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    Clinical Trial Results:
    Randomised, double-blind, 56 week placebo-controlled, parallel group, multicentre, phase 3 study to evaluate the efficacy and safety of 2 doses of benralizumab in patients with moderate to very severe COPD with a history of exacerbations

    Summary
    EudraCT number
    		 2013-004590-27
    Trial protocol
    		 CZ   DE   HU   GB   IT   NL   PL   AT   ES  
    Global end of trial date
    10 Apr 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Apr 2019
    First version publication date
    04 Apr 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D3251C00003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02138916
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Vastra Malarehamnen 9, So dertalje, Sweden, 151 85
    Public contact
    Ulbaldo Martin, AstraZeneca AB, ulbaldo.martin@astrazeneca.com
    Scientific contact
    AstraZeneca Clinical Study Information, AstraZeneca AB, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the study is to determine if benralizumab reduces COPD exacerbation rate in subjects with moderate to severe COPD
    Protection of trial subjects
    The Independent Data Monitoring Committee is responsible for monitoring the safety of the study participants, ensuring that the studies are being conducted with the highest scientific and ethical standards and making appropriate recommendations based on the available data. The IDMC functions independently of all other individuals associated with the conduct of the studies, including the study sponsor AstraZeneca. The committee is operated in accordance with an Independent Data Monitoring Committee Charter.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jun 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 39
    Country: Number of subjects enrolled
    Canada: 65
    Country: Number of subjects enrolled
    Czech Republic: 37
    Country: Number of subjects enrolled
    Germany: 129
    Country: Number of subjects enrolled
    Hungary: 116
    Country: Number of subjects enrolled
    Italy: 34
    Country: Number of subjects enrolled
    Netherlands: 27
    Country: Number of subjects enrolled
    Poland: 176
    Country: Number of subjects enrolled
    Romania: 67
    Country: Number of subjects enrolled
    Russian Federation: 233
    Country: Number of subjects enrolled
    South Africa: 29
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 46
    Country: Number of subjects enrolled
    Spain: 54
    Country: Number of subjects enrolled
    Switzerland: 36
    Country: Number of subjects enrolled
    United Kingdom: 75
    Country: Number of subjects enrolled
    United States: 402
    Country: Number of subjects enrolled
    Japan: 91
    Worldwide total number of subjects
    1656
    EEA total number of subjects
    754
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    716
    From 65 to 84 years
    939
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 4462 patients signed informed consent. 1656 patients randomized to Benralizumab 30 mg, Benralizumab 100 mg, or Placebo. All randomized patients were treated. 554 (33.5%) were randomized to Benralizumab 30 mg, 552 (33.3%) were randomized to Benralizumab 100 mg, and 550 (33.2%) were randomized to 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
    Arm description
    		 Every 8 weeks administered 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 100 mg
    Arm description
    		 Every 8 weeks administered 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
    100 mg

    Arm title
    		 Placebo
    Arm description
    		 Every 8 weeks 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
    0 mg (matching placebo dose)

    Number of subjects in period 1
    		Benralizumab 30 mg Benralizumab 100 mg Placebo
    Started
    554
    552
    550
    Completed
    497
    492
    491
    Not completed
    57
    60
    59
         Adverse event, serious fatal
    14
    11
    12
         Consent withdrawn by subject
    27
    31
    32
         incorrect enrolment
    1
    1
    -
         Adverse event, non-fatal
    4
    4
    3
         eg., meds change, lack of efficacy, etc.
    6
    9
    7
         Lost to follow-up
    4
    2
    3
         Study specific withdrawal criteria
    -
    -
    1
         Severe non-compliance
    1
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Benralizumab 30 mg
    Reporting group description
    		 Every 8 weeks administered subcutaneously

    Reporting group title
    Benralizumab 100 mg
    Reporting group description
    		 Every 8 weeks administered subcutaneously

    Reporting group title
    Placebo
    Reporting group description
    		 Every 8 weeks administered subcutaneously

    Reporting group values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo Total
    Number of subjects
    		 554 552 550 1656
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 231 231 254 716
        From 65-84 years
    		 323 320 296 939
        85 years and over
    		 0 1 0 1
    Age Continuous
    Units: Year
        arithmetic mean (standard deviation)
    		 65.9 ( 7.77 ) 65.3 ( 8.05 ) 65.2 ( 8.22 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 172 180 175 527
        Male
    		 382 372 375 1129
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 496 493 488 1477
        Black or African American
    		 4 11 10 25
        Asian
    		 48 46 46 140
        Other
    		 6 2 6 14

