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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled, Phase 3 Efficacy and Safety Study of Benralizumab (MEDI-563) to Reduce Oral Corticosteroid Use in Patients with Uncontrolled Asthma on High Dose Inhaled Corticosteroid plus Long-acting β2 Agonist and Chronic Oral Corticosteroid Therapy (ZONDA)

    Summary
    EudraCT number
    		 2013-002523-42
    Trial protocol
    		 DE   PL   ES   BG  
    Global end of trial date
    29 Sep 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Aug 2017
    First version publication date
    09 Aug 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D3250C00020
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Vastra Malarehamnen 9, Sodertalje, Sweden, 151 85
    Public contact
    Mitchell Goldman, AstraZeneca AB, Mitchell.Goldman@astrazeneca.com
    Scientific contact
    AZ Clinical Study Information, AstraZeneca AB, 46 855 326000, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Sep 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of 2 dosing regimens of benralizumab on percentage reduction of oral corticosteroid (OCS) dose in adult patients with uncontrolled asthma.
    Protection of trial subjects
    Data safety monitoring board (DSMB) evaluates cumulative safety and other clinical trial data at regular intervals and making appropriate recommendations based on the available data. The DSMB functions independently of all other individuals associated with the conduct of the studies, including the study sponsor, AstraZeneca. The committee operates in accordance with a DSMB charter.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Apr 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 10
    Country: Number of subjects enrolled
    Bulgaria: 8
    Country: Number of subjects enrolled
    Canada: 23
    Country: Number of subjects enrolled
    Chile: 9
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 45
    Country: Number of subjects enrolled
    Poland: 45
    Country: Number of subjects enrolled
    Korea, Republic of: 11
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Turkey: 11
    Country: Number of subjects enrolled
    Ukraine: 28
    Country: Number of subjects enrolled
    United States: 17
    Worldwide total number of subjects
    220
    EEA total number of subjects
    111
    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)
    192
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 369 participants signed informed consent. 271 entered run in/OCS optimization period. 220 participants were randomized to receive treatment with benralizumab 30 mg Q4W, Q8W, or placebo. Of the 220 patients randomised, all (100.0%) received treatment with study drug.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Benralizumab 30 mg q.4 weeks
    Arm description
    		 Benralizumab administered subcutaneously every 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Benralizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    30 mg

    Arm title
    		 Benralizumab 30 mg q.8 weeks
    Arm description
    		 Benralizumab administered subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Benralizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    30 mg

    Arm title
    		 Placebo
    Arm description
    		 Placebo administered subcutaneously
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    30 mg

    Number of subjects in period 1
    		Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Started
    72
    73
    75
    Completed
    68
    69
    72
    Not completed
    4
    4
    3
         Adverse event, serious fatal
    -
    2
    -
         Consent withdrawn by subject
    4
    1
    -
         Adverse event, non-fatal
    -
    -
    1
         Study specific withdrawal criteria
    -
    1
    1
         Lost to follow-up
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Benralizumab 30 mg q.4 weeks
    Reporting group description
    		 Benralizumab administered subcutaneously every 4 weeks

    Reporting group title
    Benralizumab 30 mg q.8 weeks
    Reporting group description
    		 Benralizumab administered subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered subcutaneously

    Reporting group values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo Total
    Number of subjects
    		 72 73 75 220
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 64 61 67 192
        From 65-84 years
    		 8 12 8 28
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 50.2 ( 12 ) 52.9 ( 10.1 ) 49.9 ( 11.7 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 40 47 48 135
        Male
    		 32 26 27 85

    End points

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    End points reporting groups
    Reporting group title
    Benralizumab 30 mg q.4 weeks
    Reporting group description
    		 Benralizumab administered subcutaneously every 4 weeks

    Reporting group title
    Benralizumab 30 mg q.8 weeks
    Reporting group description
    		 Benralizumab administered subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered subcutaneously

    Primary: Percentage reduction in final OCS dose compared with baseline while maintaining asthma control

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    End point title
    		 Percentage reduction in final OCS dose compared with baseline while maintaining asthma control
    End point description
    Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose–final dose)/baseline dose}*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.
    End point type
    Primary
    End point timeframe
    Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    72
    73
    75
    Units: Percent
        median (confidence interval 95%)
    75 (50 to 83.3)
    75 (60 to 87.5)
    25 (0 to 33.3)
    Statistical analysis title
    		 Wilcoxon rank-sum test
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    33.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 16.7
         upper limit
    		 50
    Statistical analysis title
    		 Wilcoxon rank-sum test
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    37.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 20.8
         upper limit
    		 50

    Secondary: Percentage reduction in final OCS dose compared with baseline while maintaining asthma control for patients with baseline eosinophils >=300/uL

