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    Clinical Trial Results:
    A multicentre, randomised, double-blind, parallel group, placebo-controlled, Phase 3 study to evaluate the efficacy and safety of benralizumab in asthmatic adults and adolescents inadequately controlled on inhaled corticosteroid plus long-acting beta2 agonist (CALIMA)

    Summary
    EudraCT number
    		 2013-002163-26
    Trial protocol
    		 DE   SE   PL  
    Global end of trial date
    04 May 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    07 Jan 2017
    First version publication date
    24 Sep 2016
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    D3250C00018
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01914757
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001214-PIP01-11
    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
    04 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    04 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the effect of two dosing regimens of benralizumab on asthma exacerbations in patients on high-dose ICS-LABA 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
    21 Aug 2013
    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
    Sweden: 10
    Country: Number of subjects enrolled
    Ukraine: 118
    Country: Number of subjects enrolled
    United States: 171
    Country: Number of subjects enrolled
    Philippines: 61
    Country: Number of subjects enrolled
    Argentina: 269
    Country: Number of subjects enrolled
    Canada: 59
    Country: Number of subjects enrolled
    Chile: 31
    Country: Number of subjects enrolled
    Germany: 159
    Country: Number of subjects enrolled
    Japan: 83
    Country: Number of subjects enrolled
    Poland: 290
    Country: Number of subjects enrolled
    Romania: 55
    Worldwide total number of subjects
    1306
    EEA total number of subjects
    514
    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)
    55
    Adults (18-64 years)
    1074
    From 65 to 84 years
    177
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 2505 participants signed informed consent, 2181 entered screening/run-in period, 1306 participants were randomised to receive treatment with benralizumab 30 mg Q4W, Q8W, or placebo. Of the 1306 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 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
    425
    441
    440
    Completed
    389
    390
    402
    Not completed
    36
    51
    38
         Severe non-compliance to protocol
    3
    1
    2
         Adverse event, serious fatal
    2
    2
    1
         Consent withdrawn by subject
    15
    27
    19
         Eligibility criteria not fulfilled
    2
    -
    2
         Adverse event, non-fatal
    4
    3
    4
         Other reasons
    5
    9
    4
         Lost to follow-up
    5
    8
    6
         Study specific withdrawal criteria
    -
    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 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
    		 425 441 440 1306
    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)
    		 11 21 23 55
        Adults (18-64 years)
    		 359 365 350 1074
        From 65-84 years
    		 55 55 67 177
        85 years and over
    		 0 0 0 0
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 50 ( 13.6 ) 49 ( 14.3 ) 48.8 ( 15.1 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 270 273 264 807
        Male
    		 155 168 176 499

    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 8 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered subcutaneously.

    Primary: Annual asthma exacerbation rate in adult and adolescent patients with uncontrolled asthma, baseline eosinophils >=300/uL

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    End point title
    		 Annual asthma exacerbation rate in adult and adolescent patients with uncontrolled asthma, baseline eosinophils >=300/uL
    End point description
    The annual exacerbation rate is based on unadjudicated annual exacerbation rate reported by the investigator in the eCRF. The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS
    End point type
    Primary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    241
    239
    248
    Units: events/year
        least squares mean (confidence interval 95%)
    0.6 (0.48 to 0.74)
    0.66 (0.54 to 0.82)
    0.93 (0.77 to 1.12)
    Statistical analysis title
    		 Negative Binomial Model
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Negative Binomial
    Parameter type
    		 Rate Ratio
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.85
    Statistical analysis title
    		 Negative Binomial Model
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.019
    Method
    		 Negative Binomial
    Parameter type
    		 Rate Ratio
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.95

    Secondary: Mean change from baseline to Week 56 in Pre-bronchodilator FEV1 (L) value for patients with baseline eosinophils >=300/uL

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    End point title
    		 Mean change from baseline to Week 56 in Pre-bronchodilator FEV1 (L) value for patients with baseline eosinophils >=300/uL
    End point description
    The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    216
    211
    221
    Units: Liter
        arithmetic mean (standard deviation)
    0.34 ( 0.469 )
    0.332 ( 0.518 )
    0.206 ( 0.471 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    432
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.116
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.028
         upper limit
    		 0.204
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.125
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.037
         upper limit
    		 0.213

    Secondary: Mean change from baseline to Week 56 asthma symptoms score for patients with baseline eosinophils >=300/uL

