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    Clinical Trial Results:
    A multicentre, randomised, double-blind, parallel group, placebo-controlled, Phase III efficacy and safety study of benralizumab (MEDI-563) added to high-dose inhaled corticosteroid plus long-acting beta2 agonist in patients with uncontrolled asthma (SIROCCO)

    Summary
    EudraCT number
    		 2013-002345-11
    Trial protocol
    		 IT   GB   CZ   ES   BG   PL  
    Global end of trial date
    11 May 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Oct 2016
    First version publication date
    14 Oct 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D3250C00017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01928771
    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
    11 May 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    11 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
    19 Sep 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
    Australia: 45
    Country: Number of subjects enrolled
    Brazil: 36
    Country: Number of subjects enrolled
    Bulgaria: 110
    Country: Number of subjects enrolled
    Czech Republic: 47
    Country: Number of subjects enrolled
    France: 91
    Country: Number of subjects enrolled
    Italy: 45
    Country: Number of subjects enrolled
    Mexico: 21
    Country: Number of subjects enrolled
    Peru: 97
    Country: Number of subjects enrolled
    Poland: 75
    Country: Number of subjects enrolled
    Russian Federation: 155
    Country: Number of subjects enrolled
    South Africa: 26
    Country: Number of subjects enrolled
    Korea, Republic of: 122
    Country: Number of subjects enrolled
    Spain: 36
    Country: Number of subjects enrolled
    Turkey: 42
    Country: Number of subjects enrolled
    United Kingdom: 38
    Country: Number of subjects enrolled
    United States: 203
    Country: Number of subjects enrolled
    Vietnam: 15
    Worldwide total number of subjects
    1204
    EEA total number of subjects
    442
    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)
    53
    Adults (18-64 years)
    1008
    From 65 to 84 years
    143
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 1205 participants were randomised to receive treatment with benralizumab 30 mg Q4W, Q8W, or placebo. Of the 1205 patients randomised, 1204 (99.9%) patients received treatment with the study drug: 399 patients received benralizumab 30 mg Q4W, 398 patients received benralizumab 30 mg Q8W, and 407 patients received placebo.

    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, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Benralizumab 30 mg q.4 weeks
    Arm description
    		 Benralizumab administered every 4 weeks subcutaneously.
    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 every 8 weeks subcutaneously.
    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 cartridge
    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
    399
    398
    407
    Completed
    354
    358
    367
    Not completed
    45
    40
    40
         Adverse event, serious fatal
    2
    2
    2
         Consent withdrawn by subject
    20
    15
    17
         Severe Non-Compliance to Protocol
    4
    2
    2
         Adverse event, non-fatal
    6
    5
    1
         Other Reasons
    9
    9
    14
         Lost to follow-up
    4
    6
    3
         Study-Specific Withdrawal Criteria
    -
    1
    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 every 4 weeks subcutaneously.

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

    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
    		 399 398 407 1204
    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 19 23 53
        Adults (18-64 years)
    		 338 339 331 1008
        From 65-84 years
    		 50 40 53 143
        85 years and over
    		 0 0 0 0
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 50.1 ( 13.4 ) 47.6 ( 14.5 ) 48.7 ( 14.9 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 275 252 269 796
        Male
    		 124 146 138 408

    End points

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

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

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered subcutaneously

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

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    End point title
    		 Annual asthma exacerbation rate in adult and adolescent patients with uncontrolled asthma for 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 population, ie, baseline eosinophils >=300/uL
    End point type
    Primary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    275
    267
    267
    Units: Rate of event over follow-up time
        least squares mean (confidence interval 95%)
    0.73 (0.6 to 0.89)
    0.65 (0.53 to 0.8)
    1.33 (1.12 to 1.58)
    Statistical analysis title
    		 Negative binomial analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Negative binomial
    Parameter type
    		 Rate ratio
    Point estimate
    0.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 0.71
    Statistical analysis title
    		 Negative binomial analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Negative binomial
    Parameter type
    		 Rate ratio
    Point estimate
    0.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.64

