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    Clinical Trial Results:
    Evaluation of the efficacy and safety of AVANZ® Phleum pratense in grass pollen-induced allergic rhinitis during controlled exposure in an environmental challenge chamber

    Summary
    EudraCT number
    		 2013-005130-38
    Trial protocol
    		 DE  
    Global end of trial date
    15 Oct 2015

    Results information
    Results version number
    		 v2(current)
    This version publication date
    05 Nov 2016
    First version publication date
    07 Oct 2016
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    spelling error

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AV-G-03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02166268
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ALK
    Sponsor organisation address
    Bøge Alle 1, Hørsholm, Denmark, 2970
    Public contact
    Global Clinical Development, ALK, 0045 45747576, clinicaltrials@alk.net
    Scientific contact
    Global Clinical Development, ALK, 0045 45747576, clinicaltrials@alk.net
    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
    30 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of AVANZ® Phleum pratense 15000 SQ+ compared to placebo in the treatment of grass pollen-induced allergic rhinitis using a Environmental Challenge Chamber.
    Protection of trial subjects
    Safety surveillance Access to symptomatic pharmacotherapy (except during specified washout period prior to and during ECC visits)
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jun 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: 140
    Worldwide total number of subjects
    140
    EEA total number of subjects
    140
    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)
    140
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were recruited from 15 trial sites in Germany. First subject first visit 5 June 2014 Last subject last visit 15 October 2015

    Pre-assignment
    Screening details
    		 Main selection criteria - Adults (18-65 years) - History of moderate-severe grass pollen rhinoconjunctivitis +/- asthma despite treatment with symptom-relieving medication during the previous 2 grass pollen seasons - Positive SPT and IgE against Phleum pratense - Minimum level of rhinitis symptoms in a grass pollen challenge (TNSS at least 6)

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Avanz
    Arm description
    		 Active treatment group: Avanz Phleum pratense 15,000 SQ+
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avanz
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were randomised to either Avanz (active treatment) or placebo. Subjects randomised to active treatment received a treatment schedule comprised by an updosing phase with 5 injections and a maintenance phase with 8 maintenance injections. During the updosing phase, injections were given in 1 week intervals; once the maintenance dose was reached, the dosage interval was increased stepwise to 2, 4, and 6 weeks. Subjects randomised to placebo received matched placebo product according to the same dosing schedule, i.e. 5 injections in the updosing treatment phase followed by 8 maintenance injections.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were randomised to either Avanz (active treatment) or placebo. Subjects randomised to active treatment received a treatment schedule comprised by an updosing phase with 5 injections and a maintenance phase with 8 maintenance injections. During the updosing phase, injections were given in 1 week intervals; once the maintenance dose was reached, the dosage interval was increased stepwise to 2, 4, and 6 weeks. Subjects randomised to placebo received matched placebo product according to the same dosing schedule, i.e. 5 injections in the updosing treatment phase followed by 8 maintenance injections.

    Number of subjects in period 1
    		Avanz Placebo
    Started
    71
    69
    Completed
    62
    66
    Not completed
    9
    3
         Consent withdrawn by subject
    3
    2
         Subject had to leave Germany for work reasons
    -
    1
         Adverse event, non-fatal
    4
    -
         Pregnancy
    1
    -
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Avanz
    Reporting group description
    		 Active treatment group: Avanz Phleum pratense 15,000 SQ+

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Avanz Placebo Total
    Number of subjects
    		 71 69 140
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 71 69 140
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34 ± 11 34 ± 12 -
    Gender categorical
    Units: Subjects
        Female
    		 35 31 66
        Male
    		 36 38 74
    Subject analysis sets

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set (FAS) – all randomised subjects, in accordance with the ICH intent-to-treat principle; FAS was the primary set for all efficacy analyses and for all baseline/demography tables, efficacy tables, and subject listings. The safety set was identical to FAS; the safety set was used for safety tables and subject listings. FAS comprised 140 subjects; 71 subjects in the Avanz group and 69 subjects in the placebo group.

    Subject analysis sets values
    		 FAS
    Number of subjects
    140
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    140
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    34 ± 11
    Gender categorical
    Units: Subjects
        Female
    66
        Male
    74

    End points

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    End points reporting groups
    Reporting group title
    Avanz
    Reporting group description
    		 Active treatment group: Avanz Phleum pratense 15,000 SQ+

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    FAS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis set (FAS) – all randomised subjects, in accordance with the ICH intent-to-treat principle; FAS was the primary set for all efficacy analyses and for all baseline/demography tables, efficacy tables, and subject listings. The safety set was identical to FAS; the safety set was used for safety tables and subject listings. FAS comprised 140 subjects; 71 subjects in the Avanz group and 69 subjects in the placebo group.