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    End point title
    		 Mean change from baseline to Week 56 asthma symptoms score for patients with baseline eosinophils >=300/uL
    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). Baseline is defined as the average of data collected from the evening of study day -10 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
    Immediately following the first administration of study drug through Study Week 56.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    184
    185
    187
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.33 ( 1.23 )
    -1.4 ( 1.17 )
    -1.2 ( 1.19 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.224
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.07
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.019
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.43
         upper limit
    		 -0.04

    Secondary: Change in asthma rescue medication use

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    End point title
    		 Change in asthma rescue medication use
    End point description
    Change from Baseline to Week 56 in number of Rescue medication use (puffs/day). The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS. The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    184
    185
    187
    Units: Puffs per day
        arithmetic mean (standard deviation)
    -2 ( 3.64 )
    -2.92 ( 3.6 )
    -2.65 ( 9.57 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.603
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 0.99
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    372
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.209
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.29
         upper limit
    		 0.28

    Secondary: Home lung function assessments based on morning PEF

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    End point title
    		 Home lung function assessments based on morning PEF
    End point description
    Change from Baseline to Week 56 in Home lung function (morning Peak expiratory flow [PEF]). The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    194
    193
    197
    Units: L/min
        arithmetic mean (standard deviation)
    41.745 ( 78.534 )
    43.375 ( 91.865 )
    23.961 ( 71.509 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Statistical analysis description
    Morning PEF Change from Baseline to Week 56
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    390
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.037
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    15.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 29.64
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Statistical analysis description
    Morning PEF Change from Baseline to Week 56
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    391
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.029
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    15.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.59
         upper limit
    		 30.12

    Secondary: Proportion of Nights with awakening due to asthma

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    End point title
    		 Proportion of Nights with awakening due to asthma
    End point description
    Change from Baseline to Week 56 on Proportion of Nights with awakening due to asthma. The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    196
    198
    203
    Units: Proportion of nights
        arithmetic mean (standard deviation)
    -0.373 ( 0.388 )
    -0.431 ( 0.4 )
    -0.372 ( 0.405 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    399
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.03
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.146
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.01

    Secondary: Mean change from baseline to Week 56 in ACQ-6 for patients with baseline eosinophils >=300/uL

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    End point title
    		 Mean change from baseline to Week 56 in ACQ-6 for patients with baseline eosinophils >=300/uL
    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. The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    192
    185
    197
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.34 ( 1.13 )
    -1.49 ( 1.13 )
    -1.21 ( 1.12 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.043
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 -0.01
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    382
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.44
         upper limit
    		 -0.07

    Secondary: Number of patients with >=1 asthma exacerbation

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    End point title
    		 Number of patients with >=1 asthma exacerbation
    End point description
    The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    241
    239
    248
    Units: Participants
    84
    95
    126
    Statistical analysis title
    		 Cochran-Mantel-Haenszel Test
    Statistical analysis description
    Proportion of patients with >=1 asthma exacerbation
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 0.69
    Statistical analysis title
    		 Cochran-Mantel-Haenszel Test
    Statistical analysis description
    Proportion of patients with >=1 asthma exacerbation
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.023
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.95

    Secondary: Annual rate of asthma exacerbation resulting emergency room visits and hospitalizations

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    End point title
    		 Annual rate of asthma exacerbation resulting emergency room visits and hospitalizations
    End point description
    Annual rate of asthma exacerbations that are associated with an emergency room visit or a hospitalization (adjudicated). The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    241
    239
    248
    Units: events/year
        least squares mean (confidence interval 95%)
    0.04 (0.02 to 0.06)
    0.05 (0.03 to 0.08)
    0.04 (0.02 to 0.07)
    Statistical analysis title
    		 Negative Bionomial
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.837
    Method
    		 negative binomial
    Parameter type
    		 Rate Ratio
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.82
    Statistical analysis title
    		 Negative Binomial
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.538
    Method
    		 negative binomial
    Parameter type
    		 Rate Ratio
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 2.35