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

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    End point title
    		 Annual asthma exacerbation rate resulting emergency room visits and hospitalizations
    End point description
    The annual exacerbation rate associated with an emergency room visit or a hospitalization (adjudicated). This analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    275
    267
    267
    Units: Rate of event over follow-up time
        least squares mean (confidence interval 95%)
    0.11 (0.07 to 0.16)
    0.06 (0.04 to 0.11)
    0.18 (0.13 to 0.25)
    Statistical analysis title
    		 Negative binomial analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Negative binomial
    Parameter type
    		 Rate ratio
    Point estimate
    0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.2
         upper limit
    		 0.67
    Statistical analysis title
    		 Negative binomial analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.053
    Method
    		 Negative binomial
    Parameter type
    		 Rate ratio
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 1.01

    Secondary: Proportion of patients with >=1 asthma exacerbations and time to first asthma exacerbation

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    End point title
    		 Proportion of patients with >=1 asthma exacerbations and time to first asthma exacerbation
    End point description
    Analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    275
    267
    267
    Units: Count
    100
    93
    135
    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
    542
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.37
         upper limit
    		 0.78
    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
    534
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.9
    Statistical analysis title
    		 Time to event analysis
    Statistical analysis description
    Time to first exacerbation
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.82
    Statistical analysis title
    		 Time to event analysis
    Statistical analysis description
    Time to first exacerbation
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 0.78

    Secondary: Mean change from baseline to Week 48 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 48 in pre-bronchodilator FEV1 (L) value for patients with baseline eosinophils >=300/uL
    End point description
    Analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    275
    267
    267
    Units: Liter
        arithmetic mean (standard deviation)
    0.353 ( 0.503 )
    0.398 ( 0.546 )
    0.237 ( 0.508 )
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.159
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.068
         upper limit
    		 0.249
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.022
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.106
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.016
         upper limit
    		 0.196

    Secondary: Mean change from baseline to Week 48 in asthma symptom score for patients with baseline eosinophils >=300/uL

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    End point title
    		 Mean change from baseline to Week 48 in asthma symptom score for patients with baseline eosinophils >=300/uL
    End point description
    Asthma symptoms during night time and day time are recorded by the patient each morning and evening in the asthma daily diary. 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. Analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL.
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    275
    267
    267
    Units: Scale of score
        arithmetic mean (standard deviation)
    -1.15 ( 1.31 )
    -1.34 ( 1.27 )
    -1.03 ( 1.07 )
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 -0.06
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.442
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 0.12

    Secondary: Change in asthma rescue medication

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    End point title
    		 Change in asthma rescue medication
    End point description
    Change from baseline to week 48 in number of rescue medication use (puffs/day). Analysis is based on primary analysis population, ie, baseline eosinophils >=300/uL
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    275
    267
    267
    Units: Puffs/day
        arithmetic mean (standard deviation)
    -2.74 ( 4.29 )
    -2.78 ( 3.9 )
    -2.18 ( 4.38 )
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.081
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.21
         upper limit
    		 0.07
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.16
         upper limit
    		 0.1

    Secondary: Home lung function assessment based on PEF

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    End point title
    		 Home lung function assessment based on PEF
    End point description
    Change from baseline to week 48 in home lung function (morning and evening peak expiratory flow [PEF]). Analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL.
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    275
    267
    267
    Units: L/min
    arithmetic mean (standard deviation)
        Morning at Week 48 (n=205, 181, 189)
    45.857 ( 84.227 )
    36.994 ( 72.002 )
    22.059 ( 74.434 )
        Evening at Week 48 (n=203, 187, 189)
    36.806 ( 86.271 )
    33.46 ( 74.017 )
    14.784 ( 68.799 )
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Statistical analysis description
    Morning PEF change from baseline to Week 48
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    23.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.2
         upper limit
    		 37.43
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Statistical analysis description
    Morning PEF change from baseline to Week 48
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.025
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    16.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.08
         upper limit
    		 30.83
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Statistical analysis description
    Evening PEF change from baseline to Week 48
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    21.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.86
         upper limit
    		 35.65
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Statistical analysis description
    Evening PEF change from baseline to Week 48
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.008
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    19.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.09
         upper limit
    		 33.28