    End points

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    End points reporting groups
    Reporting group title
    Benralizumab 30 mg
    Reporting group description
    		 Every 8 weeks administered subcutaneously

    Reporting group title
    Benralizumab 100 mg
    Reporting group description
    		 Every 8 weeks administered subcutaneously

    Reporting group title
    Placebo
    Reporting group description
    		 Every 8 weeks administered subcutaneously

    Primary: Annual COPD exacerbation rate ratio over 56 weeks treatment comparison for patients with baseline EOS>=220/uL

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    End point title
    		 Annual COPD exacerbation rate ratio over 56 weeks treatment comparison for patients with baseline EOS>=220/uL
    End point description
    A COPD exacerbation is defined by symptomatic worsening of COPD requiring: • Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or • Use of antibiotics; and/or • An inpatient hospitalization or death due to COPD
    End point type
    Primary
    End point timeframe
    From first IP to week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    382
    379
    359
    Units: Rate of event over follow-up time
        least squares mean (confidence interval 95%)
    1.19 (1.04 to 1.36)
    1.03 (0.9 to 1.19)
    1.24 (1.08 to 1.42)
    Statistical analysis title
    		 Negative binomial Analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    741
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.649
    Method
    		 Negative binomial
    Parameter type
    		 Rate ratio
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.15
    Statistical analysis title
    		 Negative binomial Analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    738
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0525
    Method
    		 Negative binomial
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1

    Secondary: Annual COPD exacerbation rate ratio over 56 weeks treatment comparison for patients with baseline EOS<220/uL

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    End point title
    		 Annual COPD exacerbation rate ratio over 56 weeks treatment comparison for patients with baseline EOS<220/uL
    End point description
    A COPD exacerbation is defined by symptomatic worsening of COPD requiring: • Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids; and/or • Use of antibiotics; and/or • An inpatient hospitalization or death due to COPD
    End point type
    Secondary
    End point timeframe
    From first IP to week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    172
    173
    191
    Units: Rate of event over follow-up time
        least squares mean (confidence interval 95%)
    1.4 (1.19 to 1.64)
    1.32 (1.12 to 1.56)
    1.30 (1.11 to 1.52)
    Statistical analysis title
    		 Negative binomial Analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    363
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5236
    Method
    		 Negative binomial
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 1.34
    Statistical analysis title
    		 Negative binomial Analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8812
    Method
    		 Negative binomial
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.27

    Secondary: Mean change from baseline to Week 56 in pre-bronchodilator FEV1 (L) value for patients with baseline EOS>=220/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 EOS>=220/uL
    End point description
    Pre-bronchodilator FEV1 (L) is collected at Weeks 0, 4, 8, 16, 24, 32, 40, 48, and 56. Baseline is the last non-missing value with quality (acceptable or borderline quality grade) prior to the first dose of study treatment.
    End point type
    Secondary
    End point timeframe
    First IP up to end of treatment Week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    329
    326
    317
    Units: Liter
        arithmetic mean (standard deviation)
    0.014 ( 0.282 )
    0.031 ( 0.294 )
    0.010 ( 0.275 )
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    646
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.755
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.007
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.035
         upper limit
    		 0.048
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    643
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3285
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.021
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.021
         upper limit
    		 0.062

    Secondary: Mean change from baseline in SGRQ total score for patients with baseline EOS>=220/uL

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    End point title
    		 Mean change from baseline in SGRQ total score for patients with baseline EOS>=220/uL
    End point description
    SGRQ is from 50-item PRO instrument. The SGRQ total score is expressed as a percentage of overall impairment, in which 100% means the worst possible health status and 0 indicates the best possible health status.
    End point type
    Secondary
    End point timeframe
    First IP up to Week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    338
    331
    317
    Units: Percentage
        arithmetic mean (standard deviation)
    -5.025 ( 14.677 )
    -6.723 ( 15.723 )
    -3.913 ( 15.039 )
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    655
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2906
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.011
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.887
         upper limit
    		 0.865
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    648
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0264
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.136
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.02
         upper limit
    		 -0.251