    Secondary: Pharmacokinetics of benralizumab

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    End point title
    		 Pharmacokinetics of benralizumab
    End point description
    Mean PK Concentration at each visit
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, Week 56, Week 60
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    425 [1]
    424
    0 [2]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Baseline (n=435, 419)
    0 ( 0 )
    0 ( 0 )
    ( )
        Week 4 (n=430, 416)
    650.04 ( 154.61 )
    703.16 ( 89.48 )
    ( )
        Week 8 (n=414, 395)
    894.86 ( 148.91 )
    939.45 ( 98.99 )
    ( )
        Week 16 (n=390, 378)
    936.43 ( 247.46 )
    252.54 ( 274.74 )
    ( )
        Week 24 (n=388, 361)
    827.09 ( 370.64 )
    188.99 ( 308.38 )
    ( )
        Week 32 (n=345, 323)
    823.21 ( 362.43 )
    166.53 ( 289.34 )
    ( )
        Week 40 (n=370, 338)
    859.69 ( 364.28 )
    172.28 ( 298.6 )
    ( )
        Week 48 (n=355, 337)
    888.09 ( 333.98 )
    186.5 ( 290.28 )
    ( )
        Week 56 (n=358, 344)
    763.98 ( 309.18 )
    173.41 ( 235.86 )
    ( )
        Week 60 (n=49, 45)
    53.63 ( 1782.96 )
    18.63 ( 756.47 )
    ( )
    Notes
    [1] - Patients were treated with q.4 weeks instead of q.8 weeks, so 435 in the analysis.
    [2] - No concentration of Experimental Product.
    No statistical analyses for this end point

    Secondary: Immunogenicity of benralizumab

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    End point title
    		 Immunogenicity of benralizumab
    End point description
    Anti-drug antibodies (ADA) responses at baseline and post baseline. Persistently positive is defined as positive at >=2 post-baseline assessments (with >=16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive is defined as having at least one post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive.
    End point type
    Secondary
    End point timeframe
    Pre-treatment until end of follow-up
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    425 [3]
    427
    440
    Units: Participants
        Positive at any visit (n=438, 427, 440)
    63
    64
    13
        Base- and post-baseline positive (n=431, 414, 430)
    5
    5
    5
        Only post-baseline positive (n=431, 420, 436)
    55
    57
    8
        Persistently positive (n=431, 420, 436)
    44
    42
    7
        Transient positive (n=431, 420, 436)
    16
    20
    6
        Only baseline positive (n=438, 421, 434)
    3
    2
    0
    Notes
    [3] - Patients were treated with q.4 rather than q.8. So 438 in the analysis
    No statistical analyses for this end point

    Secondary: Extent of exposure

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    End point title
    		 Extent of exposure
    End point description
    Extent of exposure is defined as the duration of treatment in days
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    425 [4]
    428
    440
    Units: Days
        arithmetic mean (standard deviation)
    344.14 ( 73.129 )
    331.64 ( 88.839 )
    336.69 ( 82.148 )
    Notes
    [4] - 13 more patients were treated with q.4 rather than q.8, so 438 in the analysis
    No statistical analyses for this end point

    Secondary: Mean change from baseline to Week 56 in AQLQ(S)+12

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    End point title
    		 Mean change from baseline to Week 56 in AQLQ(S)+12
    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. The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    186
    180
    191
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    1.44 ( 1.15 )
    1.61 ( 1.24 )
    1.32 ( 1.19 )
    Statistical analysis title
    		 Mixed Effect Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.019
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.45
    Statistical analysis title
    		 Mixed Effect Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.119
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.37

    Secondary: Change from baseline to Week 56 in EQ-5D-5L VAS

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    End point title
    		 Change from baseline to Week 56 in EQ-5D-5L VAS
    End point description
    EQ-5D-5L VAS is to rate current health status on a scale of 0-100, with 0 being the worst imaginable health state. The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    183
    179
    191
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    13.8 ( 21.52 )
    15.5 ( 20.36 )
    12.1 ( 20.13 )
    No statistical analyses for this end point

    Secondary: Mean work productivity loss due to asthma

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    End point title
    		 Mean work productivity loss due to asthma
    End point description
    WPAI+CIQ (Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire) contains 10 questions. Work productivity loss is derived by sum of percentage of missed work due to asthma and product of percentage of actual working hours times degree of asthma affecting work productivity while working. Percentage of missed work due to asthma is calculated by number of hours missed work due to asthma divided by total number of hours missed work plus number of hours actually worked. Analyses are for Week 56. The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS, and is only applicable for patients employed.
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    92
    74
    85
    Units: percent of productivity loss
        arithmetic mean (standard deviation)
    26.56 ( 25.589 )
    24.44 ( 24.689 )
    27.29 ( 25.802 )
    No statistical analyses for this end point

