALLERGOVIT® grasses or ALLERGOVIT® birch during the treatment period with up to 13 injections over 36 to 44 weeks. After the treatment period, all treated patients performed 2 distinct post-treatment ECC visits (ECCpost Birch and ECCpost Grass), again with an interval of at least 5 days. At least 5 days after the last post-treatment ECC visit, the final visit was scheduled.

    Subject analysis set title
    ALLERGOVIT® grasses (pre grass)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were in the Full analysis set and received a challenge with ALLERGOVIT® grasses. Full analysis set: according to the Intention-to-Treat (ITT) principle: all patients who received at least one dose of trial medication during the course of the trial and for whom an efficacy assessment after baseline was available.

    Subject analysis set title
    ALLERGOVIT® birch (pre birch)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were in the Full analysis set and received a challenge with ALLERGOVIT® birch. Full analysis set: according to the Intention-to-Treat (ITT) principle: all patients who received at least one dose of trial medication during the course of the trial and for whom an efficacy assessment after baseline was available.

    Subject analysis set title
    ALLERGOVIT® birch (post birch)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects who were in the Full analysis set and received a challenge with ALLERGOVIT® birch. Full analysis set: according to the Intention-to-Treat (ITT) principle: all patients who received at least one dose of trial medication during the course of the trial and for whom an efficacy assessment after baseline was available.

    Subject analysis set title
    ALLERGOVIT® grasses (post grass)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were in the Full analysis set and received a challenge with ALLERGOVIT® grasses. Full analysis set: according to the Intention-to-Treat (ITT) principle: all patients who received at least one dose of trial medication during the course of the trial and for whom an efficacy assessment after baseline was available.

    Subject analysis set title
    Combined specific treatment effect
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Combined specific treatment effect on all subjects in the full analysis set (both treatments).

    Subject analysis set title
    Combined unspecific treatment effect
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Combined unspecific treatment effect on all subjects in the full analysis set (both treatments).

    Subject analysis set title
    ALLERGOVIT® grasses treated patients; ECCpre birch
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients treated with ALLERGOVIT® grasses and who were exposed to birch pollen in the ECC (pre birch).

    Subject analysis set title
    ALLERGOVIT® grasses treated patients; ECCpost birch
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients treated with ALLERGOVIT® grasses and who were exposed to birch pollen in the ECC (post birch).

    Subject analysis set title
    ALLERGOVIT® birch treated patients; ECCpre grasses
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients treated with ALLERGOVIT® birch and who were exposed to grass pollen in the ECC (pre grasses).

    Subject analysis set title
    ALLERGOVIT® birch treated patients; ECCpost grasses
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients treated with ALLERGOVIT® birch and who were exposed to grass pollen in the ECC (post grasses).

    Subject analysis set title
    Specific treatment effect of ALLERGOVIT® grasses
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Specific treatment effect of ALLERGOVIT® grasses

    Subject analysis set title
    Unspecific treatment effect of ALLERGOVIT® grasses
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Unspecific treatment effect of ALLERGOVIT® grasses.

    Subject analysis set title
    Specific treatment effect of ALLERGOVIT® birch
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Specific treatment effect of ALLERGOVIT® birch

    Subject analysis set title
    Unspecific treatment effect of ALLERGOVIT® birch
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Unspecific treatment effect of ALLERGOVIT® birch.

    Subject analysis set title
    Birch pollen season: ALLERGOVIT® grasses
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients treated with ALLERGOVIT® grasses, self-assessed during the birch pollen season.

    Subject analysis set title
    Grass pollen season: ALLERGOVIT® grasses
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients treated with ALLERGOVIT® grasses, self-assessed during the grass pollen season.

    Subject analysis set title
    Birch pollen season: ALLERGOVIT® birch
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients treated with ALLERGOVIT® birch, self-assessed during the birch pollen season.

    Subject analysis set title
    Grass pollen season: ALLERGOVIT® birch
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients treated with ALLERGOVIT® birch, self-assessed during the grass pollen season.

