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    Clinical Trial Results:
    A randomised, double-blind, double dummy, 56 week placebo-controlled, multicentre, parallel group, phase 3 study evaluating efficacy/safety of 3 benralizumab doses in patients with moderate to very severe COPD with previous exacerbations.

    Summary
    EudraCT number
    2013-004579-11
    Trial protocol
    DK   SE   BE   PL   BG   SI   HR  
    Global end of trial date
    09 Apr 2018

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

    Trial information

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    Trial identification
    Sponsor protocol code
    D3251C00004
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02155660
    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
    09 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    09 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 symptomatic patients with moderate to very severe COPD who are receiving standard of care therapies.
    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
    25 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
    Argentina: 282
    Country: Number of subjects enrolled
    Australia: 24
    Country: Number of subjects enrolled
    Belgium: 37
    Country: Number of subjects enrolled
    Brazil: 99
    Country: Number of subjects enrolled
    Bulgaria: 125
    Country: Number of subjects enrolled
    Chile: 42
    Country: Number of subjects enrolled
    Colombia: 54
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    Denmark: 73
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Israel: 49
    Country: Number of subjects enrolled
    Mexico: 37
    Country: Number of subjects enrolled
    New Zealand: 25
    Country: Number of subjects enrolled
    Norway: 21
    Country: Number of subjects enrolled
    Peru: 69
    Country: Number of subjects enrolled
    Philippines: 143
    Country: Number of subjects enrolled
    Poland: 191
    Country: Number of subjects enrolled
    Serbia: 3
    Country: Number of subjects enrolled
    Slovenia: 12
    Country: Number of subjects enrolled
    Sweden: 33
    Country: Number of subjects enrolled
    Taiwan: 25
    Country: Number of subjects enrolled
    Thailand: 27
    Country: Number of subjects enrolled
    Turkey: 50
    Country: Number of subjects enrolled
    Ukraine: 178
    Country: Number of subjects enrolled
    United States: 561
    Country: Number of subjects enrolled
    Vietnam: 61
    Worldwide total number of subjects
    2254
    EEA total number of subjects
    525
    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)
    1040
    From 65 to 84 years
    1210
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    6059 participants signed informed consent form, 2254 participants were randomised to receive treatment with benralizumab 10 mg, 30 mg, 100 mg, or placebo. All randomised participants were treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Benralizumab 10 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
    10 mg

    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 infusion 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 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Started
    562
    562
    562
    568
    Completed
    504
    489
    502
    507
    Not completed
    58
    73
    60
    61
         Study-specific withdrawal criteria
    -
    1
    1
    1
         Other Reason
    8
    6
    10
    10
         Adverse event, serious fatal
    17
    19
    17
    19
         Adverse event, non-fatal
    2
    6
    3
    1
         Severe non-compliance
    -
    4
    -
    1
         Consent withdrawn by subject
    28
    31
    24
    21
         Lost to follow-up
    3
    6
    5
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Benralizumab 10 mg
    Reporting group description
    Every 8 weeks administered subcutaneously

    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 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo Total
    Number of subjects
    562 562 562 568 2254
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    263 241 275 261 1040
        From 65-84 years
    298 319 286 307 1210
        85 years and over
    1 2 1 0 4
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    64.7 ± 8.47 65.6 ± 8.61 65.0 ± 8.23 65.3 ± 8.44 -
    Sex: Female, Male
    Units: Subjects
        Female
    196 194 207 209 806
        Male
    366 368 355 359 1448
    Race/Ethnicity, Customized
    Units: Subjects
        White|
    441 444 443 446 1774
        Black or African American|
    8 12 16 19 55
        Asian|
    70 69 67 67 273
        Other|
    43 37 36 36 152

    End points

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    End points reporting groups
    Reporting group title
    Benralizumab 10 mg
    Reporting group description
    Every 8 weeks administered subcutaneously

    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
    Immediately following the first IP dose through week 56
    End point values
    Benralizumab 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    377
    394
    386
    388
    Units: Rate of event over follow-up time
        least squares mean (confidence interval 95%)
    0.99 (0.87 to 1.13)
    1.21 (1.08 to 1.37)
    1.09 (0.96 to 1.23)
    1.17 (1.04 to 1.32)
    Statistical analysis title
    Negative binomial Analysis
    Comparison groups
    Benralizumab 10 mg v Placebo
    Number of subjects included in analysis
    765
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0638
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    0.85
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.01
    Statistical analysis title
    Negative binomial analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    782
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6575
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    1.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.88
         upper limit
    1.23
    Statistical analysis title
    Negative binomial analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    774
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3988
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.78
         upper limit
    1.1