    Secondary: Mean productivity loss due to asthma in Classroom

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    End point title
    		 Mean productivity loss due to asthma in Classroom
    End point description
    WPAI+CIQ (Work Productivity and Activity Impairment plus Classroom Impairment Questionnaire) contains 10 questions. Classroom productivity loss is derived by sum of percentage of missed classes due to asthma and product of percentage of actual hours attending classes times degree of asthma affecting classroom productivity. Percentage of missed classes due to asthma is calculated by number of hours missed classes due to asthma divided by total number of hours missed classes plus number of hours actually attending classes. Analyses are for Week 56. The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS, and patients who took classes.
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    14
    5
    5
    Units: percent of productivity loss
        arithmetic mean (standard deviation)
    19.92 ( 23.765 )
    14 ( 16.733 )
    33.5 ( 25.593 )
    No statistical analyses for this end point

    Secondary: Number of participants that utilized health care resources

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    End point title
    		 Number of participants that utilized health care resources
    End point description
    The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    241
    239
    248
    Units: Participants
        Hospitalizations
    11
    14
    12
        Emergency department visits
    11
    12
    18
        Unscheduled outpatient visits
    72
    75
    83
        Home visits
    3
    1
    2
        Telephone calls
    50
    63
    58
        Ambulance transports
    2
    3
    5
    No statistical analyses for this end point

    Secondary: Patient and Clinician assessment of response to treatment

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    End point title
    		 Patient and Clinician assessment of response to treatment
    End point description
    CGIC (clinician global impression of change), and PGIC (patient global impression of change) are overall evaluation of response to treatment, conducted separately by investigator and patient using a 7-point rating scale, ranging from 1 (Very much Improved), to 7 (Very much Worse). The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS. Due to the endpoint was implemented after the second protocol amendment, thus not all patients having data to be analyzed.
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    241
    239
    248
    Units: Participants
        CGIC, Improved
    109
    96
    97
        CGIC, Much Improved
    82
    71
    65
        CGIC, Very Much Improved
    26
    23
    14
        CGIC, Total
    217
    190
    176
        PGIC, Improved
    109
    95
    99
        PGIC, Much Improved
    83
    80
    66
        PGIC, Very Much Improved
    34
    30
    17
        PGIC, Total
    226
    205
    182
    No statistical analyses for this end point

    Secondary: Annual asthma exacerbation rate in adult and adolescent patients with uncontrolled asthma, baseline eosinophils <300/uL

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    End point title
    		 Annual asthma exacerbation rate in adult and adolescent patients with uncontrolled asthma, baseline eosinophils <300/uL
    End point description
    The annual exacerbation rate is based on unadjudicated annual exacerbation rate reported by the investigator in the eCRF. The analysis is based on the analysis population of baseline eosinophils <300/uL and high-dose ICS
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug throguh Study Week 56.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    116
    125
    122
    Units: events/year
        least squares mean (confidence interval 95%)
    0.78 (0.59 to 1.02)
    0.73 (0.55 to 0.95)
    1.21 (0.96 to 1.52)
    Statistical analysis title
    		 Negative binomial analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 negative binomial
    Parameter type
    		 Rate ratio
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.86
    Statistical analysis title
    		 Negative binomial analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.015
    Method
    		 Negative binomial
    Parameter type
    		 Rate ratio
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.92

    Secondary: Mean change from baseline to Week 56 in Pre-bronchodilator FEV1 (L) value for patient with baseline eosinophils <300/uL

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    End point title
    		 Mean change from baseline to Week 56 in Pre-bronchodilator FEV1 (L) value for patient with baseline eosinophils <300/uL
    End point description
    The analysis is based on the analysis population of baseline eosinophils <300/uL and high-dose ICS
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    101
    98
    99
    Units: Liter
        arithmetic mean (standard deviation)
    0.221 ( 0.441 )
    0.164 ( 0.358 )
    0.135 ( 0.437 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.786
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.015
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.127
         upper limit
    		 0.096
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.268
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.064
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.049
         upper limit
    		 0.176

    Secondary: Mean change from baseline to Week 56 asthma symptoms score for patient with baseline eosinophils <300/uL