    Primary: 1a_Specific treatment effect on TNSS; adjusted AUC: ALLERGOVIT® grasses

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    End point title
    		 1a_Specific treatment effect on TNSS; adjusted AUC: ALLERGOVIT® grasses
    End point description
    Specific treatment effect of ALLERGOVIT® grasses defined as change of the adjusted AUC of TNSS, as measured during an exposure to grass pollen in the ECC between baseline (ECCpre) and after end of treatment (ECCpost), for patients treated with ALLERGOVIT® grasses (ECCpost grass minus ECCpre grass). TNSS is the sum of scores, taken for the following symptoms: nasal congestion, rhinorrhea, nasal itching, and sneezing at each time point. Results are based on a 4-point scale score (0 to 3): 0=no symptoms; 1=mild symptoms that were easily tolerated; 2=awareness of symptoms, which were bothersome but tolerable; 3=severe symptoms that were hard to tolerate and interfered with daily activity. AUC=Area under the curve ECC=Environmental challenge chamber TNSS=Total nasal symptom score
    End point type
    Primary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® grasses (pre grass) ALLERGOVIT® grasses (post grass)
    Number of subjects analysed
    46 [1]
    40 [2]
    Units: score
        arithmetic mean (standard deviation)
    34.8 ± 11.98
    20.28 ± 12.76
    Notes
    [1] - Full analysis set
    [2] - Full analysis set
    Statistical analysis title
    		 ECCpost grass - ECCpre grass
    Statistical analysis description
    Comparison refers to the adjusted AUC of TNSS for subjects challenged with grass pollen and represents the change between ECCpost grass (end of treatment) - ECCpre grass (baseline). The value for 'Subjects in this analysis' shown below is not correct and is due to a validation error of the EudraCT database system. The correct value for 'Subjects in this analysis' is 40.
    Comparison groups
    ALLERGOVIT® grasses (pre grass) v ALLERGOVIT® grasses (post grass)
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -13.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -17.56
         upper limit
    		 -9.54
    Notes
    [3] - Test for a specific treatment effect of ALLERGOVIT® grasses. Repeated measurement model to test the specific treatment effect in the ALLERGOVIT® grasses group, between the ECCpost - ECCpre visits. Values refer to the adjusted AUC of TNSS.

    Primary: 1b_Specific treatment effect on TNSS; adjusted AUC: ALLERGOVIT® birch

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    End point title
    		 1b_Specific treatment effect on TNSS; adjusted AUC: ALLERGOVIT® birch
    End point description
    Specific treatment effect of ALLERGOVIT® birch defined as change of the adjusted AUC of TNSS, as measured during an exposure to birch pollen in the ECC between baseline (ECCpre) and after end of treatment (ECCpost), for patients treated with ALLERGOVIT® birch (ECCpost birch minus ECCpre birch). TNSS is the sum of scores, taken for the following symptoms: nasal congestion, rhinorrhea, nasal itching, and sneezing at each time point. Results are based on a 4-point scale score (0 to 3): 0=no symptoms; 1=mild symptoms that were easily tolerated; 2=awareness of symptoms, which were bothersome but tolerable; 3=severe symptoms that were hard to tolerate and interfered with daily activity. AUC=Area under the curve ECC=Environmental challenge chamber TNSS=Total nasal symptom score
    End point type
    Primary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® birch (pre birch) ALLERGOVIT® birch (post birch)
    Number of subjects analysed
    48 [4]
    43 [5]
    Units: score
        arithmetic mean (standard deviation)
    23.31 ± 11.45
    14.35 ± 10.6
    Notes
    [4] - Full analysis set
    [5] - Full analysis set
    Statistical analysis title
    		 ECCpost birch - ECCpre birch
    Statistical analysis description
    Comparison refers to the adjusted AUC of TNSS for subjects challenged with birch pollen and represents the change between ECCpost birch (end of treatment) - ECCpre birch (baseline). The value for 'Subjects in this analysis' shown below is not correct and is due to a validation error of the EudraCT database system. The correct value for 'Subjects in this analysis' is 43.
    Comparison groups
    ALLERGOVIT® birch (pre birch) v ALLERGOVIT® birch (post birch)
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.0001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -9.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.13
         upper limit
    		 -5.5
    Notes
    [6] - Test for a specific treatment effect of ALLERGOVIT® birch. Repeated measurement model to test the specific treatment effect in the ALLERGOVIT® birch group, between the ECCpost - ECCpre visits. Values refer to the adjusted AUC of TNSS.

    Secondary: 2_Specific treatment effect of SCIT compared with unspecific treatment effect of SCIT for both treatments

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    End point title
    		 2_Specific treatment effect of SCIT compared with unspecific treatment effect of SCIT for both treatments
    End point description
    Specific treatment effect of SCIT compared with the unspecific treatment effect of SCIT for both treatments on TNSS; adjusted AUC: [end of treatment - pre treatment (baseline)] Specific treatment effect of SCIT compared with the unspecific treatment effect of SCIT for both treatments, defined as the difference of the changes of the adjusted AUC of TNSS measured during exposure to grass pollen and during exposure to birch pollen. The specific treatment effect of SCIT was defined as the combined specific treatment effect of ALLERGOVIT® grasses (ECCpost grass – ECCpre grass) and the specific treatment effect of ALLERGOVIT® birch (ECCpost birch – ECCpre birch). Whereas the unspecific treatment effect of SCIT was defined as the combined unspecific treatment effect of ALLERGOVIT® grasses (ECCpost birch – ECCpre birch) and the unspecific treatment effect of ALLERGOVIT® birch (ECCpost grass – ECCpre grass). SCIT=Specific subcutaneous immunotherapy
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 Combined specific treatment effect Combined unspecific treatment effect
    Number of subjects analysed
    83 [7]
    83 [8]
    Units: score
        arithmetic mean (standard deviation)
    -11.61 ± 13.38
    -4.82 ± 13.05
    Notes
    [7] - Full analysis set
    [8] - Full analysis set
    Statistical analysis title
    		 Unspecific - Specific treatment effect of SCIT
    Statistical analysis description
    Unspecific treatment effect - Specific treatment effect. The value for 'Subjects in this analysis' shown below is not correct and is due to a validation error of the EudraCT database system. The correct value for 'Subjects in this analysis' is 79.
    Comparison groups
    Combined unspecific treatment effect v Combined specific treatment effect
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0007
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    6.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.86
         upper limit
    		 10.28