    Secondary: Proportion of night awakening due to asthma

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    End point title
    		 Proportion of night awakening due to asthma
    End point description
    Change from baseline to Week 48 on proportion of night awakening due to asthma. Analysis is based on primary analysis population, ie, baseline eosinophils >=300/uL.
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    275
    267
    267
    Units: Proportion
        arithmetic mean (standard deviation)
    -0.314 ( 0.366 )
    -0.38 ( 0.385 )
    -0.26 ( 0.344 )
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.012
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 -0.01
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.964
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.04

    Secondary: Mean change from baseline to Week 48 in ACQ-6 for patients with baseline eosinophils >=300/uL

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    End point title
    		 Mean change from baseline to Week 48 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. Analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL.
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    275
    267
    267
    Units: Scale of score
        arithmetic mean (standard deviation)
    -1.33 ( 1.18 )
    -1.47 ( 1.05 )
    -1.12 ( 1.15 )
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 -0.1
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.111
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.34
         upper limit
    		 0.04

    Secondary: Pharmacokinetics of benralizumab

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    End point title
    		 Pharmacokinetics of benralizumab
    End point description
    Mean PK concentrations at each visit
    End point type
    Secondary
    End point timeframe
    Baseline, week 4, week 4 day 6, week 8, week 16, week 24, week 32, week 40, week 48, week 56
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    399
    391
    0 [1]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Baseline (n=395, 386)
    0 ( 0 )
    0 ( 0 )
    ( )
        Week 4 (n=393, 375)
    632.84 ( 152.14 )
    629.89 ( 169.22 )
    ( )
        Week 4 day 6 (n=54, 63)
    1368.98 ( 633.33 )
    1273.7 ( 688.2 )
    ( )
        Week 8 (n=377, 366)
    916.25 ( 142.53 )
    881.57 ( 156.12 )
    ( )
        Week 16 (n=358, 350)
    1024.26 ( 174.08 )
    250.84 ( 228.25 )
    ( )
        Week 24 (n=349, 344)
    926.62 ( 231.75 )
    184.08 ( 298.92 )
    ( )
        Week 32 (n=260, 267)
    853.67 ( 248.6 )
    152.73 ( 394.18 )
    ( )
        Week 40 (n=328, 333)
    967.15 ( 218.32 )
    157.22 ( 364.6 )
    ( )
        Week 48 (n=333, 333)
    864.37 ( 283.87 )
    162.51 ( 352.46 )
    ( )
        Week 56 (n=63, 67)
    51.7 ( 833.91 )
    6.66 ( 321.88 )
    ( )
    Notes
    [1] - Not applicable since it is not 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 the first and the 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
    399 [2]
    394
    407
    Units: Count
        Positive at any visit
    47
    58
    21
        Baseline and >=1 post baseline result available
    393
    381
    396
        Both baseline and post baseline positive
    2
    3
    10
        >=1 post baseline result available
    396
    389
    402
        Only post baseline positive
    39
    49
    10
        Persistently positive
    23
    39
    16
        Transiently positive
    18
    13
    4
        Baseline result available
    399
    385
    401
        Only baseline positive
    6
    6
    1
    Notes
    [2] - 4 patients randomized to q8, but treated with q4, so 403 in the analysis.
    No statistical analyses for this end point

    Secondary: Extend of exposure

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    End point title
    		 Extend of exposure
    End point description
    Extend of exposure is defined as duration of treatment in days
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    399 [3]
    394
    407
    Units: Days
        arithmetic mean (standard deviation)
    285.86 ( 67.446 )
    288.02 ( 66.683 )
    289.38 ( 61.527 )
    Notes
    [3] - 4 patients randomized to q8, but treated q4, so 403 in the analysis.
    No statistical analyses for this end point