    Secondary: Mean change from baseline in CAT total score for patients with baseline EOS>=220/uL

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    End point title
    		 Mean change from baseline in CAT total score for patients with baseline EOS>=220/uL
    End point description
    CAT is an 8-item PRO developed to measure the impact of COPD on health status. The instrument uses semantic differential six-point response scales. A CAT total score is the sum of item responses. Score ranges from 0 to 40 with higher scores indicative of greater COPD impact on health status.
    End point type
    Secondary
    End point timeframe
    First IP up to Week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    338
    335
    319
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -1.50 ( 6.89 )
    -2.43 ( 6.34 )
    -1.22 ( 6.53 )
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    657
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6782
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.08
         upper limit
    		 0.7
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    654
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0753
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 0.08

    Secondary: Mean change from baseline in E-RS: COPD total score for patients with baseline EOS>=220/uL

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    End point title
    		 Mean change from baseline in E-RS: COPD total score for patients with baseline EOS>=220/uL
    End point description
    The E-RS: COPD is an 11-item PRO developed to evaluate the severity of respiratory symptoms of COPD. Summation of E-RS: COPD item responses produces a total score ranging from 0 to 40, with higher scores indicating greater severity.
    End point type
    Secondary
    End point timeframe
    First IP up to Week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    324
    328
    295
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -1.085 ( 5.273 )
    -1.354 ( 5.599 )
    -0.504 ( 5.674 )
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0889
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.585
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.26
         upper limit
    		 0.089
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    623
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0413
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.703
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.378
         upper limit
    		 -0.028

    Secondary: Mean change from baseline in total rescue medication use (number of puffs per day) for patients with baseline EOS>=220/uL

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    End point title
    		 Mean change from baseline in total rescue medication use (number of puffs per day) for patients with baseline EOS>=220/uL
    End point description
    The number of rescue medication inhalations and nebulizer treatments taken are recorded by the patient in the eDiary twice daily. Total rescue medication use is the sum of daytime and night-time use.
    End point type
    Secondary
    End point timeframe
    First IP up to Week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    321
    322
    291
    Units: Puffs/day
        arithmetic mean (standard deviation)
    -0.05 ( 3.21 )
    -0.27 ( 2.71 )
    0.29 ( 3.03 )
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    612
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0728
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.348
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.728
         upper limit
    		 0.032
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    613
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0121
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.487
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.868
         upper limit
    		 -0.107

    Secondary: Mean change from baseline in proportion of nights awakenings due to respiratory symptoms for patients with baseline EOS>=220/uL

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    End point title
    		 Mean change from baseline in proportion of nights awakenings due to respiratory symptoms for patients with baseline EOS>=220/uL
    End point description
    The number of rescue medication inhalations and nebulizer treatments taken are recorded by the patient in the eDiary twice daily. Total rescue medication use is the sum of daytime and night-time use.
    End point type
    Secondary
    End point timeframe
    First IP up to Week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    325
    323
    297
    Units: Proportion
        arithmetic mean (standard deviation)
    -0.088 ( 0.310 )
    -0085 ( 0.283 )
    -0.049 ( 0.307 )
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    622
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0235
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.041
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.077
         upper limit
    		 -0.006
    Statistical analysis title
    		 Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0158
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.044
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 -0.008

    Secondary: Number of COPD exacerbations based on EXACT-PRO for patients with baseline EOS>=220/uL

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    End point title
    		 Number of COPD exacerbations based on EXACT-PRO for patients with baseline EOS>=220/uL
    End point description
    The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences “today”. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an event has occurred.
    End point type
    Secondary
    End point timeframe
    Immediately following first IP up to week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    382
    378
    358
    Units: Participants
        0 exacerbation
    180
    184
    179
        1 exacerbation
    101
    103
    99
        2 exacerbations
    42
    49
    34
        3 exacerbations
    25
    14
    15
        4 exacerbations
    17
    13
    14
        5 exacerbations
    5
    6
    5
        6 exacerbations
    4
    4
    2
        7 exacerbations
    6
    1
    5
        8 exacerbations
    1
    1
    4
        9 exacerbations
    1
    2
    1
        10 exacerbations
    0
    1
    0
    No statistical analyses for this end point