    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
    Immediately following the first IP dose through week 56
    End point values
    Benralizumab 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    185
    168
    176
    180
    Units: Rate of event over follow-up time
        least squares mean (confidence interval 95%)
    1.23 (1.03 to 1.46)
    1.27 (1.05 to 1.53)
    1.21 (1.00 to 1.45)
    1.18 (0.98 to 1.41)
    Statistical analysis title
    Negative binomial analysis
    Comparison groups
    Benralizumab 10 mg v Placebo
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7564
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    1.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    1.32
    Statistical analysis title
    Negative binomial analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    348
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5573
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.84
         upper limit
    1.37
    Statistical analysis title
    Negative binomial analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    356
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8644
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    1.3

    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 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    325
    322
    347
    344
    Units: Liter
        arithmetic mean (standard deviation)
    0.021 ± 0.346
    0.011 ± 0.289
    0.033 ± 0.291
    0.016 ± 0.292
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 10 mg v Placebo
    Number of subjects included in analysis
    669
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5043
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.015
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.029
         upper limit
    0.059
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    666
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7691
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.007
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.051
         upper limit
    0.037
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    691
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3767
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.024
         upper limit
    0.064

    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 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    331
    329
    354
    349
    Units: Percentage
        arithmetic mean (standard deviation)
    -7.733 ± 14.996
    -8.674 ± 17.910
    -7.257 ± 15.989
    -6.863 ± 16.344
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 10 mg v Placebo
    Number of subjects included in analysis
    680
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3636
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.011
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.192
         upper limit
    1.171
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    678
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2106
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.388
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.562
         upper limit
    0.786
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    703
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5851
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.602
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.763
         upper limit
    1.56

    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 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    332
    331
    354
    350
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -2.18 ± 6.78
    -2.43 ± 7.18
    -2.36 ± 6.67
    -2.36 ± 6.54
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 10 mg v Placebo
    Number of subjects included in analysis
    682
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8525
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.82
         upper limit
    0.99
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    681
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.987
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.91
         upper limit
    0.89
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    704
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8204
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0.79

    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 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    316
    302
    317
    325
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -1.657 ± 5.701
    -2.219 ± 6.381
    -1.593 ± 5.665
    -1.137 ± 5.935
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 10 mg v Placebo
    Number of subjects included in analysis
    641
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2636
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.102
         upper limit
    0.301
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    627
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4087
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.296
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.998
         upper limit
    0.406
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    642
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2336
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.425
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.125
         upper limit
    0.275

    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 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    305
    290
    310
    314
    Units: Puffs/day
        arithmetic mean (standard deviation)
    -0.36 ± 3.04
    -0.24 ± 3.36
    -0.17 ± 3.02
    0.23 ± 3.55
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 10 mg v Placebo
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0012
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.642
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.029
         upper limit
    -0.254
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    604
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0852
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.727
         upper limit
    0.047
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    624
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.065
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.364
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.75
         upper limit
    0.023

    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 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    316
    298
    321
    322
    Units: Proportion
        arithmetic mean (standard deviation)
    -0.092 ± 0.297
    -0.131 ± 0.332
    -0.084 ± 0.334
    -0.053 ± 0.345
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 10 mg v Placebo
    Number of subjects included in analysis
    638
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0415
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.041
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.081
         upper limit
    -0.002
    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
    = 0.2008
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.026
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.065
         upper limit
    0.014
    Statistical analysis title
    Mix effect repeated measurement analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    620
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0069
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.055
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.094
         upper limit
    -0.015

    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 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    377
    394
    385
    388
    Units: Participants
        0 exacerbation
    166
    173
    162
    159
        1 exacerbation
    108
    107
    113
    119
        2 exacerbations
    45
    51
    56
    46
        3 exacerbations
    21
    27
    25
    27
        4 exacerbations
    14
    16
    13
    13
        5 exacerbations
    8
    8
    9
    12
        6 exacerbations
    7
    6
    4
    7
        7 exacerbations
    2
    4
    1
    2
        8 exacerbations
    4
    1
    2
    1
        9 exacerbations
    0
    1
    0
    1
        10 exacerbations
    2
    0
    0
    0
        11 exacerbations
    0
    0
    0
    1
    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 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    211
    221
    223
    229
    Units: Score on a scale
        arithmetic mean (standard deviation)
    50.3 ± 12.30
    52.1 ± 11.3
    51.2 ± 11.0
    51.0 ± 11.7
    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 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    211
    221
    223
    229
    Units: Days
        arithmetic mean (standard deviation)
    110.1 ± 114.0
    96.1 ± 109.3
    99.8 ± 114.8
    99.9 ± 113.9
    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 the first IP dose through week 56
    End point values
    Benralizumab 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    377
    394
    385
    388
    Units: Rate of event over follow-up time
        least squares mean (confidence interval 95%)
    1.20 (1.05 to 1.37)
    1.21 (1.06 to 1.37)
    1.13 (0.99 to 1.29)
    1.23 (1.08 to 1.40)
    Statistical analysis title
    Negative binomial analysis
    Comparison groups
    Benralizumab 10 mg v Placebo
    Number of subjects included in analysis
    765
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8158
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    1.18
    Statistical analysis title
    Negative binomial analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    782
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8378
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    1.18
    Statistical analysis title
    Negative bionomail analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    773
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3759
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1.11