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    End point title
    		 Percentage reduction in final OCS dose compared with baseline while maintaining asthma control for patients with baseline eosinophils >=300/uL
    End point description
    Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose–final dose)/baseline dose}*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    62
    61
    64
    Units: Percent
        median (confidence interval 95%)
    75 (60 to 100)
    75 (60 to 91.7)
    0 (0 to 28.6)
    Statistical analysis title
    		 Wilcoxon rank-sum test
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    125
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    50
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25
         upper limit
    		 66.7
    Statistical analysis title
    		 Wilcoxon rank-sum test
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    50
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25
         upper limit
    		 66.7

    Secondary: The proportion of patients with ≥50% reduction in average daily OCS dose at Visit 14 compared with baseline dose at Visit 6, while maintaining asthma control

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    End point title
    		 The proportion of patients with ≥50% reduction in average daily OCS dose at Visit 14 compared with baseline dose at Visit 6, while maintaining asthma control
    End point description
    Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose–final dose)/baseline dose}*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    72
    73
    75
    Units: Participants
    48
    48
    28
    Statistical analysis title
    		 CMH test
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.79
         upper limit
    		 7.22
    Notes
    [1] - Controlling for region
    Statistical analysis title
    		 CMH test
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.57
         upper limit
    		 5.86
    Notes
    [2] - Controlling for region

    Secondary: The proportion of eligible patients with ≥100% reduction in average daily OCS dose at Visit 14 compared with baseline dose at Visit 6, while maintaining asthma control

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    End point title
    		 The proportion of eligible patients with ≥100% reduction in average daily OCS dose at Visit 14 compared with baseline dose at Visit 6, while maintaining asthma control
    End point description
    Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. The percentage reduction from baseline is defined as: {(Baseline dose–final dose)/baseline dose}*100%. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    39 [3]
    42 [4]
    42 [5]
    Units: Participants
    22
    22
    8
    Notes
    [3] - Only eligible (ie, baseline OCS dose<=12.5 mg) included.
    [4] - Only eligible (ie, baseline OCS dose<=12.5 mg) included.
    [5] - Only eligible (ie, baseline OCS dose<=12.5 mg) included.
    Statistical analysis title
    		 CMH test
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.002
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.58
         upper limit
    		 11.12
    Notes
    [6] - Controlling for region
    Statistical analysis title
    		 CMH test
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    5.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.92
         upper limit
    		 14.21
    Notes
    [7] - Controlling for region

    Secondary: The proportion of patients with ≤5.0 mg reduction on daily OCS dose at Visit 14 compared with baseline dose at Visit 6, while maintaining asthma control.

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    End point title
    		 The proportion of patients with ≤5.0 mg reduction on daily OCS dose at Visit 14 compared with baseline dose at Visit 6, while maintaining asthma control.
    End point description
    Baseline OCS dose is the dose upon which the patient is stabilised at randomisation (Week 0). Final OCS dose is the dose at Week 28. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    72
    73
    75
    Units: Participants
    22
    25
    38
    Statistical analysis title
    		 CMH test
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.012
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 0.83
    Notes
    [8] - Controlling for region
    Statistical analysis title
    		 CMH test
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.053
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 1.01
    Notes
    [9] - Controlling for region

    Secondary: The proportion of patients with average final OCS dose ≤5.0 mg daily at Visit 14, while maintaining asthma control

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    End point title
    		 The proportion of patients with average final OCS dose ≤5.0 mg daily at Visit 14, while maintaining asthma control
    End point description
    Final OCS dose is the dose at Week 28. If a patient discontinues from the study during a given dose reduction period, or the patient experiences an exacerbation between Weeks 24 and 28 or immediately before discontinuation, then the final OCS dose will be 1 dose level higher than that which directly preceded the event.
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    72
    73
    75
    Units: Participants
    44
    43
    25
    Statistical analysis title
    		 CMH test
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.002
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.41
         upper limit
    		 5.31
    Notes
    [10] - Controlling for region
    Statistical analysis title
    		 CMH test
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.6
         upper limit
    		 6.23
    Notes
    [11] - Controlling for region

    Secondary: Proportion of patients with ≥1 asthma exacerbation

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    End point title
    		 Proportion of patients with ≥1 asthma exacerbation
    End point description
    Number and percentage of patients with at least one post randomization asthma exacerbation.
    End point type
    Secondary
    End point timeframe
    Immediately following the randomisation through Study Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    72
    73
    75
    Units: Participants
    19
    17
    39
    Statistical analysis title
    		 CMH test
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 0.65
    Notes
    [12] - Controlling for region
    Statistical analysis title
    		 CMH test
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.56
    Notes
    [13] - Controlling for region