    Secondary: Severity of EXACT-PRO for patients with baseline EOS>=220/uL

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    End point title
    		 Severity of EXACT-PRO for patients with baseline EOS>=220/uL
    End point description
    The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences “today”. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an event has occurred. The severity of an event is indicated by the worst (highest) EXACT-PRO total score during an event.
    End point type
    Secondary
    End point timeframe
    Immediately following first IP up to week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    202
    194
    179
    Units: Score on a scale
        arithmetic mean (standard deviation)
    51.5 ( 11.30 )
    50.8 ( 10.70 )
    52.0 ( 11.20 )
    No statistical analyses for this end point

    Secondary: Duration of EXACT-PRO for patients with baseline EOS>=220/uL

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    End point title
    		 Duration of EXACT-PRO for patients with baseline EOS>=220/uL
    End point description
    The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while onsidering their experiences “today”. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Event frequency is calculated by comparing the baseline with daily total scores. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an event has occurred. Calculation of event duration after identification of the following five parameters: 1) onset; 2) three-day rolling average; 3) maximum observed value; 4) threshold for improvement; and 5) recovery.
    End point type
    Secondary
    End point timeframe
    Immediately following first IP up to week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    202
    194
    179
    Units: Days
        arithmetic mean (standard deviation)
    82.2 ( 95.80 )
    88.3 ( 105.30 )
    101.7 ( 113.70 )
    No statistical analyses for this end point

    Secondary: Annual EXACT-PRO exacerbation rate ratio over 56 weeks treatment comparison for patients with baseline EOS>=220/uL

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    End point title
    		 Annual EXACT-PRO exacerbation rate ratio over 56 weeks treatment comparison for patients with baseline EOS>=220/uL
    End point description
    The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity and duration of COPD exacerbations. Respondents are instructed to complete the electronic diary (eDiary) each evening just prior to bedtime and to answer the questions while considering their experiences “today”. The daily EXACT-PRO total score has a range of 0-100 with higher scores indicative of greater severity. Total score changes are used to identify the onset and recovery from an EXACT-PRO defined exacerbation event. An increase in EXACT-PRO total score ≥9 for 3 days or ≥12 for 2 days indicate an event has occurred.
    End point type
    Secondary
    End point timeframe
    Immediately following first IP up to week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    382
    378
    358
    Units: Rate of event over follow-up time
        least squares mean (confidence interval 95%)
    1.14 (0.98 to 1.31)
    1.02 (0.88 to 1.19)
    1.04 (0.90 to 1.21)
    Statistical analysis title
    		 Negative binomial analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    740
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.408
    Method
    		 Negative binomial
    Parameter type
    		 Rate ratio
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 1.34
    Statistical analysis title
    		 Negative binomial analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    736
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8688
    Method
    		 Negative binomial
    Parameter type
    		 Rate ratio
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.21

    Secondary: Number of participants having at least 1 COPD exacerbation for patients with baseline EOS>=220/uL

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    End point title
    		 Number of participants having at least 1 COPD exacerbation for patients with baseline EOS>=220/uL
    End point description
    A COPD exacerbation is defined by symptomatic worsening COPD requiring systemic corticosteroids, antibiotics, or an inpatient hospitalization/death due to COPD.
    End point type
    Secondary
    End point timeframe
    Immediately following first IP up to week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    382
    379
    359
    Units: Participants
    204
    203
    198
    Statistical analysis title
    		 Cochran-Mantel-Haenszel Test (odds ratio)
    Statistical analysis description
    Proportion of participants with >=1 COPD exacerbation.
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    741
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.485
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.66
         upper limit
    		 1.22
    Statistical analysis title
    		 Cochran-Mantel-Haenszel Test (odds ratio)
    Statistical analysis description
    Proportion of participants with >=1 COPD exacerbation.
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    738
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4489
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.21

    Secondary: Time to first COPD exacerbation

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    End point title
    		 Time to first COPD exacerbation
    End point description
    Time to first COPD exacerbation is from the randomization date to the first occurrence of COPD exacerbation
    End point type
    Secondary
    End point timeframe
    Immediately following first IP up to week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    382
    379
    359
    Units: Days
        median (confidence interval 95%)
    333 (273 to 400)
    329 (262 to 396)
    337 (261 to 390)
    No statistical analyses for this end point

    Secondary: Annual COPD exacerbation rate ratio associated with ER or hospitalization over 56 weeks treatment comparison for patients with baseline EOS>=220/uL