    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 dose up to week 56
    End point values
    Benralizumab 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    377
    394
    386
    388
    Units: Participants
    203
    241
    214
    208
    Statistical analysis title
    Cochran-Mantel-Haenszel Test (odds ratio)
    Statistical analysis description
    Proportion of participants with >=1 COPD exacerbation.
    Comparison groups
    Benralizumab 10 mg v Placebo
    Number of subjects included in analysis
    765
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9141
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    1.36
    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
    782
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0323
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.03
         upper limit
    1.87
    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
    774
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5109
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    1.48

    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 dose to week 56
    End point values
    Benralizumab 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    377
    394
    386
    388
    Units: Days
        median (confidence interval 95%)
    315 (244 to 380)
    260 (225 to 291)
    322 (278 to 373)
    337 (261 to 400)
    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 the first IP dose through week 56
    End point values
    Benralizumab 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    377
    394
    386
    388
    Units: Rate of event over follow-up time
        least squares mean (confidence interval 95%)
    0.22 (0.17 to 0.29)
    0.29 (0.23 to 0.36)
    0.22 (0.17 to 0.28)
    0.32 (0.26 to 0.40)
    Statistical analysis title
    Negative binomial analysis
    Comparison groups
    Benralizumab 10 mg v Placebo
    Number of subjects included in analysis
    765
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0287
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    0.96
    Statistical analysis title
    Negative binomial analysis
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    782
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4631
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.65
         upper limit
    1.22
    Statistical analysis title
    Negative binomial analysis
    Comparison groups
    Benralizumab 100 mg v Placebo
    Number of subjects included in analysis
    774
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0185
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.48
         upper limit
    0.94

    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 dose up to Week 56
    End point values
    Benralizumab 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    377
    394
    386
    388
    Units: Participants
        Hospitalisations|
    45
    67
    48
    59
        Emergency department|
    49
    72
    58
    71
        Unscheduled outpatient visits|
    208
    230
    225
    211
        Home visits|
    14
    20
    17
    14
        Telephone calls|
    98
    112
    109
    114
        Ambulance transports|
    10
    19
    20
    22
    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 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    561
    562 [1]
    562
    568
    Units: Days
        arithmetic mean (standard deviation)
    307.4 ± 80.38
    302.2 ± 84.62
    303.0 ± 88.48
    308.8 ± 78.95
    Notes
    [1] - 1 pat. rand. to 10 mg, but treated with 30 mg, so total 563 treated with 30 mg.
    No statistical analyses for this end point

    Secondary: Serum concentration of Benralizumab

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    End point title
    Serum concentration of Benralizumab [2]
    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
    [2] - 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: It is not applicable for Placebo treatment group having Benralizumab concentration. Thus no data is available for this arm.
    End point values
    Benralizumab 10 mg Benralizumab 30 mg Benralizumab 100 mg
    Number of subjects analysed
    558
    560
    552
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Baseline|
    0 ± 0
    0 ± 0
    0 ± 51.95
        Week 56|
    42.51 ± 384.81
    222.92 ± 248.24
    594.33 ± 321.66
    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 10 mg Benralizumab 30 mg Benralizumab 100 mg Placebo
    Number of subjects analysed
    561
    562 [3]
    562
    568
    Units: Participants
        ADA prevalence|
    70
    52
    77
    26
        ADA incidence|
    60
    39
    65
    16
        Both base/post-baseline positive|
    9
    8
    5
    10
        Only post baseline|
    57
    38
    64
    14
        Only baseline|
    4
    6
    8
    2
        ADA persistently positive|
    42
    30
    43
    6
        ADA transiently positive|
    15
    8
    21
    8
        nAb prevalence|
    55
    37
    59
    13
        nAb incidence|
    50
    33
    52
    9
    Notes
    [3] - 1 pat. rand. to 10 mg, but treated with 30 mg, so total 563 treated with 30 mg.
    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
    Benra 10 mg
    Reporting group description
    -