    Secondary: Time to the first asthma exacerbation

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    End point title
    		 Time to the first asthma exacerbation
    End point description
    Time to the first occurrence of asthma exacerbation post randomisation
    End point type
    Secondary
    End point timeframe
    The time from randomisation to the date of first asthma exacerbation
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    72 [14]
    73 [15]
    75 [16]
    Units: Participants
        Number of patients with exacerbations
    19
    37
    39
    Notes
    [14] - median survival time is not estimable due to number of exacerbations had not reached 50%.
    [15] - median survival time is not estimable due to number of exacerbations had not reached 50%.
    [16] - median survival time = 155 days, however upper 95% CI for median is not estimable.
    Statistical analysis title
    		 Cox regression
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 < 0.001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 0.66
    Notes
    [17] - Covariates of treatment group, region, and number of exacerbations in the previous year.
    Statistical analysis title
    		 Cox regression
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 < 0.001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.57
    Notes
    [18] - Covariates of treatment group, region, and number of exacerbations in the previous year.

    Secondary: Time to the first asthma exacerbation requiring hospitalization or ER visit

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    End point title
    		 Time to the first asthma exacerbation requiring hospitalization or ER visit
    End point description
    Time to the first exacerbation requiring hospitalization or ER visit post randomisation
    End point type
    Secondary
    End point timeframe
    The time from randomisation to the date of first asthma exacerbation
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    72 [19]
    73 [20]
    75 [21]
    Units: Participants
        # of pt. with exacerbations equiring HOSP/ER
    4
    1
    9
    Notes
    [19] - No est. median survival time, # of exacerbations resulting hospitalization/ER had not reached 50%.
    [20] - No est. median survival time, # of exacerbations resulting hospitalization/ER had not reached 50%.
    [21] - No est. median survival time, # of exacerbations resulting hospitalization/ER had not reached 50%.
    Statistical analysis title
    		 Cox regression
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.042
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.63
    Notes
    [22] - Covariates of treatment group, region, and any exacerbations in the previous year requiring hospitalization or ER.
    Statistical analysis title
    		 Cox regression
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.291
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 1.64
    Notes
    [23] - Covariates of treatment group, region, and any exacerbations in the previous year requiring hospitalization or ER.

    Secondary: Annual rate of asthma exacerbations

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    End point title
    		 Annual rate of asthma exacerbations
    End point description
    The annual asthma exacerbation rate is based on unadjudicated asthma exacerbations reported by the investigator.
    End point type
    Secondary
    End point timeframe
    The time from randomisation to the date of week 28 visit (end of treatment) or last contact if the patient is lost to follow up
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    72
    73
    75
    Units: events/year
        least squares mean (confidence interval 95%)
    0.83 (0.55 to 1.26)
    0.54 (0.34 to 0.88)
    1.83 (1.33 to 2.5)
    Statistical analysis title
    		 Negative binomial (generalized linear model)
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 < 0.001
    Method
    		 negative binomial model
    Parameter type
    		 Rate ratio
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.53
    Notes
    [24] - Covariates of treatment group, region, number of exacerbations in the previous year
    Statistical analysis title
    		 Negative binomial (generalized linear model)
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.003
    Method
    		 negative binomial model
    Parameter type
    		 Rate ratio
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 0.76
    Notes
    [25] - Covariates of treatment group, region, number of exacerbations in the previous year

    Secondary: Annual rate of asthma exacerbations that are associated with an emergency room visit or a hospitalization

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    End point title
    		 Annual rate of asthma exacerbations that are associated with an emergency room visit or a hospitalization
    End point description
    The annual exacerbation rate associated with hospitalization or ER is based on unadjudicated annual exacerbations reported by the investigator.
    End point type
    Secondary
    End point timeframe
    The time from randomisation to the date of week 28 visit (end of treatment) or last contact if the patient is lost to follow up
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    72
    73
    75
    Units: events/year
        least squares mean (confidence interval 95%)
    0.14 (0.05 to 0.38)
    0.02 (0 to 0.18)
    0.32 (0.16 to 0.65)
    Statistical analysis title
    		 Negative binomial (generalized linear model)
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 = 0.018
    Method
    		 negative binomial model
    Parameter type
    		 Rate ratio
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 0.63
    Notes
    [26] - Covariates of treatment group, region, any exacerbation requiring hospitalization/ER in the previous year
    Statistical analysis title
    		 Negative binomial (generalized linear model)
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.187
    Method
    		 negative binomial model
    Parameter type
    		 Rate ratio
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 1.49
    Notes
    [27] - Covariates of treatment group, region, any exacerbation requiring hospitalization/ER in the previous year