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    End point title
    		 Annual COPD exacerbation rate ratio associated with ER or hospitalization over 56 weeks treatment comparison for patients with baseline EOS>=220/uL
    End point description
    A COPD exacerbation is defined by symptomatic worsening COPD requiring systemic corticosteroids, antibiotics, or an inpatient hospitalization/death due to COPD.
    End point type
    Secondary
    End point timeframe
    Immediately following first IP up to week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    382
    379
    359
    Units: Rate of event over follow-up time
        least squares mean (confidence interval 95%)
    0.27 (0.20 to 0.35)
    0.15 (0.11 to 0.20)
    0.25 (0.19 to 0.33)
    Statistical analysis title
    		 Negative binomial analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    741
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7733
    Method
    		 Negative binomial
    Parameter type
    		 Rate ratio
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.53
    Statistical analysis title
    		 Negative binomial analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    738
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0114
    Method
    		 Nagative binomial
    Parameter type
    		 Rate ratio
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.89

    Secondary: Number of participants had COPD-related healthcare encounter for patient with baseline EOS>=220/uL

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    End point title
    		 Number of participants had COPD-related healthcare encounter for patient with baseline EOS>=220/uL
    End point description
    Types of healthcare encounter: Hospitalisations (inc. intensive care and/or general care), Emergency department visits, Unscheduled outpatients visits, Home visits, Telephone calls, and ambulance transports.
    End point type
    Secondary
    End point timeframe
    Immediately following first IP up to week 56
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    382
    379
    359
    Units: Participants
        Hospitalisations|
    60
    38
    50
        Emergency Department Visits|
    36
    35
    43
        Unscheduled Outpatient Visits|
    219
    236
    202
        Home Visits|
    18
    22
    18
        Telephone calls|
    110
    111
    104
        Ambulance transports|
    16
    12
    20
    No statistical analyses for this end point

    Secondary: Duration of study treatment administration

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    End point title
    		 Duration of study treatment administration
    End point description
    Duration of study treatment is calculated from first dose date to last dose date + 1 day.
    End point type
    Secondary
    End point timeframe
    From first dose date to last dose date
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    554
    552
    550
    Units: Days
        arithmetic mean (standard deviation)
    302.4 ( 85.73 )
    304.0 ( 82.40 )
    302.5 ( 88.47 )
    No statistical analyses for this end point

    Secondary: Serum concentration of Benralizumab

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    End point title
    		 Serum concentration of Benralizumab [1]
    End point description
    PK serum samples were collected pre-dose at each visit.
    End point type
    Secondary
    End point timeframe
    From first dose to 1 cycle after discontinuation of treatment
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This summary is on the serum concentration of Benralizumab, thus the placebo group is not applicable.
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg
    Number of subjects analysed
    553
    550
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Baseline|
    0 ( 0 )
    0 ( 0 )
        Week 56|
    219.45 ( 233.21 )
    699.89 ( 243.20 )
    No statistical analyses for this end point

    Secondary: Immunogenicity of Benralizumab

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    End point title
    		 Immunogenicity of Benralizumab
    End point description
    ADA responses such as ADA prevalence, ADA incidence, ADA persistently positive counts, etc. were presented
    End point type
    Secondary
    End point timeframe
    Pre-treatment until end of follow-up
    End point values
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    554
    552
    550
    Units: Participants
        ADA prevalence|
    53
    64
    39
        ADA incidence|
    44
    47
    24
        Both base/post-baseline positive|
    5
    7
    17
        Only post baseline positive|
    43
    46
    20
        Only baseline positive|
    5
    11
    2
        ADA persistently positive|
    28
    34
    14
        ADA transiently positive|
    15
    12
    6
        nAb prevalence|
    43
    43
    25
        nAb incidence|
    41
    37
    18
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until last study visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Benralizumab 30 mg
    Reporting group description
    		 -