    Secondary: 3a_Unspecific treatment effect of ALLERGOVIT® grasses

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    End point title
    		 3a_Unspecific treatment effect of ALLERGOVIT® grasses
    End point description
    The unspecific treatment effect of ALLERGOVIT® preparations was calculated as shown below. •Unspecific treatment effect of ALLERGOVIT® grasses: ECCpost birch – ECCpre birch, for patients given ALLERGOVIT® grasses Results show the evaluation of the unspecific effect of ALLERGOVIT® grasses, i.e. the change of the adjusted AUC of TNSS, as measured during ECCpre Birch and ECCpost Birch for patients treated with ALLERGOVIT® grasses. AUC=Area under the curve ECC=Environmental challenge chamber TNSS=Total nasal symptom score
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® grasses treated patients; ECCpre birch ALLERGOVIT® grasses treated patients; ECCpost birch
    Number of subjects analysed
    46 [9]
    41 [10]
    Units: score
        arithmetic mean (standard deviation)
    23.65 ± 8.85
    19.39 ± 11.72
    Notes
    [9] - Full analysis set
    [10] - Full analysis set
    Statistical analysis title
    		 Unspecific treatment effect of ALLERGOVIT® grasses
    Statistical analysis description
    Unspecific treatment effect of ALLERGOVIT® grasses; ECCpost birch - ECCpre birch The value for 'Subjects in this analysis' shown below is not correct and is due to a validation error of the EudraCT database system. The correct value for 'Subjects in this analysis' is 41.
    Comparison groups
    ALLERGOVIT® grasses treated patients; ECCpre birch v ALLERGOVIT® grasses treated patients; ECCpost birch
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0702
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.92
         upper limit
    		 -0.29

    Secondary: 3b_Unspecific treatment effect of ALLERGOVIT® birch

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    End point title
    		 3b_Unspecific treatment effect of ALLERGOVIT® birch
    End point description
    The unspecific treatment effect of ALLERGOVIT® preparations was calculated as shown below. •Unspecific treatment effect of ALLERGOVIT® birch: ECCpost grasses – ECCpre grasses, for patients given ALLERGOVIT® birch Results show the evaluation of the unspecific effect of ALLERGOVIT® birch, i.e. the change of the adjusted AUC of TNSS, as measured during ECCpre grasses and ECCpost grasses for patients treated with ALLERGOVIT® birch. AUC=Area under the curve ECC=Environmental challenge chamber TNSS=Total nasal symptom score
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® birch treated patients; ECCpre grasses ALLERGOVIT® birch treated patients; ECCpost grasses
    Number of subjects analysed
    48 [11]
    42 [12]
    Units: score
        arithmetic mean (standard deviation)
    30.75 ± 11.86
    25.21 ± 13.75
    Notes
    [11] - Full analysis set
    [12] - Full analysis set
    Statistical analysis title
    		 Unspecific treatment effect of ALLERGOVIT® birch
    Statistical analysis description
    Unspecific treatment effect of ALLERGOVIT® grasses; ECCpost birch - ECCpre birch The value for 'Subjects in this analysis' shown below is not correct and is due to a validation error of the EudraCT database system. The correct value for 'Subjects in this analysis' is 42.
    Comparison groups
    ALLERGOVIT® birch treated patients; ECCpre grasses v ALLERGOVIT® birch treated patients; ECCpost grasses
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0074
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.79
         upper limit
    		 -1.78

    Secondary: 4a_Specific compared with unspecific treatment effect of ALLERGOVIT® grasses