    Secondary: Number of days in hospital due to asthma

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    End point title
    		 Number of days in hospital due to asthma
    End point description
    Number of days in hospital due to asthma, if none, 0 day is considered
    End point type
    Secondary
    End point timeframe
    The time from randomisation to the date of week 28 visit (end of treatment) or last contact if the patient is lost to follow up
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    72
    73
    75
    Units: Days
        arithmetic mean (standard deviation)
    0.3 ( 1.41 )
    0.5 ( 3.86 )
    1.2 ( 6.66 )
    No statistical analyses for this end point

    Secondary: Change from baseline to week 28 in pre-bronchodilator FEV1

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    End point title
    		 Change from baseline to week 28 in pre-bronchodilator FEV1
    End point description
    Baseline is defined as the last non-missing value prior to the first dose of study treatment. Change from baseline to Week 28 in two treatment groups is compared to placebo group.
    End point type
    Secondary
    End point timeframe
    From baseline to week 28, every four weeks
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    68
    68
    73
    Units: Liter
        arithmetic mean (standard deviation)
    0.23 ( 0.429 )
    0.255 ( 0.508 )
    0.114 ( 0.401 )
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 = 0.153
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.105
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.251
    Notes
    [28] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.129
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.112
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.033
         upper limit
    		 0.258
    Notes
    [29] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction

    Secondary: Change from baseline to week 28 in asthma symptom scores (Total)

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    End point title
    		 Change from baseline to week 28 in asthma symptom scores (Total)
    End point description
    Asthma symptoms during night time and daytime are recorded by the patient in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma, or unable to do normal activities due to asthma), and total asthma symptom score is the sum of the daytime and night time score (0 to 6). Lower score (0) is indicating better asthma symptom, while higher score (6) is indicating worse asthma symptom. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each time point is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better.
    End point type
    Secondary
    End point timeframe
    From baseline to week 28, every two weeks
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    67
    68
    67
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -0.58 ( 1.03 )
    -0.77 ( 1.03 )
    -0.58 ( 1.03 )
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 = 0.947
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 0.32
    Notes
    [30] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.291
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 0.16
    Notes
    [31] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction

    Secondary: Change from baseline to week 28 in asthma symptom scores (Daytime)

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    End point title
    		 Change from baseline to week 28 in asthma symptom scores (Daytime)
    End point description
    Asthma symptoms during daytime are recorded by the patient in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma, or unable to do normal activities due to asthma). Lower score (0) is indicating better asthma symptom, while higher score (3) is indicating worse asthma symptom. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each time point is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better.
    End point type
    Secondary
    End point timeframe
    From baseline to week 28, every two weeks
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    67
    69
    69
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -0.32 ( 0.56 )
    -0.44 ( 0.52 )
    -0.32 ( 0.57 )
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [32]
    P-value
    		 = 0.998
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0.18
    Notes
    [32] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 = 0.177
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.05
    Notes
    [33] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction

    Secondary: Change from baseline to week 28 in asthma symptom scores (Nighttime)

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    End point title
    		 Change from baseline to week 28 in asthma symptom scores (Nighttime)
    End point description
    Asthma symptoms during night time are recorded by the patient in the asthma daily diary. Symptom score values are from 0 (No asthma symptom) to 3 (unable to sleep because of asthma, or unable to do normal activities due to asthma). Lower score (0) is indicating better asthma symptom, while higher score (3) is indicating worse asthma symptom. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each time point is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this is considered as missing. Symptom score lower is better.
    End point type
    Secondary
    End point timeframe
    From baseline to week 28, every two weeks
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    67
    68
    67
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -0.27 ( 0.51 )
    -0.34 ( 0.54 )
    -0.27 ( 0.54 )
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 = 0.973
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.17
    Notes
    [34] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 = 0.48
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.11
    Notes
    [35] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction

    Secondary: Change from baseline to week 28 in rescue medication use

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    End point title
    		 Change from baseline to week 28 in rescue medication use
    End point description
    Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1. Each timepoint is calculated as bi-weekly means based on daily diary data. If more than 50% of scores are missing in a 14 day period then this will be considered as missing. The number of inhalations (puffs) per day will be calculated as follows: Number of night inhaler puffs + 2 x [number of night nebulizer times] + number of day inhaler puffs + 2 x [number of day nebulizer times].
    End point type
    Secondary
    End point timeframe
    From baseline to week 28, every two weeks
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    67
    68
    67
    Units: number of puffs per day
        arithmetic mean (standard deviation)
    -1.39 ( 2.86 )
    -2.58 ( 4.36 )
    -1.07 ( 2.86 )
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [36]
    P-value
    		 = 0.006
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.42
         upper limit
    		 -0.41
    Notes
    [36] - Covariates of treatment group, region, baseline total asthma rescue medication use, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 = 0.397
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.44
         upper limit
    		 0.57
    Notes
    [37] - Covariates of treatment group, region, baseline total asthma rescue medication use, visit, and visit by treatment group interaction