    Secondary: Mean change from baseline to week 48 in AQLQ(S)+12

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    End point title
    		 Mean change from baseline to week 48 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. Analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL.
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    275
    267
    267
    Units: Scale of score
        arithmetic mean (standard deviation)
    1.44 ( 1.18 )
    1.56 ( 1.17 )
    1.25 ( 1.18 )
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    542
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.081
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 0.37
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    534
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.5

    Secondary: Mean change from baseline to week 48 in EQ-5D-5L VAS

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    End point title
    		 Mean change from baseline to week 48 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. Analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    191
    186
    181
    Units: Scale of score
        arithmetic mean (standard deviation)
    13.5 ( 21.82 )
    16.5 ( 23.66 )
    12.5 ( 21.41 )
    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 loss at Week 48. Analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL, and also only patients who were employed are applicable.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    85
    79
    76
    Units: Percent
        arithmetic mean (standard deviation)
    23.31 ( 24.169 )
    26.11 ( 23.06 )
    35.36 ( 24.537 )
    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 productivity loss at Week 48 in classroom. Analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL, and also only patients who attended classes are applicable.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    8
    6
    18
    Units: Percent
        arithmetic mean (standard deviation)
    30.97 ( 25.311 )
    27.17 ( 38.456 )
    49.1 ( 25.801 )
    No statistical analyses for this end point

    Secondary: Number of healthcare utilization

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    End point title
    		 Number of healthcare utilization
    End point description
    Analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL.
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    275
    267
    267
    Units: Count
        Hospitalizations
    14
    12
    20
        Emergency department visits
    20
    10
    26
        Unscheduled outpatient visits
    77
    87
    109
        Home visits
    2
    1
    3
        Telephone calls
    46
    41
    62
        Ambulance transports
    6
    3
    9
    No statistical analyses for this end point

    Secondary: Patient and clinician's responder assessment to treatment

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    End point title
    		 Patient and clinician's responder assessment to treatment
    End point description
    CGIC (Clinical 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 7-point rating scale, ranging from 1 (very much improved), to 7 (very much worse). Analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL. Due to the measurement was added after the second amendment of the protocol, not all patients had data for the analyses.
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    275
    267
    267
    Units: Count
        CGIC improved
    80
    76
    88
        CGIC much improved
    59
    58
    58
        CGIC very much improved
    18
    12
    5
        CGIC total responder
    157
    146
    151
        PGIC improved
    84
    80
    91
        PGIC much improved
    55
    58
    65
        PGIC very much improved
    26
    19
    11
        PGIC total responder
    165
    157
    167
    No statistical analyses for this end point

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

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    End point title
    		 Annual asthma exacerbation rate in adult and adolescent patients with uncontrolled asthma for 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 based on patients with baseline eosinophils <300/uL.
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    124
    131
    140
    Units: Rate of event over follow-up time
        least squares mean (confidence interval 95%)
    0.85 (0.65 to 1.11)
    1 (0.78 to 1.28)
    1.21 (0.96 to 1.52)
    Statistical analysis title
    		 Negative binomial analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.047
    Method
    		 Negative binomial
    Parameter type
    		 rate ratio
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1
    Statistical analysis title
    		 Negative binomial analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.268
    Method
    		 Negative binomial
    Parameter type
    		 Rate ratio
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.16

    Secondary: Mean change from baseline to Week 48 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 48 in pre-bronchodilator FEV1 (L) value for patients with baseline eosinophils <300/uL
    End point description
    Analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    124
    131
    140
    Units: Liter
        arithmetic mean (standard deviation)
    0.115 ( 0.417 )
    0.238 ( 0.483 )
    0.14 ( 0.4 )
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.644
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.025
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.134
         upper limit
    		 0.083
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.057
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.102
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.003
         upper limit
    		 0.208

    Secondary: Mean change from baseline to Week 48 in asthma symptom score for patients with baseline eosinophils <300/uL