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    End point title
    		 4a_Specific compared with unspecific treatment effect of ALLERGOVIT® grasses
    End point description
    For patients treated with ALLERGOVIT® grasses: • Specific treatment effect of ALLERGOVIT® grasses: ECCpost grass – ECCpre grass • Unspecific treatment effect of ALLERGOVIT® grasses: ECCpost birch – ECCpre birch ECC=Environmental challenge chamber
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 Specific treatment effect of ALLERGOVIT® grasses Unspecific treatment effect of ALLERGOVIT® grasses
    Number of subjects analysed
    40 [13]
    41 [14]
    Units: score
        arithmetic mean (standard deviation)
    -13.55 ± 12.55
    -3.32 ± 11.42
    Notes
    [13] - Full analysis set
    [14] - Full analysis set
    Statistical analysis title
    		 ALLERGOVIT® grasses: Unspec-Spec treatment effect
    Statistical analysis description
    ALLERGOVIT® grasses treated patients Unspecific treatment effect - Specific treatment effect The value for 'Subjects in this analysis' shown below is not correct and is due to a validation error of the EudraCT database system. The correct value for 'Subjects in this analysis' is 40.
    Comparison groups
    Specific treatment effect of ALLERGOVIT® grasses v Unspecific treatment effect of ALLERGOVIT® grasses
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0007
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    10.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.6
         upper limit
    		 15.7

    Secondary: 4b_Specific compared with unspecific treatment effect of ALLERGOVIT® birch

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    End point title
    		 4b_Specific compared with unspecific treatment effect of ALLERGOVIT® birch
    End point description
    For patients treated with ALLERGOVIT® birch: • Specific treatment effect of ALLERGOVIT® birch: ECCpost birch – ECCprebirch • Unspecific treatment effect of ALLERGOVIT® birch: ECCpost grass – ECCpre grass ECC=Environmental challenge chamber
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 Specific treatment effect of ALLERGOVIT® birch Unspecific treatment effect of ALLERGOVIT® birch
    Number of subjects analysed
    43 [15]
    42 [16]
    Units: score
        arithmetic mean (standard deviation)
    -9.81 ± 14.01
    -6.29 ± 14.46
    Notes
    [15] - Full analysis set
    [16] - Full analysis set
    Statistical analysis title
    		 ALLERGOVIT® birch: Unspec-Spec treatment effect
    Statistical analysis description
    ALLERGOVIT® birch treated patients Unspecific treatment effect - Specific treatment effect The value for 'Subjects in this analysis' shown below is not correct and is due to a validation error of the EudraCT database system. The correct value for 'Subjects in this analysis' is 39.
    Comparison groups
    Specific treatment effect of ALLERGOVIT® birch v Unspecific treatment effect of ALLERGOVIT® birch
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2374
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.99
         upper limit
    		 7.78

    Secondary: 4c_Specific compared with unspecific treatment effect: ALLERGOVIT® grasses vs ALLERGOVIT® birch

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    End point title
    		 4c_Specific compared with unspecific treatment effect: ALLERGOVIT® grasses vs ALLERGOVIT® birch
    End point description
    Specific compared with unspecific treatment effect: ALLERGOVIT® grasses vs ALLERGOVIT® birch Specific treatment effect of ALLERGOVIT® grasses: ECCpost grass – ECCpre grass, given ALLERGOVIT® grasses; unspecific treatment effect of ALLERGOVIT® birch: ECCpost grass – ECCpre grass, given ALLERGOVIT® birch.
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 Specific treatment effect of ALLERGOVIT® grasses Unspecific treatment effect of ALLERGOVIT® birch
    Number of subjects analysed
    40 [17]
    42 [18]
    Units: score
        arithmetic mean (standard deviation)
    -13.55 ± 12.55
    -6.29 ± 14.46
    Notes
    [17] - Full analysis set
    [18] - Full analysis set
    Statistical analysis title
    		 Specific (Grasses) vs Unspecific (birch) effect
    Statistical analysis description
    The specific treatment effect of ALLERGOVIT® grasses (mean diff. AUC TNSS -13.55[±12.55]) was significantly (p = 0.0172) larger than the unspecific treatment effect of ALLERGOVIT® birch (mean difference in adjusted AUC TNSS -6.29 [±14.46]). Thus, superiority of the specific treatment effects of ALLERGOVIT® grasses or birch over the unspecific treatment effects of ALLERGOVIT® birch or grasses, respectively, could be shown.
    Comparison groups
    Specific treatment effect of ALLERGOVIT® grasses v Unspecific treatment effect of ALLERGOVIT® birch
    Number of subjects included in analysis
    82
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0172 [19]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [19] - p-value from 2-sided two-sample t-test

    Secondary: 4d_Specific compared with unspecific treatment effect: ALLERGOVIT® birch vs ALLERGOVIT® grasses