    Primary: Average TNSS measured during the EOT ECC visit

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    End point title
    		 Average TNSS measured during the EOT ECC visit
    End point description
    The rhinoconjunctivitis symptoms included 4 rhinitis symptoms (runny nose, blocked nose, sneezing, and itchy nose) and 2 conjunctivitis symptoms (gritty feeling/red/itchy eyes and watery eyes) which were scored from 0 to 3 as follows: 0 = no symptoms 1 = mild symptoms (i.e. symptom clearly present but hardly noticeable; easily tolerated) 2 = moderate symptoms (i.e. symptom clearly uncomfortable/bothersome but tolerable) 3 = severe symptoms (i.e. symptom that is hard to tolerate) The TNSS consisted of symptom scores from the 4 nose symptoms, resulting in a TNSS scale ranging from 0-12. TNSS was calculated pre-challenge and every 20 minutes during the 3-hour challenge in the ECC. The average TNSS at each ECC visit was calculated for each subject as the average of non-missing TNSS collected from hour 1 to 3 during the ECC session.
    End point type
    Primary
    End point timeframe
    Average TNSS measured during the EOT ECC visit after approximately 11 months of treatment
    End point values
    		 Avanz Placebo
    Number of subjects analysed
    71
    69
    Units: 0-12
        least squares mean (confidence interval 95%)
    4.87 (3.91 to 5.84)
    5.56 (4.58 to 6.54)
    Statistical analysis title
    		 Analysis of the average TNSS during the EOT ECC
    Statistical analysis description
    'Average TNSS during EOT ECC' is analysed using a linear mixed effect (LME) model. Treatment is a fixed class effect, TNSS at baseline ECC is a fixed regression variable and chamber cohort is a random class variable. Different residual errors for each treatment group is specified in the LME model. The LME model is estimated using the method of REML. The primary outcome is the difference in adjusted means between active and placebo with coherent p-values and confidence limits.
    Comparison groups
    Avanz v Placebo
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.112
    Method
    		 Linear mixed effect (LME) model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 1.54

    Secondary: Average TNSS measured during the M3 ECC visit

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    End point title
    		 Average TNSS measured during the M3 ECC visit
    End point description
    The rhinoconjunctivitis symptoms included 4 rhinitis symptoms (runny nose, blocked nose, sneezing, and itchy nose) and 2 conjunctivitis symptoms (gritty feeling/red/itchy eyes and watery eyes) which were scored from 0 to 3 as follows: 0 = no symptoms 1 = mild symptoms (i.e. symptom clearly present but hardly noticeable; easily tolerated) 2 = moderate symptoms (i.e. symptom clearly uncomfortable/bothersome but tolerable) 3 = severe symptoms (i.e. symptom that is hard to tolerate) The TNSS consisted of symptom scores from the 4 nose symptoms, resulting in a TNSS scale ranging from 0-12. TNSS was calculated pre-challenge and every 20 minutes during the 3-hour challenge in the ECC. The average TNSS at each ECC visit was calculated for each subject as the average of non-missing TNSS collected from hour 1 to 3 during the ECC session.
    End point type
    Secondary
    End point timeframe
    Average TNSS measured during the M3 ECC visit after approximantely 4 months of treatment.
    End point values
    		 Avanz Placebo
    Number of subjects analysed
    71
    69
    Units: 0-12
        least squares mean (confidence interval 95%)
    4.94 (4.23 to 5.65)
    5.61 (4.88 to 6.33)
    Statistical analysis title
    		 Analysis of the average TNSS during M3 ECC
    Statistical analysis description
    'Average TNSS during M3 ECC' is analysed using a linear mixed effect (LME) model. Treatment is a fixed class effect, TNSS at baseline ECC is a fixed regression variable and chamber cohort is a random class variable. Different residual errors for each treatment group is specified in the LME model. The LME model is estimated using the method of REML. The primary outcome is the difference in adjusted means between active and placebo with coherent p-values and confidence limits.
    Comparison groups
    Avanz v Placebo
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.092
    Method
    		 Linear mixed effect (LME) model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 1.44