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    End point title
    		 Mean change from baseline to Week 48 in asthma symptom score for patients with baseline eosinophils <300/uL
    End point description
    Asthma symptoms during night time and day time are recorded by the patient each morning and evening in the asthma daily diary. 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. Analysis is based on the primary analysis population, ie, baseline eosinophils >=300/uL.
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    124
    131
    140
    Units: Scale of score
        arithmetic mean (standard deviation)
    -0.98 ( 1.19 )
    -1.04 ( 1.24 )
    -0.78 ( 0.99 )
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.169
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 0.08
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.043
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.57
         upper limit
    		 -0.01

    Secondary: Mean change from baseline to Week 48 in ACQ-6 for patients with baseline eosinophils <300/uL

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    End point title
    		 Mean change from baseline to Week 48 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. Analysis is based on the primary analysis population, ie, baseline eosinophils <300/uL.
    End point type
    Secondary
    End point timeframe
    Immediately following the first administration of study drug through Study Week 48.
    End point values
    		 Benralizumab 30 mg q.4 weeks Benralizumab 30 mg q.8 weeks Placebo
    Number of subjects analysed
    124
    131
    140
    Units: Scale of score
        arithmetic mean (standard deviation)
    -0.77 ( 1.07 )
    -1.14 ( 1.11 )
    -0.89 ( 1.01 )
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.4 weeks v Placebo
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.99
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 0.27
    Statistical analysis title
    		 Mixed effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg q.8 weeks v Placebo
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.107
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 0.05

    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
    Benralizumab 30 mg q.4 weeks
    Reporting group description
    		 Benralizumab administered every 4 weeks subcutaneously.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered subcutaneously