    Reporting group title
    Benralizumab 100 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Benralizumab 30 mg Benralizumab 100 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    151 / 554 (27.26%)
    177 / 552 (32.07%)
    176 / 550 (32.00%)
         number of deaths (all causes)
    15
    12
    13
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Benign lung neoplasm
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Colon neoplasm
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Glioblastoma multiforme
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Haemangioma of skin
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Meningioma
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Non-small cell lung cancer metastatic
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Non-small cell lung cancer stage IIIB
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Plasma cell myeloma
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 554 (0.36%)
    1 / 552 (0.18%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer stage II
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Renal neoplasm
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sarcoma
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Small cell lung cancer
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Small cell lung cancer metastatic
         subjects affected / exposed
    0 / 554 (0.00%)
    2 / 552 (0.36%)
    0 / 550 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsil cancer
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Transitional cell carcinoma
         subjects affected / exposed
    2 / 554 (0.36%)
    0 / 552 (0.00%)
    0 / 550 (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
    Vascular disorders
    Arterial haemorrhage
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    3 / 550 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         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
    1 / 554 (0.18%)
    1 / 552 (0.18%)
    0 / 550 (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
    Hypotension
         subjects affected / exposed
    0 / 554 (0.00%)
    2 / 552 (0.36%)
    0 / 550 (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
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Peripheral venous disease
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Death
         subjects affected / exposed
    1 / 554 (0.18%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Oedema peripheral
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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 cardiac death
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Immune system disorders
    Anaphylactic shock
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Prostatitis
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Bronchiectasis
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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 chronic
         subjects affected / exposed
    1 / 554 (0.18%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    97 / 554 (17.51%)
    78 / 552 (14.13%)
    100 / 550 (18.18%)
         occurrences causally related to treatment / all
    5 / 145
    1 / 101
    0 / 142
         deaths causally related to treatment / all
    0 / 7
    0 / 1
    0 / 2
    Chronic respiratory failure
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Dyspnoea
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Hypercapnia
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Lung consolidation
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Pickwickian syndrome
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Pneumonia aspiration
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Pneumothorax
         subjects affected / exposed
    2 / 554 (0.36%)
    1 / 552 (0.18%)
    5 / 550 (0.91%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 554 (0.18%)
    1 / 552 (0.18%)
    4 / 550 (0.73%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Pulmonary hypertension
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Pulmonary mass
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         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 failure
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    3 / 550 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Mental status changes
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram ST-T change
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Airway burns
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Ankle fracture
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Arterial bypass occlusion
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asbestosis
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Chest injury
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Dural tear
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Femoral neck fracture
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 554 (0.00%)
    2 / 552 (0.36%)
    0 / 550 (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
    Foot fracture
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Fractured coccyx
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Joint dislocation
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Patella fracture
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         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 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin flap necrosis
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         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 compression fracture
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Subdural haematoma
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Tendon rupture
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 554 (0.18%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Upper limb fracture
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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 bypass dysfunction
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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 graft occlusion
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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 procedure complication
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Wound
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Exomphalos
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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 coronary syndrome
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    2 / 554 (0.36%)
    1 / 552 (0.18%)
    4 / 550 (0.73%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute right ventricular failure
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Angina pectoris
         subjects affected / exposed
    1 / 554 (0.18%)
    3 / 552 (0.54%)
    0 / 550 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    2 / 554 (0.36%)
    2 / 552 (0.36%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         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
    4 / 554 (0.72%)
    8 / 552 (1.45%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 554 (0.54%)
    2 / 552 (0.36%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 554 (0.36%)
    2 / 552 (0.36%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Cor pulmonale chronic
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 554 (0.18%)
    1 / 552 (0.18%)
    0 / 550 (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
    Coronary artery insufficiency
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Coronary artery occlusion
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Coronary artery stenosis
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    3 / 550 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Myocardial infarction
         subjects affected / exposed
    4 / 554 (0.72%)
    3 / 552 (0.54%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Cerebrovascular accident
         subjects affected / exposed
    2 / 554 (0.36%)
    1 / 552 (0.18%)
    0 / 550 (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
    Dizziness
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperaesthesia
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Monoparesis
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radicular syndrome
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Radiculopathy
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Sciatica
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         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
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus headache
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Stupor
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 554 (0.18%)
    1 / 552 (0.18%)
    0 / 550 (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
    Thrombotic stroke
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Transient ischaemic attack
         subjects affected / exposed
    0 / 554 (0.00%)
    2 / 552 (0.36%)
    0 / 550 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypochromic anaemia
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 554 (0.00%)