    Reporting group title
    Benra 30 mg
    Reporting group description
    -

    Reporting group title
    Benra 100 mg
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Benra 10 mg Benra 30 mg Benra 100 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    144 / 561 (25.67%)
    177 / 563 (31.44%)
    127 / 562 (22.60%)
    158 / 568 (27.82%)
         number of deaths (all causes)
    17
    21
    17
    19
         number of deaths resulting from adverse events
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    2 / 562 (0.36%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    2 / 568 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Penetrating aortic ulcer
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Abdominal neoplasm
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myeloid leukaemia
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain cancer metastatic
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Brain neoplasm benign
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer female
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colorectal cancer metastatic
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Follicular thyroid cancer
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lip and/or oral cavity cancer
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    2 / 568 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 561 (0.00%)
    2 / 563 (0.36%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic malignant melanoma
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine carcinoma metastatic
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Oesophageal adenocarcinoma stage 0
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 561 (0.00%)
    2 / 563 (0.36%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polycythaemia vera
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    2 / 562 (0.36%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sweat gland tumour
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transitional cell cancer of the renal pelvis and ureter
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Food allergy
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Oedema
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol abuse
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcoholism
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    2 / 561 (0.36%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post-traumatic stress disorder
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Acquired hydrocele
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    2 / 562 (0.36%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic prolapse
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal injury
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia postoperative
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carbon monoxide poisoning
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Open fracture
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic haemorrhage
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Anticoagulation drug level above therapeutic
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    False positive tuberculosis test
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    1 / 562 (0.18%)
    3 / 568 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    2 / 561 (0.36%)
    7 / 563 (1.24%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 7
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    2 / 561 (0.36%)
    1 / 563 (0.18%)
    1 / 562 (0.18%)
    2 / 568 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    3 / 561 (0.53%)
    2 / 563 (0.36%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 561 (0.36%)
    1 / 563 (0.18%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 561 (0.00%)
    2 / 563 (0.36%)
    3 / 562 (0.53%)
    2 / 568 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    2 / 561 (0.36%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    3 / 561 (0.53%)
    2 / 563 (0.36%)
    4 / 562 (0.71%)
    4 / 568 (0.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 561 (0.53%)
    1 / 563 (0.18%)
    3 / 562 (0.53%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 561 (0.00%)
    2 / 563 (0.36%)
    0 / 562 (0.00%)
    2 / 568 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 561 (0.00%)
    2 / 563 (0.36%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polycythaemia
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    3 / 561 (0.53%)
    1 / 563 (0.18%)
    4 / 562 (0.71%)
    5 / 568 (0.88%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    Aspiration
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    92 / 561 (16.40%)
    107 / 563 (19.01%)
    80 / 562 (14.23%)
    89 / 568 (15.67%)
         occurrences causally related to treatment / all
    0 / 129
    0 / 136
    0 / 106
    0 / 140
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    0 / 5
    0 / 2
    Chronic respiratory failure
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    2 / 562 (0.36%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystic lung disease
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 561 (0.53%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    2 / 568 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    2 / 568 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    6 / 561 (1.07%)
    0 / 563 (0.00%)
    3 / 562 (0.53%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 561 (0.00%)
    2 / 563 (0.36%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 561 (0.53%)
    2 / 563 (0.36%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Nervous system disorders
    Carotid arteriosclerosis
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebellar haemorrhage
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 561 (0.18%)
    4 / 563 (0.71%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cervical myelopathy
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    2 / 562 (0.36%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    2 / 562 (0.36%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intercostal neuralgia
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    1 / 562 (0.18%)
    2 / 568 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Lumbosacral radiculopathy
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple sclerosis relapse
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 561 (0.36%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombotic cerebral infarction