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

    Serious adverse events
    		 Benralizumab 30 mg q.4 weeks Placebo Benralizumab 30 mg q.8 weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    51 / 403 (12.66%)
    58 / 407 (14.25%)
    54 / 394 (13.71%)
         number of deaths (all causes)
    2
    2
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenolymphoma
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         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 adenoma
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian epithelial cancer
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Hypertension
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Injection site erythema
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Oedema peripheral
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Sudden death
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Immune system disorders
    Allergic granulomatous angiitis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Contrast media allergy
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Asthma
         subjects affected / exposed
    23 / 403 (5.71%)
    32 / 407 (7.86%)
    24 / 394 (6.09%)
         occurrences causally related to treatment / all
    0 / 29
    0 / 42
    0 / 33
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    2 / 403 (0.50%)
    1 / 407 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 403 (0.25%)
    2 / 407 (0.49%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Sinus polyp
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Anxiety
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Panic attack
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Facial bones fracture
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Femoral neck fracture
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Ligament sprain
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Incisional hernia
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         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 vertebral fracture
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Lower limb fracture
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle rupture
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Overdose
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Post procedural complication
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Tendon rupture
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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 disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 403 (0.25%)
    1 / 407 (0.25%)
    0 / 394 (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
    Angina unstable
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         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
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         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
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Nervous system disorders
    Aphonia
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Cerebral venous thrombosis
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Blood and lymphatic system disorders
    Hypercoagulation
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         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 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Optic nerve disorder
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Gastric ulcer
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Gastritis
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Inguinal hernia
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         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 gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Volvulus
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         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
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         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 acute
         subjects affected / exposed
    2 / 403 (0.50%)
    1 / 407 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Dermatitis atopic
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erythema nodosum
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Rash papular
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         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 papular
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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 failure
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Foot deformity
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Intervertebral disc degeneration
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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 / 403 (0.25%)
    2 / 407 (0.49%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Vertebral foraminal stenosis
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         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
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Bullous impetigo
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 403 (0.50%)
    1 / 407 (0.25%)
    0 / 394 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Parotitis
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         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 / 403 (0.00%)
    3 / 407 (0.74%)
    2 / 394 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         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 pneumococcal
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Pneumonia viral
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Pyelonephritis
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 403 (0.00%)
    2 / 407 (0.49%)
    0 / 394 (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
    Urinary tract infection enterococcal
         subjects affected / exposed
    0 / 403 (0.00%)
    1 / 407 (0.25%)
    0 / 394 (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
    Vestibular neuronitis
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 403 (0.25%)
    0 / 407 (0.00%)
    0 / 394 (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
    Diabetes mellitus
         subjects affected / exposed
    0 / 403 (0.00%)
    0 / 407 (0.00%)
    1 / 394 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         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
    		 Benralizumab 30 mg q.4 weeks Placebo Benralizumab 30 mg q.8 weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    214 / 403 (53.10%)
    219 / 407 (53.81%)
    199 / 394 (50.51%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    31 / 403 (7.69%)
    21 / 407 (5.16%)
    37 / 394 (9.39%)
         occurrences all number
    38
    28
    61
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    16 / 403 (3.97%)
    8 / 407 (1.97%)
    12 / 394 (3.05%)
         occurrences all number
    21
    8
    19
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    8 / 403 (1.99%)
    8 / 407 (1.97%)
    12 / 394 (3.05%)
         occurrences all number
    12
    9
    14
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    15 / 403 (3.72%)
    11 / 407 (2.70%)
    13 / 394 (3.30%)
         occurrences all number
    17
    15
    14
    Asthma
         subjects affected / exposed
    48 / 403 (11.91%)
    60 / 407 (14.74%)
    27 / 394 (6.85%)
         occurrences all number
    64
    102
    38
    Rhinitis allergic
         subjects affected / exposed
    11 / 403 (2.73%)
    8 / 407 (1.97%)
    12 / 394 (3.05%)
         occurrences all number
    11
    9
    12
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 403 (2.73%)
    12 / 407 (2.95%)
    18 / 394 (4.57%)
         occurrences all number
    13
    19
    20
    Pain in extremity
         subjects affected / exposed
    3 / 403 (0.74%)
    5 / 407 (1.23%)
    13 / 394 (3.30%)
         occurrences all number
    3
    6
    13
    Back pain
         subjects affected / exposed
    12 / 403 (2.98%)
    15 / 407 (3.69%)
    8 / 394 (2.03%)
         occurrences all number
    13
    15
    9
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    10 / 403 (2.48%)
    11 / 407 (2.70%)
    13 / 394 (3.30%)
         occurrences all number
    11
    15
    14
    Bronchitis
         subjects affected / exposed
    27 / 403 (6.70%)
    30 / 407 (7.37%)
    19 / 394 (4.82%)
         occurrences all number
    28
    41
    22
    Gastroenteritis
         subjects affected / exposed
    10 / 403 (2.48%)
    6 / 407 (1.47%)
    12 / 394 (3.05%)
         occurrences all number
    16
    6
    14
    Nasopharyngitis
         subjects affected / exposed
    47 / 403 (11.66%)
    49 / 407 (12.04%)
    47 / 394 (11.93%)
         occurrences all number
    62
    64
    69
    Influenza
         subjects affected / exposed
    15 / 403 (3.72%)
    23 / 407 (5.65%)
    19 / 394 (4.82%)
         occurrences all number
    19
    31
    21
    Pharyngitis
         subjects affected / exposed
    17 / 403 (4.22%)
    14 / 407 (3.44%)
    23 / 394 (5.84%)
         occurrences all number
    21
    20
    24
    Sinusitis
         subjects affected / exposed
    18 / 403 (4.47%)
    29 / 407 (7.13%)
    22 / 394 (5.58%)
         occurrences all number
    23
    43
    34
    Rhinitis
         subjects affected / exposed
    16 / 403 (3.97%)
    15 / 407 (3.69%)
    10 / 394 (2.54%)
         occurrences all number
    17
    17
    11
    Upper respiratory tract infection
         subjects affected / exposed
    45 / 403 (11.17%)
    37 / 407 (9.09%)
    32 / 394 (8.12%)
         occurrences all number
    74
    73
    51

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 May 2014
    addition of adolescent patient population, amended incl/exclusion criteria, additional lab measurements
    23 Apr 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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