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    End point title
    		 Mean change from baseline to Week 56 asthma symptoms score for patient with baseline eosinophils <300/uL
    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). Baseline is defined as the average of data collected from the evening of study day -10 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. The analysis is based on the population of baseline eosinophils <300/uL and high-dose ICS.
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    88
    85
    89
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.05 ( 1.14 )
    -0.95 ( 1.13 )
    -0.88 ( 1.12 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.287
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.44
         upper limit
    		 0.13
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.966
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 0.29

    Secondary: Mean change from baseline to Week 56 in ACQ-6 for patients with baseline eosinophils <300/uL

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    End point title
    		 Mean change from baseline to Week 56 in ACQ-6 for patients with baseline eosinophils <300/uL
    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. The analysis is based on the analysis population of baseline eosinophils <300/uL and high-dose ICS
    End point type
    Secondary
    End point timeframe
    Immediately followwing the first administration of study drug through Study Week 56.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    88
    83
    92
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.22 ( 1.16 )
    -1.06 ( 1.02 )
    -0.83 ( 1.07 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    180
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.078
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 0.03
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.449
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 0.16

    Secondary: Time to first asthma exacerbation

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    End point title
    		 Time to first asthma exacerbation
    End point description
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    241
    239
    248
    Units: Participants
    84
    95
    126
    Statistical analysis title
    		 Cox regression
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    489
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.8
    Statistical analysis title
    		 Cox regression
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    487
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.018
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 0.95

    Secondary: Home lung function assessments based on evening PEF

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    End point title
    		 Home lung function assessments based on evening PEF
    End point description
    Change from Baseline to Week 56 in Home lung function (evening Peak expiratory flow [PEF]). The analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL and high-dose ICS
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 56
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    194
    192
    197
    Units: L/min
        arithmetic mean (standard deviation)
    35.142 ( 75.489 )
    39.27 ( 89.772 )
    15.448 ( 78.341 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Statistical analysis description
    Evening PEF Change from Baseline to Week 56
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    389
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    21.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.65
         upper limit
    		 35.79
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Statistical analysis description
    Evening PEF Change from Baseline to Week 56
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    391
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.018
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    17.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.07
         upper limit
    		 32

    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.8 weeks
    Reporting group description
    		 Benralizumab administered subcutaneously event 8 weeks