    Secondary: Average TSS measured during the EOT ECC visit

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    End point title
    		 Average TSS measured during the EOT ECC visit
    End point description
    The rhinoconjunctivitis symptoms included 4 rhinitis symptoms (runny nose, blocked nose, sneezing, and itchy nose) and 2 conjunctivitis symptoms (gritty feeling/red/itchy eyes and watery eyes) which were scored from 0 to 3 as follows: 0 = no symptoms 1 = mild symptoms (i.e. symptom clearly present but hardly noticeable; easily tolerated) 2 = moderate symptoms (i.e. symptom clearly uncomfortable/bothersome but tolerable) 3 = severe symptoms (i.e. symptom that is hard to tolerate) The TSS consisted of symptom scores from the 4 nose symptoms and the 2 eye symptoms, resulting in a TSS scale ranging from 0-18. TSS was calculated pre-challenge and every 20 minutes during the 3-hour challenge in the ECC. The average TSS at each ECC visit was calculated for each subject as the average of non-missing TSS collected from hour 1 to 3 during the ECC session.
    End point type
    Secondary
    End point timeframe
    Average TSS measured during the EOT ECC visit after approximately 11 months of treatment.
    End point values
    		 Avanz Placebo
    Number of subjects analysed
    71
    69
    Units: 0-18
        least squares mean (confidence interval 95%)
    5.85 (4.55 to 7.16)
    7.1 (5.75 to 8.46)
    Statistical analysis title
    		 Average TSS measured during the EOT ECC visit
    Statistical analysis description
    'Average TSS during EOT ECC' is analysed using a linear mixed effect (LME) model. Treatment is a fixed class effect, TNSS at baseline ECC is a fixed regression variable and chamber cohort is a random class variable. Different residual errors for each treatment group is specified in the LME model. The LME model is estimated using the method of REML. The primary outcome is the difference in adjusted means between active and placebo with coherent p-values and confidence limits.
    Comparison groups
    Avanz v Placebo
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.038
    Method
    		 Linear mixed effect (LME) model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 2.43

    Secondary: Average TSS measured during the M3 ECC visit

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    End point title
    		 Average TSS measured during the M3 ECC visit
    End point description
    The rhinoconjunctivitis symptoms included 4 rhinitis symptoms (runny nose, blocked nose, sneezing, and itchy nose) and 2 conjunctivitis symptoms (gritty feeling/red/itchy eyes and watery eyes) which were scored from 0 to 3 as follows: 0 = no symptoms 1 = mild symptoms (i.e. symptom clearly present but hardly noticeable; easily tolerated) 2 = moderate symptoms (i.e. symptom clearly uncomfortable/bothersome but tolerable) 3 = severe symptoms (i.e. symptom that is hard to tolerate) The TSS consisted of symptom scores from the 4 nose symptoms and the 2 eye symptoms, resulting in a TSS scale ranging from 0-18. TSS was calculated pre-challenge and every 20 minutes during the 3-hour challenge in the ECC. The average TSS at each ECC visit was calculated for each subject as the average of non-missing TSS collected from hour 1 to 3 during the ECC session.
    End point type
    Secondary
    End point timeframe
    Average TSS measured during the M3 ECC visit after approximately 4 months of treatment.
    End point values
    		 Avanz Placebo
    Number of subjects analysed
    71
    69
    Units: 0-18
        least squares mean (confidence interval 95%)
    6.33 (5.3 to 7.35)
    7.51 (6.43 to 8.59)
    Statistical analysis title
    		 Average TSS measured during the M3 ECC visit
    Statistical analysis description
    'Average TSS during M3 ECC' is analysed using a linear mixed effect (LME) model. Treatment is a fixed class effect, TNSS at baseline ECC is a fixed regression variable and chamber cohort is a random class variable. Different residual errors for each treatment group is specified in the LME model. The LME model is estimated using the method of REML. The primary outcome is the difference in adjusted means between active and placebo with coherent p-values and confidence limits.
    Comparison groups
    Avanz v Placebo
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.033
    Method
    		 Linear mixed effect (LME) model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 2.27