    2 / 552 (0.36%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 554 (0.36%)
    1 / 552 (0.18%)
    0 / 550 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 554 (0.00%)
    2 / 552 (0.36%)
    0 / 550 (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
    Enterocolitis
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric polyps
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 554 (0.18%)
    1 / 552 (0.18%)
    0 / 550 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Haematochezia
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Ileus
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 554 (0.00%)
    3 / 552 (0.54%)
    0 / 550 (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
    Intestinal obstruction
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Intestinal perforation
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Intestinal polyp
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Large intestine perforation
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Large intestine polyp
         subjects affected / exposed
    0 / 554 (0.00%)
    2 / 552 (0.36%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Melaena
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Oesophageal spasm
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Pancreatitis
         subjects affected / exposed
    1 / 554 (0.18%)
    2 / 552 (0.36%)
    0 / 550 (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
    Pancreatitis acute
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salivary gland calculus
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         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
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         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
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 554 (0.36%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatomyositis
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         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 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Psoriasis
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin laxity
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Acute kidney injury
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Gouty arthritis
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 554 (0.18%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Osteoarthritis
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Appendicitis
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Arthritis bacterial
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         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 mycobacterial infection
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical mycobacterial lower respiratory tract infection
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 554 (0.18%)
    3 / 552 (0.54%)
    3 / 550 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Cellulitis
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Cellulitis pharyngeal
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Disseminated tuberculosis
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Diverticulitis
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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
    Infectious pleural effusion
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Influenza
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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 respiratory tract infection
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Periorbital cellulitis
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         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
    22 / 554 (3.97%)
    18 / 552 (3.26%)
    16 / 550 (2.91%)
         occurrences causally related to treatment / all
    1 / 24
    2 / 19
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    5 / 554 (0.90%)
    8 / 552 (1.45%)
    10 / 550 (1.82%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 9
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Pneumonia klebsiella
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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 moraxella
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Pneumonia necrotising
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Pneumonia pneumococcal
         subjects affected / exposed
    2 / 554 (0.36%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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 streptococcal
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         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 viral
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         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 syncytial virus infection
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Rhinovirus infection
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    0 / 550 (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 / 554 (0.00%)
    2 / 552 (0.36%)
    0 / 550 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 554 (0.18%)
    1 / 552 (0.18%)
    0 / 550 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 554 (0.18%)
    0 / 552 (0.00%)
    0 / 550 (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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 554 (0.36%)
    2 / 552 (0.36%)
    0 / 550 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    2 / 550 (0.36%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 554 (0.00%)
    0 / 552 (0.00%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 554 (0.00%)
    1 / 552 (0.18%)
    1 / 550 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    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 Benralizumab 100 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    401 / 554 (72.38%)
    427 / 552 (77.36%)
    390 / 550 (70.91%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    19 / 554 (3.43%)
    19 / 552 (3.44%)
    18 / 550 (3.27%)
         occurrences all number
    19
    19
    19
    Nervous system disorders
    Headache
         subjects affected / exposed
    21 / 554 (3.79%)
    26 / 552 (4.71%)
    20 / 550 (3.64%)
         occurrences all number
    29
    30
    21
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    11 / 554 (1.99%)
    26 / 552 (4.71%)
    11 / 550 (2.00%)
         occurrences all number
    13
    28
    11
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    17 / 554 (3.07%)
    19 / 552 (3.44%)
    15 / 550 (2.73%)
         occurrences all number
    19
    19
    17
    Diarrhoea
         subjects affected / exposed
    17 / 554 (3.07%)
    15 / 552 (2.72%)
    6 / 550 (1.09%)
         occurrences all number
    18
    18
    7
    Nausea
         subjects affected / exposed
    13 / 554 (2.35%)
    18 / 552 (3.26%)
    13 / 550 (2.36%)
         occurrences all number
    17
    22
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 554 (2.89%)
    14 / 552 (2.54%)
    21 / 550 (3.82%)
         occurrences all number
    18
    20
    30
    Dyspnoea
         subjects affected / exposed
    24 / 554 (4.33%)
    17 / 552 (3.08%)
    23 / 550 (4.18%)
         occurrences all number
    30
    19
    37
    Oropharyngeal pain
         subjects affected / exposed
    14 / 554 (2.53%)
    18 / 552 (3.26%)
    13 / 550 (2.36%)
         occurrences all number
    15
    21
    17
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    21 / 554 (3.79%)
    25 / 552 (4.53%)
    19 / 550 (3.45%)
         occurrences all number
    23
    30
    19
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    59 / 554 (10.65%)
    84 / 552 (15.22%)
    80 / 550 (14.55%)
         occurrences all number
    74
    113
    121
    Lower respiratory tract infection
         subjects affected / exposed
    50 / 554 (9.03%)
    32 / 552 (5.80%)
    29 / 550 (5.27%)
         occurrences all number
    76
    47
    39
    Oral candidiasis
         subjects affected / exposed
    17 / 554 (3.07%)
    13 / 552 (2.36%)
    15 / 550 (2.73%)
         occurrences all number
    21
    18
    16
    Respiratory tract infection
         subjects affected / exposed
    10 / 554 (1.81%)
    11 / 552 (1.99%)
    18 / 550 (3.27%)
         occurrences all number
    10
    14
    26
    Respiratory tract infection viral
         subjects affected / exposed
    15 / 554 (2.71%)
    12 / 552 (2.17%)
    19 / 550 (3.45%)
         occurrences all number
    21
    18
    23
    Sinusitis
         subjects affected / exposed
    13 / 554 (2.35%)
    17 / 552 (3.08%)
    20 / 550 (3.64%)
         occurrences all number
    16
    22
    22
    Upper respiratory tract infection
         subjects affected / exposed
    69 / 554 (12.45%)
    74 / 552 (13.41%)
    65 / 550 (11.82%)
         occurrences all number
    87
    104
    97
    Urinary tract infection
         subjects affected / exposed
    23 / 554 (4.15%)
    22 / 552 (3.99%)
    15 / 550 (2.73%)
         occurrences all number
    27
    30
    22
    Viral upper respiratory tract infection
         subjects affected / exposed
    83 / 554 (14.98%)
    95 / 552 (17.21%)
    66 / 550 (12.00%)
         occurrences all number
    126
    134
    98