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    End point title
    		 4d_Specific compared with unspecific treatment effect: ALLERGOVIT® birch vs ALLERGOVIT® grasses
    End point description
    Specific compared with unspecific treatment effect: ALLERGOVIT® birch vs ALLERGOVIT® grasses Specific treatment effect of ALLERGOVIT® birch: ECCpost birch – ECCpre birch, given ALLERGOVIT® birch; unspecific treatment effect of ALLERGOVIT® grasses: ECCpost birch – ECCpre birch, given ALLERGOVIT® grasses.
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 Unspecific treatment effect of ALLERGOVIT® grasses Specific treatment effect of ALLERGOVIT® birch
    Number of subjects analysed
    41 [20]
    43 [21]
    Units: score
        arithmetic mean (standard deviation)
    -3.32 ± 11.42
    -9.81 ± 14.01
    Notes
    [20] - Full analysis set
    [21] - Full analysis set
    Statistical analysis title
    		 Specific (birch) vs Unspecific (grasses) effect
    Statistical analysis description
    The specific treatment effect of ALLERGOVIT® birch (mean difference in adjusted AUC TNSS -9.81 [±14.01]) was significantly (p = 0.0221) larger than the unspecific treatment effect of ALLERGOVIT® grasses (mean difference in adjusted AUC TNSS -3.32 [±11.42]). Thus, superiority of the specific treatment effects of ALLERGOVIT® grasses or birch over the unspecific treatment effects of ALLERGOVIT® birch or grasses, respectively, could be shown.
    Comparison groups
    Unspecific treatment effect of ALLERGOVIT® grasses v Specific treatment effect of ALLERGOVIT® birch
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0221 [22]
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Confidence interval
    Notes
    [22] - p-value from 2-sided two-sample t-test

    Secondary: 5a_Grass pollen specific IgG4: ALLERGOVIT® grasses-treated subjects

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    End point title
    		 5a_Grass pollen specific IgG4: ALLERGOVIT® grasses-treated subjects
    End point description
    Data summarizes the changes from baseline in grass pollen specific IgG4 (serum) in patients treated with ALLERGOVIT® grasses. Within the treatment group analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® grasses (pre grass) ALLERGOVIT® grasses (post grass)
    Number of subjects analysed
    45 [23]
    45 [24]
    Units: mg/L
        arithmetic mean (standard deviation)
    0.5 ± 1.31
    3.02 ± 4.67
    Notes
    [23] - Full analysis set
    [24] - Full analysis set
    Statistical analysis title
    		 Grass pollen specific IgG4 change from baseline
    Statistical analysis description
    Grass pollen specific IgG4 change from baseline in subjects treated with ALLERGOVIT® grasses The value for 'Subjects in this analysis' shown below is not correct and is due to a validation error of the EudraCT database system. The correct value for 'Subjects in this analysis' is 45.
    Comparison groups
    ALLERGOVIT® grasses (pre grass) v ALLERGOVIT® grasses (post grass)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [25]
    Method
    		 Wilcoxon signed rank test
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.46
         upper limit
    		 3.58
    Notes
    [25] - p-value from 2-sided Wilcoxon signed rank test to test differences between baseline and final visit.

    Secondary: 5b_Birch pollen specific IgG4: ALLERGOVIT® grasses-treated subjects

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    End point title
    		 5b_Birch pollen specific IgG4: ALLERGOVIT® grasses-treated subjects
    End point description
    Data summarizes the changes from baseline in birch pollen specific IgG4 (serum) in patients treated with ALLERGOVIT® grasses. Within the treatment group analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® grasses (pre grass) ALLERGOVIT® grasses (post grass)
    Number of subjects analysed
    45 [26]
    45 [27]
    Units: mg/L
        arithmetic mean (standard deviation)
    0.94 ± 2.14
    0.87 ± 1.97
    Notes
    [26] - Full analysis set
    [27] - Full analysis set
    Statistical analysis title
    		 Birch pollen specific IgG4 change from baseline
    Statistical analysis description
    Birch pollen specific IgG4 change from baseline in subjects treated with ALLERGOVIT® grasses. The value for 'Subjects in this analysis' shown below is not correct and is due to a validation error of the EudraCT database system. The correct value for 'Subjects in this analysis' is 45.
    Comparison groups
    ALLERGOVIT® grasses (pre grass) v ALLERGOVIT® grasses (post grass)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3414 [28]
    Method
    		 Wilcoxon signed rank test
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.03
    Notes
    [28] - p-value from 2-sided Wilcoxon signed rank test to test differences between baseline and final visit.

    Secondary: 5c_Grass pollen specific IgG4: ALLERGOVIT® birch-treated subjects

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    End point title
    		 5c_Grass pollen specific IgG4: ALLERGOVIT® birch-treated subjects
    End point description
    Data summarizes the changes from baseline in grass pollen specific IgG4 (serum) in patients treated with ALLERGOVIT® birch. Within the treatment group analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® birch (pre birch) ALLERGOVIT® birch (post birch)
    Number of subjects analysed
    48 [29]
    48 [30]
    Units: mg/L
        arithmetic mean (standard deviation)
    0.53 ± 1.32
    0.49 ± 0.78
    Notes
    [29] - Full analysis set
    [30] - Full analysis set
    Statistical analysis title
    		 Grass pollen specific IgG4 change from baseline
    Statistical analysis description
    Grass pollen specific IgG4 change from baseline in subjects treated with ALLERGOVIT® birch. The value for 'Subjects in this analysis' shown below is not correct and is due to a validation error of the EudraCT database system. The correct value for 'Subjects in this analysis' is 48.
    Comparison groups
    ALLERGOVIT® birch (pre birch) v ALLERGOVIT® birch (post birch)
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.584 [31]
    Method
    		 Wilcoxon signed rank test
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0.17
    Notes
    [31] - p-value from 2-sided Wilcoxon signed rank test to test differences between baseline and final visit.