    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

    Serious adverse events
    		 Benra 30 mg q.8 weeks Benra 30 mg q.4 weeks Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    41 / 428 (9.58%)
    46 / 438 (10.50%)
    61 / 440 (13.86%)
         number of deaths (all causes)
    2
    3
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer female
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon neoplasm
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gallbladder cancer
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Gastric cancer
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Thyroid adenoma
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Phlebitis
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 428 (0.23%)
    1 / 438 (0.23%)
    0 / 440 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Drug hypersensitivity
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         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
    19 / 428 (4.44%)
    21 / 438 (4.79%)
    23 / 440 (5.23%)
         occurrences causally related to treatment / all
    1 / 27
    0 / 25
    0 / 38
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperventilation
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasal turbinate hypertrophy
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Pleural effusion
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Depression
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Injury, poisoning and procedural complications
    Anastomotic ulcer
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Humerus fracture
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Procedural complication
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Road traffic accident
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Acute myocardial infarction
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Aortic valve stenosis
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         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 fibrillation
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Atrioventricular block complete
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Coronary artery disease
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    2 / 440 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Syncope
         subjects affected / exposed
    1 / 428 (0.23%)
    1 / 438 (0.23%)
    0 / 440 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroduodenitis
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Inguinal hernia
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Large intestine polyp
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Rectal polyp
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Cholecystitis acute
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Cholelithiasis
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Hepatitis alcoholic
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Skin and subcutaneous tissue disorders
    Parakeratosis
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urticaria papular
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Calculus ureteric
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Nephrolithiasis
         subjects affected / exposed
    0 / 428 (0.00%)
    2 / 438 (0.46%)
    0 / 440 (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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Dupuytren's contracture
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Epiphysiolysis
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaw cyst
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Muscular weakness
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Osteoarthritis
         subjects affected / exposed
    1 / 428 (0.23%)
    1 / 438 (0.23%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Spondylolisthesis
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Bacterial infection
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Bronchitis
         subjects affected / exposed
    1 / 428 (0.23%)
    1 / 438 (0.23%)
    0 / 440 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis haemophilus
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Chronic sinusitis
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Cytomegalovirus hepatitis
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Herpes zoster
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Influenza
         subjects affected / exposed
    2 / 428 (0.47%)
    0 / 438 (0.00%)
    0 / 440 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 428 (0.00%)
    2 / 438 (0.46%)
    4 / 440 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 428 (0.00%)
    2 / 438 (0.46%)
    3 / 440 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomonas bronchitis
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         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 tract infection bacterial
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Sepsis
         subjects affected / exposed
    0 / 428 (0.00%)
    1 / 438 (0.23%)
    0 / 440 (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
    Sinusitis
         subjects affected / exposed
    0 / 428 (0.00%)
    0 / 438 (0.00%)
    1 / 440 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Urinary tract infection
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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
    Metabolism and nutrition disorders
    Obesity
         subjects affected / exposed
    1 / 428 (0.23%)
    0 / 438 (0.00%)
    0 / 440 (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.8 weeks Benra 30 mg q.4 weeks Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    232 / 428 (54.21%)
    244 / 438 (55.71%)
    264 / 440 (60.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 428 (4.21%)
    12 / 438 (2.74%)
    22 / 440 (5.00%)
         occurrences all number
    23
    12
    24
    Nervous system disorders
    Headache
         subjects affected / exposed
    34 / 428 (7.94%)
    33 / 438 (7.53%)
    32 / 440 (7.27%)
         occurrences all number
    65
    63
    57
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    13 / 428 (3.04%)
    16 / 438 (3.65%)
    6 / 440 (1.36%)
         occurrences all number
    13
    20
    6
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    32 / 428 (7.48%)
    50 / 438 (11.42%)
    52 / 440 (11.82%)
         occurrences all number
    50
    76
    96
    Cough
         subjects affected / exposed
    14 / 428 (3.27%)
    10 / 438 (2.28%)
    8 / 440 (1.82%)
         occurrences all number
    18
    11
    12
    Rhinitis allergic
         subjects affected / exposed
    16 / 428 (3.74%)
    21 / 438 (4.79%)
    24 / 440 (5.45%)
         occurrences all number
    19
    25
    28
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    14 / 428 (3.27%)
    8 / 438 (1.83%)
    10 / 440 (2.27%)
         occurrences all number
    16
    10
    14
    Back pain
         subjects affected / exposed
    11 / 428 (2.57%)
    17 / 438 (3.88%)
    16 / 440 (3.64%)
         occurrences all number
    11
    18
    20
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    5 / 428 (1.17%)
    6 / 438 (1.37%)
    14 / 440 (3.18%)
         occurrences all number
    6
    6
    19
    Bronchitis
         subjects affected / exposed
    45 / 428 (10.51%)
    40 / 438 (9.13%)
    54 / 440 (12.27%)
         occurrences all number
    54
    51
    72
    Influenza
         subjects affected / exposed
    12 / 428 (2.80%)
    24 / 438 (5.48%)
    25 / 440 (5.68%)
         occurrences all number
    17
    27
    27
    Nasopharyngitis
         subjects affected / exposed
    82 / 428 (19.16%)
    90 / 438 (20.55%)
    92 / 440 (20.91%)
         occurrences all number
    131
    132
    147
    Pharyngitis
         subjects affected / exposed
    10 / 428 (2.34%)
    17 / 438 (3.88%)
    8 / 440 (1.82%)
         occurrences all number
    10
    21
    9
    Rhinitis
         subjects affected / exposed
    18 / 428 (4.21%)
    12 / 438 (2.74%)
    17 / 440 (3.86%)
         occurrences all number
    24
    13
    22
    Sinusitis
         subjects affected / exposed
    21 / 428 (4.91%)
    23 / 438 (5.25%)
    39 / 440 (8.86%)
         occurrences all number
    30
    31
    56
    Upper respiratory tract infection
         subjects affected / exposed
    37 / 428 (8.64%)
    29 / 438 (6.62%)
    42 / 440 (9.55%)
         occurrences all number
    53
    35
    53

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 May 2014
    addition of adolescent patient population, amended incl/exclusion criteria, additional lab measurements
    16 Mar 2015
    addition of PRO questionaries’’, addition of MACE/Malignancies Adjudication, additional laboratory mesurments

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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