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 561 (0.36%)
    1 / 563 (0.18%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal artery embolism
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal incarcerated hernia
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 561 (0.36%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    2 / 568 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 561 (0.00%)
    2 / 563 (0.36%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonic pseudo-obstruction
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral hernia strangulated
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal polyp haemorrhage
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    0 / 561 (0.00%)
    2 / 563 (0.36%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar hernia
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal hypomotility
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 561 (0.00%)
    2 / 563 (0.36%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 561 (0.71%)
    0 / 563 (0.00%)
    2 / 562 (0.36%)
    3 / 568 (0.53%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Chronic kidney disease
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Renal infarct
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Henoch-Schonlein purpura
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psoriasis
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psoriatic arthropathy
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigger finger
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Alcohol intolerance
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    2 / 568 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 561 (0.18%)
    2 / 563 (0.36%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 561 (0.00%)
    4 / 563 (0.71%)
    1 / 562 (0.18%)
    3 / 568 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis infective
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter site cellulitis
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 561 (0.36%)
    2 / 563 (0.36%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    2 / 562 (0.36%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal sepsis
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    2 / 562 (0.36%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    19 / 561 (3.39%)
    22 / 563 (3.91%)
    9 / 562 (1.60%)
    30 / 568 (5.28%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 25
    1 / 10
    0 / 34
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 3
    Pneumonia bacterial
         subjects affected / exposed
    5 / 561 (0.89%)
    5 / 563 (0.89%)
    2 / 562 (0.36%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonas bronchitis
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 561 (0.00%)
    2 / 563 (0.36%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 561 (0.53%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 561 (0.00%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 561 (0.00%)
    1 / 563 (0.18%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 561 (0.18%)
    1 / 563 (0.18%)
    1 / 562 (0.18%)
    4 / 568 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 561 (0.18%)
    2 / 563 (0.36%)
    0 / 562 (0.00%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    1 / 562 (0.18%)
    1 / 568 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 561 (0.18%)
    0 / 563 (0.00%)
    0 / 562 (0.00%)
    0 / 568 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    Benra 10 mg Benra 30 mg Benra 100 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    365 / 561 (65.06%)
    382 / 563 (67.85%)
    368 / 562 (65.48%)
    378 / 568 (66.55%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    17 / 561 (3.03%)
    16 / 563 (2.84%)
    12 / 562 (2.14%)
    21 / 568 (3.70%)
         occurrences all number
    22
    17
    12
    22
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    8 / 561 (1.43%)
    10 / 563 (1.78%)
    20 / 562 (3.56%)
    24 / 568 (4.23%)
         occurrences all number
    10
    13
    24
    34
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 561 (3.39%)
    16 / 563 (2.84%)
    27 / 562 (4.80%)
    24 / 568 (4.23%)
         occurrences all number
    20
    17
    34
    36
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    15 / 561 (2.67%)
    9 / 563 (1.60%)
    17 / 562 (3.02%)
    9 / 568 (1.58%)
         occurrences all number
    17
    9
    18
    10
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    11 / 561 (1.96%)
    12 / 563 (2.13%)
    17 / 562 (3.02%)
    15 / 568 (2.64%)
         occurrences all number
    11
    12
    20
    15
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    66 / 561 (11.76%)
    70 / 563 (12.43%)
    63 / 562 (11.21%)
    66 / 568 (11.62%)
         occurrences all number
    94
    100
    87
    88
    Influenza
         subjects affected / exposed
    11 / 561 (1.96%)
    20 / 563 (3.55%)
    15 / 562 (2.67%)
    11 / 568 (1.94%)
         occurrences all number
    11
    22
    15
    12
    Lower respiratory tract infection
         subjects affected / exposed
    26 / 561 (4.63%)
    22 / 563 (3.91%)
    15 / 562 (2.67%)
    21 / 568 (3.70%)
         occurrences all number
    27
    29
    16
    27
    Oral candidiasis
         subjects affected / exposed
    21 / 561 (3.74%)
    12 / 563 (2.13%)
    15 / 562 (2.67%)
    12 / 568 (2.11%)
         occurrences all number
    25
    13
    20
    17
    Sinusitis
         subjects affected / exposed
    15 / 561 (2.67%)
    13 / 563 (2.31%)
    15 / 562 (2.67%)
    20 / 568 (3.52%)
         occurrences all number
    18
    19
    21
    24
    Upper respiratory tract infection
         subjects affected / exposed
    68 / 561 (12.12%)
    71 / 563 (12.61%)
    67 / 562 (11.92%)
    65 / 568 (11.44%)
         occurrences all number
    109
    98
    92
    89
    Urinary tract infection
         subjects affected / exposed
    24 / 561 (4.28%)
    24 / 563 (4.26%)
    28 / 562 (4.98%)
    18 / 568 (3.17%)
         occurrences all number
    34
    26
    32
    22
    Viral upper respiratory tract infection
         subjects affected / exposed
    61 / 561 (10.87%)
    47 / 563 (8.35%)
    60 / 562 (10.68%)
    70 / 568 (12.32%)
         occurrences all number
    73
    68
    92
    93

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 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
    10 Feb 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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