    Secondary: 5d_Birch pollen specific IgG4: ALLERGOVIT® birch-treated subjects

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    End point title
    		 5d_Birch pollen specific IgG4: ALLERGOVIT® birch-treated subjects
    End point description
    Data summarizes the changes from baseline in birch pollen specific IgG4 (serum) in patients treated with ALLERGOVIT® birch. Within the treatment group analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® birch (pre birch) ALLERGOVIT® birch (post birch)
    Number of subjects analysed
    48 [32]
    48 [33]
    Units: mg/L
        arithmetic mean (standard deviation)
    0.68 ± 0.77
    2.89 ± 2.73
    Notes
    [32] - Full analysis set
    [33] - Full analysis set
    Statistical analysis title
    		 Birch pollen specific IgG4 change from baseline
    Statistical analysis description
    Birch pollen specific IgG4 change from baseline in patients treated with ALLERGOVIT® birch. The value for 'Subjects in this analysis' shown below is not correct and is due to a validation error of the EudraCT database system. The correct value for 'Subjects in this analysis' is 48.
    Comparison groups
    ALLERGOVIT® birch (pre birch) v ALLERGOVIT® birch (post birch)
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [34]
    Method
    		 Wilcoxon signed rank test
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.61
         upper limit
    		 2.81
    Notes
    [34] - p-value from 2-sided Wilcoxon signed rank test to test differences between baseline and final visit.

    Secondary: 6a_Clinical chemistry: Blood transaminases; Transferase

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    End point title
    		 6a_Clinical chemistry: Blood transaminases; Transferase
    End point description
    Clinical chemistry: blood transaminases, transferase Alanine aminotransferase; Aspartate aminotransferase; Gamma glutamyl transferase. Change to baseline: Final Visit - Baseline
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® grasses ALLERGOVIT® birch
    Number of subjects analysed
    45 [35]
    47 [36]
    Units: U/mL
    arithmetic mean (confidence interval 95%)
        Alanine aminotransferase
    11.6 (-7 to 30.3)
    5.3 (-2.6 to 13.2)
        Aspartate aminotransferase
    7.2 (-0.6 to 14.9)
    5.1 (1.4 to 8.9)
        Gamma glutamyl transferase
    4.6 (-1.9 to 11.1)
    1.1 (-4.1 to 6.2)
    Notes
    [35] - Safety set
    [36] - Safety set
    No statistical analyses for this end point

    Secondary: 6b_Clinical chemistry: Blood Bilirubin; Creatinine; Glucose

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    End point title
    		 6b_Clinical chemistry: Blood Bilirubin; Creatinine; Glucose
    End point description
    Clinical chemistry: Blood Bilirubin, Creatinine, Glucose Change to baseline: Final Visit - Baseline
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® grasses ALLERGOVIT® birch
    Number of subjects analysed
    45 [37]
    47 [38]
    Units: mg/dL
    arithmetic mean (confidence interval 95%)
        Bilirubin
    0.036 (-0.051 to 0.123)
    -0.005 (-0.078 to 0.067)
        Creatinine
    0.075 (0.043 to 0.107)
    0.056 (0.025 to 0.087)
        Glucose
    1.1 (-4.9 to 7.1)
    -0.6 (-5.7 to 4.5)
    Notes
    [37] - Safety set
    [38] - Safety set
    No statistical analyses for this end point

    Secondary: 7a_Haematology: Haemoglobin

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    End point title
    		 7a_Haematology: Haemoglobin
    End point description
    Haematology: Haemoglobin Change to baseline: Final Visit - Baseline
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® grasses ALLERGOVIT® birch
    Number of subjects analysed
    43 [39]
    47 [40]
    Units: g/dL
    arithmetic mean (confidence interval 95%)
        Haemoglobin
    -0.33 (-0.57 to -0.08)
    -0.31 (-0.56 to -0.07)
    Notes
    [39] - Safety set
    [40] - Safety set
    No statistical analyses for this end point

    Secondary: 7b_Haematology: Leukocytes; Platelets

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    End point title
    		 7b_Haematology: Leukocytes; Platelets
    End point description
    Haematology: Leukocytes, Platelets Change to baseline: Final Visit - Baseline
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® grasses ALLERGOVIT® birch
    Number of subjects analysed
    43 [41]
    47 [42]
    Units: 10^9/L
    arithmetic mean (confidence interval 95%)
        Leukocytes
    -0.37 (-0.86 to 0.11)
    0.14 (-0.27 to 0.56)
        Platelets
    7.1 (-1.9 to 16.2)
    13.8 (4.7 to 22.9)
    Notes
    [41] - Safety set
    [42] - Safety set
    No statistical analyses for this end point