    Secondary: Change from baseline to week 28 in home lung function (morning peak expiratory flow)

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    End point title
    		 Change from baseline to week 28 in home lung function (morning peak expiratory flow)
    End point description
    Morning peak expiratory flow change from baseline to week 28. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1.Each timepoint is calculated as bi-weekly means based on daily diary data
    End point type
    Secondary
    End point timeframe
    From baseline to week 28, every two weeks
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    67
    68
    67
    Units: Liter/min
        arithmetic mean (standard deviation)
    32.697 ( 89.457 )
    43.022 ( 73.303 )
    10.884 ( 69.356 )
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [38]
    P-value
    		 = 0.143
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    19.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.58
         upper limit
    		 45.07
    Notes
    [38] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 = 0.023
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    30.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.26
         upper limit
    		 55.76
    Notes
    [39] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction

    Secondary: Change from baseline to week 28 in home lung function (evening peak expiratory flow)

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    End point title
    		 Change from baseline to week 28 in home lung function (evening peak expiratory flow)
    End point description
    Evening peak expiratory flow change from baseline to week 28. Baseline is defined as the average of data collected from the evening of study day -14 to the morning of study day 1.Each timepoint is calculated as bi-weekly means based on daily diary data
    End point type
    Secondary
    End point timeframe
    From baseline to week 28, every two weeks
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    67
    69
    66
    Units: Liter/min
        arithmetic mean (standard deviation)
    21.885 ( 83.136 )
    34.157 ( 69.287 )
    2.933 ( 72.302 )
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [40]
    P-value
    		 = 0.237
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    15.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.08
         upper limit
    		 40.46
    Notes
    [40] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 = 0.014
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    31.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.32
         upper limit
    		 56.71
    Notes
    [41] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction

    Secondary: Change from baseline to week 28 in the proportion of nights with awakening due to asthma requiring rescue medication

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    End point title
    		 Change from baseline to week 28 in the proportion of nights with awakening due to asthma requiring rescue medication
    End point description
    Baseline is defined as the proportion of nights from the evening of study day -14 to the morning of study day 1.Each timepoint is calculated as bi-weekly proportions based on daily diary data. If more than 50% of data are missing in a 14 day period then this will be considered as missing.Proportion of nights with noctural awakenings is defined as the number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data.
    End point type
    Secondary
    End point timeframe
    From baseline to week 28, measure each two weeks
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    67
    68
    67
    Units: Proportion
        arithmetic mean (standard deviation)
    -0.158 ( 0.283 )
    -0.2 ( 0.337 )
    -0.186 ( 0.344 )
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [42]
    P-value
    		 = 0.742
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.11
    Notes
    [42] - Covariates of treatment group, region, baseline proportion of nights with nocturnal awakening, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 = 0.693
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.07
    Notes
    [43] - Covariates of treatment group, region, baseline proportion of nights with nocturnal awakening, visit, and visit by treatment group interaction

    Secondary: Change from baseline to week 28 in ACQ-6

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    End point title
    		 Change from baseline to week 28 in ACQ-6
    End point description
    ACQ-6 contains one bronchodilator question and 5 symptom questions. Questions are rated from 0 (totally controlled) to 6 (severely uncontrolled). Mean ACQ-6 score is the average of the responses. Mean scores of <=0.75 indicates well-controlled asthma, scores between 0.75 to <=1.5 indicate partly controlled asthma, and >1.5 indicates not well controlled asthma.
    End point type
    Secondary
    End point timeframe
    From baseline to week 28, every two weeks
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    66
    66
    67
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -0.86 ( 0.95 )
    -1.09 ( 1.09 )
    -0.68 ( 1.1 )
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [44]
    P-value
    		 = 0.139
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 0.08
    Notes
    [44] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.86
         upper limit
    		 -0.23
    Notes
    [45] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction

    Secondary: ACQ-6 responders (improvement) at Week 28

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    End point title
    		 ACQ-6 responders (improvement) at Week 28
    End point description
    Improvement is defined as ACQ-6 (End of treatment - baseline) <= -0.5. No change is defined as ACQ-6 (End of treatment - baseline) >-0.5 and <0.5. Deterioration is defined as ACQ-6 (End of treatment - baseline) >= 0.5. ACQ-6 score is defined as the average of the first 6 items of the ACQ questionnaire on symptoms, activity limitations and rescue medication.Scores range from 0 (totally controlled) to 6 (severely uncontrolled). Baseline is defined as the last non-missing value prior to randomisation. End of treatment is defined as week 28. Patients with missing or non-evaluable ACQ-6 at week 28 are considered non-responder.
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    72
    73
    75
    Units: Participants
    41
    46
    41
    Statistical analysis title
    		 Logistic regression
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [46]
    P-value
    		 = 0.155
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.661
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.826
         upper limit
    		 3.34
    Notes
    [46] - Covariates of treatment group, region, baseline value, and number of exacerbations in the previous year
    Statistical analysis title
    		 Logistics regression
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [47]
    P-value
    		 = 0.658
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.165
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.592
         upper limit
    		 2.295
    Notes
    [47] - Covariates of treatment group, region, baseline value, and number of exacerbations in the previous year