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Apr 2014
    o Changed population from ‘severe to very severe’ to ‘Moderate to very severe’ o Inclusion criteria amended from FEV1 <50% to >20% and ≤65%; and exac history from >/=1 to >/= 2 moderate or >/=1 severe o Added sites, extended projected LSLV from Q2-17 to Q4-17 o Revised secondary endpoint from ‘COPD specific resource utilization’ to annual rate of hosp visits, ED visits, unscheduled study visits, other unscheduled visits due to COPD o Exclusion criteria for prior SCS/antibiotics/hosp changed from 8 weeks prior to enrolment to 2 weeks prior o Added excl criterion for ALT/AST >1.5x ULN (was previously just for hepatic disease) o Removed local eos measurement at V3 used for randomization stratification o Added adjudication of MACE
    27 Jan 2015
    o Added sites; reduced N to 1566/2088 {was originally 1743/2324} o Added exploratory CGIC and PGIC o Clarified Excl #23, to exclude history of immunodeficiency disorder and/or hep B/C as exclusion and allow patients with history of hep B vaccination without history of hepatitis o Section 3.5 entirely revised to clarify on con meds and restrictions, added requirement to captured COPD background meds for past year o Shift ePRO dispensing from V1 to V2 o Added collection of historical eos (from past year) if available o Amended to specify sequence of enrolment procedures when the low eos stratum is closed at site or country level (to allow ample time between V1-2 to receive central lab result, SF low eos pts) o Added clarity for re-screening (once per subject, discuss other reasons with STP) o Specified minimal time between doses (3wks) and procedures if need to postpone IP dosing o Added adjudication of malignancies
    03 Jul 2015
    o ≥220/μL now considered the boundary for the primary and the two key secondary efficacy variables analysis o Three baseline eosinophil count cohorts: ≥300/μL; 220-299/μL; <220/μL o Approximately 2:1 ratio of subjects above and below the boundary of 220/μL (rather than 300) o Defined sample size for each cohort, increased overall N to 1626/2168 for Galathea/Terranova; added sites o TB exclusion refined to specify first positive test must be treated according to guidelines before being considered for enrolment o One additional re-screening allowed for eos stratum closure, to be discussed with STP (NB: ‘reason for change’ indicates for pts with borderline eos, but CSP text doesn’t stipulate that) o Specify that nAb will be tested on all ADA positive samples (instead of at EOT/FU/IPD timepoints) o All subgroup analyses will be described in the SAP

    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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