    Secondary: 8a_Vital signs: Systolic blood pressure; Diastolic blood pressure

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    End point title
    		 8a_Vital signs: Systolic blood pressure; Diastolic blood pressure
    End point description
    Vital signs: Systolic blood pressure; Diastolic blood pressure Change to baseline: Final Visit - Baseline
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® grasses ALLERGOVIT® birch
    Number of subjects analysed
    45 [43]
    48 [44]
    Units: mmHg
    arithmetic mean (confidence interval 95%)
        Systolic blood pressure
    0.9 (-2 to 3.8)
    2.2 (-0.8 to 5.2)
        Diastolic blood pressure
    -0.5 (-3 to 2)
    1.8 (-0.7 to 4.3)
    Notes
    [43] - Safety set
    [44] - Safety set
    No statistical analyses for this end point

    Secondary: 8b_Vital signs: Heart rate

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    End point title
    		 8b_Vital signs: Heart rate
    End point description
    Vital signs: Heart rate Change to baseline: Final Visit - Baseline
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® grasses ALLERGOVIT® birch
    Number of subjects analysed
    45 [45]
    48 [46]
    Units: bpm
    arithmetic mean (confidence interval 95%)
        Heart rate
    1.5 (-1.6 to 4.6)
    1.6 (-1.7 to 5)
    Notes
    [45] - Safety set
    [46] - Safety set
    No statistical analyses for this end point

    Secondary: 8c_Vital signs: Respiratory rate

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    End point title
    		 8c_Vital signs: Respiratory rate
    End point description
    Vital signs: Respiratory rate Change to baseline: Final Visit - Baseline
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® grasses ALLERGOVIT® birch
    Number of subjects analysed
    45 [47]
    48 [48]
    Units: breaths/min
    arithmetic mean (confidence interval 95%)
        Respiratory rate
    -0.4 (-1 to 0.1)
    -0.3 (-1.1 to 0.4)
    Notes
    [47] - Safety set
    [48] - Safety set
    No statistical analyses for this end point

    Secondary: 9_Tolerability assessment: Investigator; Patient

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    End point title
    		 9_Tolerability assessment: Investigator; Patient
    End point description
    Tolerability assessment: Investigator; Patient Performed by the patient and the investigator, using a 5-point score (Likert scale); score 1=very bad; score 5=very good Evaluated as continuous variable.
    End point type
    Secondary
    End point timeframe
    Baseline (pre treatment) to end of treatment (at approximately 9 months).
    End point values
    		 ALLERGOVIT® grasses ALLERGOVIT® birch
    Number of subjects analysed
    45 [49]
    48 [50]
    Units: score
    arithmetic mean (confidence interval 95%)
        Investigator
    4.2 (4 to 4.5)
    4.4 (4.2 to 4.6)
        Patient
    4 (3.8 to 4.3)
    4.3 (4.1 to 4.5)
    Notes
    [49] - Safety set Investigator N=45 (available for analysis) Patient N=44 (available for analysis)
    [50] - Safety set
    No statistical analyses for this end point

    Secondary: 10_Severity of allergic symptoms during the pollen seasons

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    End point title
    		 10_Severity of allergic symptoms during the pollen seasons
    End point description
    Severity of allergic symptoms during the grass pollen season and the birch pollen season, measured by a VRS in patients treated with ALLERGOVIT® grasses or ALLERGOVIT® birch. Patients rated at home their symptoms during the birch and grass pollen season, respectively. The rating of symptoms during the birch pollen season was performed in calendar week 19. The symptoms experienced during the grass pollen season were rated in calendar week 26. The score scale was from 1 (very good) to 10 (very poor). VRS=Visual rating scale
    End point type
    Secondary
    End point timeframe
    Calendar week 19 and calendar week 26.
    End point values
    		 ALLERGOVIT® grasses ALLERGOVIT® birch
    Number of subjects analysed
    44 [51]
    46 [52]
    Units: score
    arithmetic mean (confidence interval 95%)
        Grass pollen season
    4.18 (3.42 to 4.94)
    4.89 (4.29 to 5.5)
        Birch pollen season
    4.52 (3.83 to 5.22)
    4.24 (3.66 to 4.81)
    Notes
    [51] - Full analysis set
    [52] - Full analysis set
    Statistical analysis title
    		 Diffr. btw treat groups: grass pollen season
    Statistical analysis description
    Grass pollen season Difference between the treatment groups within one pollen season.
    Comparison groups
    ALLERGOVIT® grasses v ALLERGOVIT® birch
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0588 [53]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (net)
    Point estimate
    4.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.07
         upper limit
    		 5.02
    Notes
    [53] - p-value from two-sided Mann-Whitney U-test comparing the results from the different treatments within a season
    Statistical analysis title
    		 Diffr. btw treat groups: birch pollen season
    Statistical analysis description
    Birch pollen season Difference between the treatment groups within one pollen season.
    Comparison groups
    ALLERGOVIT® grasses v ALLERGOVIT® birch
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7132
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (net)
    Point estimate
    4.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.94
         upper limit
    		 4.82