    Secondary: Change from baseline to week 28 in AQLQ(S)+12 (Overall)

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    End point title
    		 Change from baseline to week 28 in AQLQ(S)+12 (Overall)
    End point description
    AQLQ(S)+12 overall score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. AQLQ(S)+12 is a 7-point scale questionnaire, ranging from 7 (no impairment) to 1 (severe impairment). Total or domain score change of >=0.5 are considered clinically meaningful.
    End point type
    Secondary
    End point timeframe
    From baseline to week 28, every four weeks
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    66
    67
    68
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    0.9 ( 0.93 )
    1.05 ( 1.04 )
    0.67 ( 1.1 )
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [48]
    P-value
    		 = 0.151
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.53
    Notes
    [48] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [49]
    P-value
    		 = 0.004
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.76
    Notes
    [49] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction

    Secondary: AQLQ(s)+12 responders (improvement) at Week 28

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    End point title
    		 AQLQ(s)+12 responders (improvement) at Week 28
    End point description
    AQLQ(S)+12 overall score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. Improvement is defined as AQLQ(S)+12 (End of treatment - baseline)>=0.5. No change is defined as AQLQ(S)+12 (End of treatment - baseline) >-0.5 and <0.5. Deterioration is defined as AQLQ(S)+12 (End of treatment - baseline) <= -0.5. Baseline is defined as the last AQLQ(S)+12 score prior to randomisation. End of treatment is defined as week 28. Patients with missing or non-evaluable score at week 28 are considered as non-responder.
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    72
    73
    75
    Units: Participants
    43
    44
    39
    Statistical analysis title
    		 Logistic regression
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [50]
    P-value
    		 = 0.22
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.538
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.773
         upper limit
    		 3.06
    Notes
    [50] - Covariates of treatment group, region, baseline value, and number of exacerbations in the previous year
    Statistical analysis title
    		 Logistic regression
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [51]
    P-value
    		 = 0.108
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.783
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.882
         upper limit
    		 3.605
    Notes
    [51] - Covariates of treatment group, region, baseline value, and number of exacerbations in the previous year

    Secondary: Extent of Exposure

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    End point title
    		 Extent of Exposure
    End point description
    Duration of exposure from first dose date to last dose date.
    End point type
    Secondary
    End point timeframe
    From first dose to Week 24
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    72
    73
    75
    Units: Days
        arithmetic mean (standard deviation)
    162.53 ( 30.09 )
    159.77 ( 35.781 )
    167.05 ( 10.697 )
    No statistical analyses for this end point

    Secondary: Serum concentration of Benralizumab

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    End point title
    		 Serum concentration of Benralizumab
    End point description
    Pre-dose serum concentrations at each visit
    End point type
    Secondary
    End point timeframe
    Pre-first dose to Week 36
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    71
    72
    0 [52]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Baseline (n=69, 71)
    0 ( 0 )
    0 ( 0 )
    ( )
        Week 4 (n=67, 71)
    804.37 ( 52.77 )
    721.42 ( 52.3 )
    ( )
        week 8 (n=66, 69)
    1152.96 ( 53.16 )
    1019.65 ( 89.51 )
    ( )
        Week 12 (n=68, 67)
    1319.14 ( 66.05 )
    1057.91 ( 125.74 )
    ( )
        Week 16 (n=67,67)
    1337.98 ( 118.9 )
    303.54 ( 144.53 )
    ( )
        Week 24 (n=65, 66)
    1162.62 ( 151.35 )
    185.17 ( 278.32 )
    ( )
        Week 28 (n=65, 65)
    1125.96 ( 173.79 )
    684.57 ( 205.67 )
    ( )
        Week 36 (n=2, 4)
    11.11 ( 2140.87 )
    5.92 ( 1230.68 )
    ( )
    Notes
    [52] - No active drug in placebo group, thus not in the PK population
    No statistical analyses for this end point

    Secondary: Anti-drug antibody response

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    End point title
    		 Anti-drug antibody response
    End point description
    Number and percentage of patients in different ADA response categories
    End point type
    Secondary
    End point timeframe
    From baseline to follow-up Week 36
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    72
    73
    75
    Units: Participant
        Positive at any visit (n=72, 73, 75)
    5
    7
    6
        Baseline and Post-baseline Postive (n=68, 69, 75)
    0
    0
    3
        Only post-baseline positive (n=71, 70, 75)
    5
    6
    3
        Only baseline positive (n=69, 72, 75)
    0
    1
    0
        Persistently positive (n=71, 70, 75)
    4
    6
    5
        Transient positive (n=71, 70, 75)
    1
    0
    1
    No statistical analyses for this end point