    Secondary: Average TOSS measured during the EOT ECC visit

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    End point title
    		 Average TOSS measured during the EOT ECC visit
    End point description
    The rhinoconjunctivitis symptoms included 4 rhinitis symptoms (runny nose, blocked nose, sneezing, and itchy nose) and 2 conjunctivitis symptoms (gritty feeling/red/itchy eyes and watery eyes) which were scored from 0 to 3 as follows: 0 = no symptoms 1 = mild symptoms (i.e. symptom clearly present but hardly noticeable; easily tolerated) 2 = moderate symptoms (i.e. symptom clearly uncomfortable/bothersome but tolerable) 3 = severe symptoms (i.e. symptom that is hard to tolerate) The TOSS consisted of symptom scores from the 2 eye symptoms, resulting in a TOSS scale ranging from 0-6. TOSS was calculated pre-challenge and every 20 minutes during the 3-hour challenge in the ECC. The average TOSS at each ECC visit was calculated for each subject as the average of non-missing TOSS collected from hour 1 to 3 during the ECC session.
    End point type
    Secondary
    End point timeframe
    Average TOSS measured during the EOT ECC visit after approximately 11 months of treatment.
    End point values
    		 Avanz Placebo
    Number of subjects analysed
    71
    69
    Units: 0-6
        least squares mean (confidence interval 95%)
    0.97 (0.62 to 1.32)
    1.58 (1.17 to 1.99)
    Statistical analysis title
    		 Average TOSS measured during the EOT ECC visit
    Statistical analysis description
    'Average TOSS during EOT ECC' is analysed using a linear mixed effect (LME) model. Treatment is a fixed class effect, TNSS at baseline ECC is a fixed regression variable and chamber cohort is a random class variable. Different residual errors for each treatment group is specified in the LME model. The LME model is estimated using the method of REML. The primary outcome is the difference in adjusted means between active and placebo with coherent p-values and confidence limits.
    Comparison groups
    Avanz v Placebo
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 Linear mixed effect (LME) model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 1.05

    Secondary: Average TOSS measured during the M3 ECC visit

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    End point title
    		 Average TOSS measured during the M3 ECC visit
    End point description
    The rhinoconjunctivitis symptoms included 4 rhinitis symptoms (runny nose, blocked nose, sneezing, and itchy nose) and 2 conjunctivitis symptoms (gritty feeling/red/itchy eyes and watery eyes) which were scored from 0 to 3 as follows: 0 = no symptoms 1 = mild symptoms (i.e. symptom clearly present but hardly noticeable; easily tolerated) 2 = moderate symptoms (i.e. symptom clearly uncomfortable/bothersome but tolerable) 3 = severe symptoms (i.e. symptom that is hard to tolerate) The TOSS consisted of symptom scores from the 2 eye symptoms, resulting in a TOSS scale ranging from 0-6. TOSS was calculated pre-challenge and every 20 minutes during the 3-hour challenge in the ECC. The average TOSS at each ECC visit was calculated for each subject as the average of non-missing TOSS collected from hour 1 to 3 during the ECC session.
    End point type
    Secondary
    End point timeframe
    Average TOSS measured during the M3 ECC visit after approximately 4 months of treatment.
    End point values
    		 Avanz Placebo
    Number of subjects analysed
    71
    69
    Units: 0-6
        least squares mean (confidence interval 95%)
    1.37 (0.95 to 1.8)
    1.91 (1.45 to 2.37)
    Statistical analysis title
    		 Average TOSS measured during the M3 ECC visit
    Statistical analysis description
    'Average TOSS during M3 ECC' is analysed using a linear mixed effect (LME) model. Treatment is a fixed class effect, TNSS at baseline ECC is a fixed regression variable and chamber cohort is a random class variable. Different residual errors for each treatment group is specified in the LME model. The LME model is estimated using the method of REML. The primary outcome is the difference in adjusted means between active and placebo with coherent p-values and confidence limits.
    Comparison groups
    Avanz v Placebo
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 Linear mixed effect (LME) model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.97

    Secondary: Pre- to post-treatment change in IgG4 against Phleum pratense

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    End point title
    		 Pre- to post-treatment change in IgG4 against Phleum pratense
    End point description
    End point type
    Secondary
    End point timeframe
    Pre- to post-treatment change in IgG4 against Phleum pratense, i.e. change in levels from the screening visit to the final visit after approximately 11 months of treatment.
    End point values
    		 Avanz Placebo
    Number of subjects analysed
    71
    69
    Units: 0
        least squares mean (confidence interval 95%)
    1.134 (1.05 to 1.22)
    0.068 (0 to 0.14)
    Statistical analysis title
    		 Change from baseline in IgG4 (Phleum pratense)
    Statistical analysis description
    Analysis via LDA with change from baseline as the response variable, treatment, visit and their two-factor interaction as fixed class variables, the immunological baseline value as a fixed regression variable, subject as a random class variable and adjusted for different error variation for each treatment group.
    Comparison groups
    Avanz v Placebo
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 LDA model
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.066
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.95
         upper limit
    		 1.18