    Secondary: 11_Quality of life (SF-12 Questionnaire)

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    End point title
    		 11_Quality of life (SF-12 Questionnaire)
    End point description
    QoL completed during the grass pollen season and the birch pollen season, measured by the SF-12 Questionnaire The questionnaire was completed by the patients treated with ALLERGOVIT® grasses or ALLERGOVIT® birch during the grass pollen season and the birch pollen season. Additionally, three scores gained from the data of the SF-12 were analyzed and compared between the treatment groups. These were the physical component summary score, the mental health score, and the utility index score. Data for one item of the questionnaire of the SF-12 is available directly in the EudraCT database entry. Results of the complete questionnaire and of the analysis of the three scores gained from the data are provided in the attached files. QoL=Quality of life
    End point type
    Secondary
    End point timeframe
    Calendar week 19 and calendar week 26.
    End point values
    		 Birch pollen season: ALLERGOVIT® grasses Grass pollen season: ALLERGOVIT® grasses Birch pollen season: ALLERGOVIT® birch Grass pollen season: ALLERGOVIT® birch
    Number of subjects analysed
    46 [54]
    46 [55]
    48 [56]
    48 [57]
    Units: subject
        Excellent
    6
    4
    8
    6
        Very good
    21
    22
    15
    15
        Good
    11
    15
    17
    21
        Fair
    7
    3
    4
    4
        Poor
    0
    0
    2
    0
        Missing
    0
    0
    0
    0
    Attachments
    		 Study AL 1303AV__ QoL SF-12
    Untitled (Filename: QoL-SF12__AL1303AV (AL05)_scores gained--EudraCT.pdf)
    Notes
    [54] - Full analysis set
    [55] - Full analysis set
    [56] - Full analysis set
    [57] - Full analysis set
    Statistical analysis title
    		 Birch pollen season: overall QoL
    Statistical analysis description
    Birch pollen season: overall QoL - data from from patients treated with ALLERGOVIT® grasses or ALLERGOVIT® birch.
    Comparison groups
    Birch pollen season: ALLERGOVIT® grasses v Birch pollen season: ALLERGOVIT® birch
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7102 [58]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [58] - p-value from two-sided Mann-Whitney U-test comparing the results from the different treatments within a season
    Statistical analysis title
    		 Grass pollen season: overall QoL
    Statistical analysis description
    Grass pollen season: overall QoL - data from from patients treated with ALLERGOVIT® grasses or ALLERGOVIT® birch.
    Comparison groups
    Grass pollen season: ALLERGOVIT® grasses v Grass pollen season: ALLERGOVIT® birch
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.395 [59]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [59] - p-value from two-sided Mann-Whitney U-test comparing the results from the different treatments within a season

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the period from the first screening including trial-related procedures until 30 days after the last IMP application or trial-related procedure were recorded.
    Adverse event reporting additional description
    In total, 7 serious treatment-emergent SAEs were reported in 3 patients (3.2%), which were not related to IMP or trial procedures.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    ALLERGOVIT® grasses
    Reporting group description
    		 -

    Reporting group title
    ALLERGOVIT® birch
    Reporting group description
    		 -

    Serious adverse events
    		 ALLERGOVIT® grasses ALLERGOVIT® birch
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 48 (4.17%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin erosion
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 48 (2.08%)
         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
    		 ALLERGOVIT® grasses ALLERGOVIT® birch
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 47 (76.60%)
    31 / 48 (64.58%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 47 (8.51%)
    4 / 48 (8.33%)
         occurrences all number
    4
    8
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    8 / 47 (17.02%)
    8 / 48 (16.67%)
         occurrences all number
    22
    13
    Injection site pruritus
         subjects affected / exposed
    8 / 47 (17.02%)
    6 / 48 (12.50%)
         occurrences all number
    11
    14
    Injection site swelling
         subjects affected / exposed
    11 / 47 (23.40%)
    5 / 48 (10.42%)
         occurrences all number
    19
    7
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 47 (25.53%)
    16 / 48 (33.33%)
         occurrences all number
    13
    26

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Feb 2014
    The original trial protocol, dated 13 Dec 2013, was amended once on 28 Feb 2014 to final Trial Protocol 2.0 prior to enrollment of any patient (first patient, first screening was on 03 Apr 2014).

    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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