    Secondary: Percent change from baseline in blood eosinophil counts

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    End point title
    		 Percent change from baseline in blood eosinophil counts
    End point description
    Percent change from baseline in blood eosinophil counts at week 28
    End point type
    Secondary
    End point timeframe
    From baseline to Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    63
    62
    66
    Units: percent
        arithmetic mean (standard deviation)
    -97.4 ( 12.93 )
    -94.9 ( 16.54 )
    45.5 ( 239.51 )
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [53]
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -159.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -217.9
         upper limit
    		 -100.9
    Notes
    [53] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [54]
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -162.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -220.1
         upper limit
    		 -104.3
    Notes
    [54] - Covariates of treatment group, region, baseline value, visit, and visit by treatment group interaction

    Secondary: Total Lung Capacity

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    End point title
    		 Total Lung Capacity
    End point description
    Change from baseline in total lung capacity
    End point type
    Secondary
    End point timeframe
    From baseline to Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    22
    26
    23
    Units: Liter
    arithmetic mean (standard deviation)
        Week 12 (n=17, 23, 17)
    -0.02 ( 0.95 )
    -0.07 ( 0.68 )
    -0.3 ( 1.08 )
        Week 28 (n=14, 18, 15)
    0.11 ( 1.31 )
    -0.21 ( 0.7 )
    -0.47 ( 1.47 )
    No statistical analyses for this end point

    Secondary: Residual Volume

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    End point title
    		 Residual Volume
    End point description
    Change from baseline in residual volume
    End point type
    Secondary
    End point timeframe
    From baseline to Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    22
    26
    23
    Units: Liter
    arithmetic mean (standard deviation)
        Week 12 (n=17, 23, 17)
    0.02 ( 1 )
    -0.22 ( 0.74 )
    -0.35 ( 1.03 )
        Week 28 (n=14, 18, 15)
    0.07 ( 1.34 )
    -0.31 ( 0.71 )
    -0.41 ( 1.27 )
    No statistical analyses for this end point

    Secondary: Vital Capacity

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    End point title
    		 Vital Capacity
    End point description
    Change from baseline in vital capacity
    End point type
    Secondary
    End point timeframe
    From baseline to Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    22
    26
    23
    Units: Liter
    arithmetic mean (standard deviation)
        Week 12 (n=17, 24, 18)
    0.15 ( 0.8 )
    0.18 ( 0.35 )
    0.13 ( 0.89 )
        Week 28 (n=14, 18, 15)
    0.15 ( 0.41 )
    0.11 ( 0.48 )
    -0.08 ( 0.41 )
    No statistical analyses for this end point

    Secondary: Functional Residual Capacity

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    End point title
    		 Functional Residual Capacity
    End point description
    Change from baseline in functional residual capacity
    End point type
    Secondary
    End point timeframe
    From baseline to Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    22
    26
    23
    Units: Liter
    arithmetic mean (standard deviation)
        Week 12 (n=17,23, 18)
    -0.05 ( 1.06 )
    -0.09 ( 0.74 )
    -0.38 ( 0.99 )
        Week 28 (n=13,18, 15)
    -0.15 ( 1.49 )
    -0.26 ( 0.74 )
    -0.43 ( 1.25 )
    No statistical analyses for this end point

    Secondary: Inspiratory Capacity

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    End point title
    		 Inspiratory Capacity
    End point description
    Change from baseline in inspiratory capacity
    End point type
    Secondary
    End point timeframe
    From baseline to Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    22
    26
    23
    Units: Liter
    arithmetic mean (standard deviation)
        Week 12 (n=17, 23, 17)
    0.44 ( 1.22 )
    0.14 ( 0.88 )
    -0.01 ( 0.4 )
        Week 28 (n=14, 17, 15)
    0.52 ( 1.16 )
    0.09 ( 1.01 )
    -0.02 ( 0.4 )
    No statistical analyses for this end point

    Secondary: Categories of percent reduction from baseline in final OCS dose while maintaining asthma control