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the entire trial.
    Adverse event reporting additional description
    Adverse events meeting the definition of an AE were recorded and reported from the time the subject signed the informed consent and until the final visit. An AE was defined according to ICH Harmonised Tripartite Guideline E2A, Step 5.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Avanz
    Reporting group description
    		 Active treatment group: Avanz Phleum pratense 15,000 SQ+

    Serious adverse events
    		 Placebo Avanz
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 69 (1.45%)
    5 / 71 (7.04%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Surgical and medical procedures
    Knee arthroplasty
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 69 (0.00%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteochondrosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 69 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Avanz
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 69 (59.42%)
    61 / 71 (85.92%)
    Nervous system disorders
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 69 (2.90%)
    10 / 71 (14.08%)
         occurrences all number
    2
    12
    General disorders and administration site conditions
    Injection site erythema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    14 / 69 (20.29%)
    21 / 71 (29.58%)
         occurrences all number
    63
    109
    Injection site nodule
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 69 (10.14%)
    1 / 71 (1.41%)
         occurrences all number
    16
    1
    Injection site pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    9 / 69 (13.04%)
    6 / 71 (8.45%)
         occurrences all number
    27
    8
    Injection site pruritus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 69 (8.70%)
    24 / 71 (33.80%)
         occurrences all number
    27
    78
    Injection site swelling
    alternative assessment type: Non-systematic
         subjects affected / exposed
    20 / 69 (28.99%)
    32 / 71 (45.07%)
         occurrences all number
    86
    119
    Injection site urticaria
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 69 (2.90%)
    11 / 71 (15.49%)
         occurrences all number
    3
    16
    Injection site warmth
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 69 (7.25%)
    12 / 71 (16.90%)
         occurrences all number
    22
    62
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 69 (1.45%)
    4 / 71 (5.63%)
         occurrences all number
    1
    4
    Skin and subcutaneous tissue disorders
    Pruritus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 69 (1.45%)
    5 / 71 (7.04%)
         occurrences all number
    1
    6
    Urticaria
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 69 (2.90%)
    7 / 71 (9.86%)
         occurrences all number
    2
    7
    Infections and infestations
    Nasopharyngitis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    15 / 69 (21.74%)
    17 / 71 (23.94%)
         occurrences all number
    17
    21

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Feb 2014
    Amendment 1 to the protocol: The following updates has been made to the protocol. Section 4.1 Inclusion Criteria • Wording of Inclusion criterion I3 altered An update of section 8 has been made to reflect that both AVANZ® Phleum pratense and the grass pollen (Dactylis glomeratis) that are used in the ECC is considered IMP. Section 8.1 IMP • Dactylis glomeratis added to the section. Dactylis glomeratis will be considered as an IMP. Section 8.2 NIMP • Section updated to reflect that the subjects will be offered an antihistamine after the grass pollen challenge in the ECC.
    05 May 2014
    Amendment 2 to the protocol: The following updates has been made to the protocol. Protocol synopsis: Synopsis updated to reflect that first baseline ECC visit will be conducted from end of August 2014. Section 1.2: Section updated to correct the information provided on the doses used in the pre-clinical study in mice. Section 3.1: Section updated to reflect that the first baseline ECC visit will be conducted from end of August 2014. Section 4.1: Footnote to inclusion criterion I5 updated to reflect that the that skin prick test is invalid if the reaction to the positive control is <3 mm. Section 6.3: Instructions for code break updated. Section 7: Text added to instruct the sites that the ECC visits should be postponed (or cancelled if a postponement is not possible), if the subject has taken restricted medication. Section 10: • Instructions for the procedures performed at the ECC visits updated. Pre- and post challenge interviews by physician added. • Instruction given at the post challenge interview at the ECC visits added. • Instructions for scheduling of the 3rd maintenance ECC 4visit and the EOT ECC visit added to visit 10 and 16, for subjects receiving an antihistamine before IMP treatment. Section 11.8: Section updated to reflect that vital signs will be measured before and after the grass pollen challenge at the ECC visits. Section 11.16: An column has been added to Table 10 to list the post grass pollen challenge activities performed at the ECC site. Section 11.20: Additional risk minimisation activities added. In case the subjects peak flow drops with 20 % from baseline for two consecutive measurements the subject will be offered treatment with a β2-agonist. Section 11.21: New section added to describe the risk minimisation activities performed during the ECC visit, not mentioned in section 11.16 (environmental challenge chamber) or 11.20 (peak flow). Section 13: Text on interim analysis deleted.

    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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