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    End point title
    		 Categories of percent reduction from baseline in final OCS dose while maintaining asthma control
    End point description
    Percent reduction from baseline in final OCS dose, separated by categories.
    End point type
    Secondary
    End point timeframe
    Week 28
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    72
    73
    75
    Units: Participant
        >=90% reduction
    24
    27
    9
        >=75% reduction
    38
    37
    15
        >=50% reduction
    48
    48
    28
        >0% reduction
    55
    58
    40
        No change or any increase
    17
    15
    35
    Statistical analysis title
    		 Proportional odds ratio model
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [55]
    P-value
    		 < 0.001
    Method
    		 Multinomial logit
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.22
         upper limit
    		 7.63
    Notes
    [55] - Covariates of treatment group, region, and baseline OCS dosage
    Statistical analysis title
    		 Proportional odds ratio model
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [56]
    P-value
    		 < 0.001
    Method
    		 Multinomial logit
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.22
         upper limit
    		 7.57
    Notes
    [56] - Covariates of treatment group, region, and baseline OCS dosage

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall study period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Benra 30 mg q.4 weeks
    Reporting group description
    		 Benralizumab administered subcutaneously every 4 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered subcutaneously

    Reporting group title
    Benra 30 mg q.8 weeks
    Reporting group description
    		 Benralizumab administered subcutaneously every 8 weeks

    Serious adverse events
    		 Benra 30 mg q.4 weeks Placebo Benra 30 mg q.8 weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 72 (9.72%)
    14 / 75 (18.67%)
    7 / 73 (9.59%)
         number of deaths (all causes)
    0
    0
    2
         number of deaths resulting from adverse events
    0
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pericarditis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Oesophagitis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Gallbladder polyp
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 75 (0.00%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    3 / 72 (4.17%)
    4 / 75 (5.33%)
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status asthmaticus
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 75 (4.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 75 (2.67%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 75 (4.00%)
    2 / 73 (2.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 75 (1.33%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 75 (0.00%)
    0 / 73 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Benra 30 mg q.4 weeks Placebo Benra 30 mg q.8 weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 72 (47.22%)
    49 / 75 (65.33%)
    34 / 73 (46.58%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 72 (2.78%)
    2 / 75 (2.67%)
    3 / 73 (4.11%)
         occurrences all number
    2
    2
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 72 (6.94%)
    4 / 75 (5.33%)
    6 / 73 (8.22%)
         occurrences all number
    7
    4
    10
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 75 (2.67%)
    3 / 73 (4.11%)
         occurrences all number
    5
    2
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 72 (1.39%)
    3 / 75 (4.00%)
    0 / 73 (0.00%)
         occurrences all number
    1
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    6 / 72 (8.33%)
    14 / 75 (18.67%)
    1 / 73 (1.37%)
         occurrences all number
    11
    17
    2
    Cough
         subjects affected / exposed
    2 / 72 (2.78%)
    4 / 75 (5.33%)
    1 / 73 (1.37%)
         occurrences all number
    2
    4
    1
    Dyspnoea
         subjects affected / exposed
    2 / 72 (2.78%)
    4 / 75 (5.33%)
    1 / 73 (1.37%)
         occurrences all number
    2
    4
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 72 (2.78%)
    4 / 75 (5.33%)
    2 / 73 (2.74%)
         occurrences all number
    2
    5
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    5 / 72 (6.94%)
    12 / 75 (16.00%)
    8 / 73 (10.96%)
         occurrences all number
    7
    13
    10
    Influenza
         subjects affected / exposed
    3 / 72 (4.17%)
    5 / 75 (6.67%)
    1 / 73 (1.37%)
         occurrences all number
    3
    5
    1
    Nasopharyngitis
         subjects affected / exposed
    11 / 72 (15.28%)
    15 / 75 (20.00%)
    12 / 73 (16.44%)
         occurrences all number
    13
    17
    14
    Oral candidiasis
         subjects affected / exposed
    0 / 72 (0.00%)
    4 / 75 (5.33%)
    0 / 73 (0.00%)
         occurrences all number
    0
    4
    0
    Rhinitis
         subjects affected / exposed
    2 / 72 (2.78%)
    2 / 75 (2.67%)
    6 / 73 (8.22%)
         occurrences all number
    2
    2
    7
    Sinusitis
         subjects affected / exposed
    5 / 72 (6.94%)
    8 / 75 (10.67%)
    4 / 73 (5.48%)
         occurrences all number
    8
    11
    5
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 72 (5.56%)
    5 / 75 (6.67%)
    5 / 73 (6.85%)
         occurrences all number
    7
    7
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Apr 2015
    Pulmonary function objectives and change from baseline in blood eosinophils moved from exploratory to secondary objectives; additional secondary endpoints added; change power calculation method from t-test to Wilcoxon rank-sum test; lower eosinophil cut-point for recruitment; clarification of dose titration.
    10 Feb 2016
    The timing of database lock and unblinding of CSR was clarified to occur after the last patient had completed the EOT or IPD visit. If, at this time, there were any patients who did not elect to continue in the separate extension study (BORA), and had yet to complete final study-related assessments at the safety follow-up (Visit 15), these assessments were still to be conducted and the data was to be listed separately in an addendum to the CSR.

    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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