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    Clinical Trial Results:
    A Multicentre, Double-blind, Randomized, Parallel Group, Phase 3 Safety Extension Study to Evaluate the Safety and Tolerability of Benralizumab (MEDI-563) in Asthmatic Adults and Adolescents on Inhaled Corticosteroid Plus Long-acting β2 Agonist (BORA)

    Summary
    EudraCT number
    		 2014-001086-27
    Trial protocol
    		 GB   CZ   PL   DE   SE   BG   ES   FR  
    Global end of trial date
    14 Aug 2018

    Results information
    Results version number
    		 v1
    This version publication date
    27 Dec 2018
    First version publication date
    27 Dec 2018
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D3250C00021
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02258542
    WHO universal trial number (UTN)
    		 U1111-1162-2422
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Vastra Malarehamnen 9, Sodertalje, Sweden, 151 85
    Public contact
    Ubaldo Martin, Global Clinical Lead Benralizumab, AstraZeneca AB, Ubaldo.Martin@astrazeneca.com
    Scientific contact
    AZ Clinical Study Information, AstraZeneca AB, 46 855 326000, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    31 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To assess the safety and tolerability of 2 dosing regimens of benralizumab for adult patients during the 56-week treatment period and through the follow-up period (16 weeks from day of last dose) 2. To assess the safety and tolerability of 2 dosing regimens of benralizumab for adolescent patients during the 108-week treatment period and through the follow-up period (16 weeks from day of last dose)
    Protection of trial subjects
    Data safety monitoring board (DSMB) evaluates cumulative safety and other clinical trial data at regular intervals and making appropriate recommendations based on the available data. The DSMB functions independently of all other individuals associated with the conduct of the studies, including the study sponsor, AstraZeneca. The committee operates in accordance with a DSMB charter.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Nov 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: 220
    Country: Number of subjects enrolled
    Australia: 36
    Country: Number of subjects enrolled
    Brazil: 31
    Country: Number of subjects enrolled
    Bulgaria: 93
    Country: Number of subjects enrolled
    Canada: 74
    Country: Number of subjects enrolled
    Chile: 30
    Country: Number of subjects enrolled
    Czech Republic: 42
    Country: Number of subjects enrolled
    France: 83
    Country: Number of subjects enrolled
    Germany: 178
    Country: Number of subjects enrolled
    Japan: 73
    Country: Number of subjects enrolled
    Peru: 50
    Country: Number of subjects enrolled
    Philippines: 60
    Country: Number of subjects enrolled
    Poland: 355
    Country: Number of subjects enrolled
    Romania: 41
    Country: Number of subjects enrolled
    Russian Federation: 130
    Country: Number of subjects enrolled
    South Africa: 17
    Country: Number of subjects enrolled
    Korea, Republic of: 124
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    Turkey: 42
    Country: Number of subjects enrolled
    Ukraine: 114
    Country: Number of subjects enrolled
    United Kingdom: 35
    Country: Number of subjects enrolled
    United States: 254
    Country: Number of subjects enrolled
    Vietnam: 8
    Worldwide total number of subjects
    2133
    EEA total number of subjects
    870
    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)
    72
    Adults (18-64 years)
    1742
    From 65 to 84 years
    319
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 2133 patients were entered. 10 were excluded due to a GCP breach. Of remaining 2123 patients, 1926 entered from SIROCCO/CALIMA, and 197 from ZONDA. 2 patients were not treated, and a total of 447 patients (348 SIROCCO/CALIMA and 99 ZONDA) were enrolled into MELTEMI without completing the full follow-up, thus not in the main analyses.

    Pre-assignment
    Screening details
    		 953 participants from study SIROCCO/CALIMA receive benralizumab 30 mg at every 4 weeks schedule. 971 participants from study SIROCCO/CALIMA receive treatment at every 8 weeks schedule. 100 participants from study ZONDA receive treatment at every 4 weeks schedule. 97 participants from study ZONDA receive treatment at every 8 weeks schedule.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks
    Arm description
    		 Benralizumab administered subcutaneously every 4 weeks
    Arm type
    		 Experimental

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

    Arm title
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks
    Arm description
    		 Benralizumab administered subcutaneously every 8 weeks
    Arm type
    		 Experimental

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

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

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

    Arm title
    		 ZONDA - Benralizumab 30 mg q.8 weeks
    Arm description
    		 Benralizumab administered subcutaneously every 8 weeks
    Arm type
    		 Experimental

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

    Number of subjects in period 1 [1]
    		SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks
    Started
    953
    973
    100
    97
    Treated
    953
    971
    100
    97
    Completed
    892
    871
    92
    92
    Not completed
    61
    102
    8
    5
         Adverse event, serious fatal
    5
    4
    -
    1
         Consent withdrawn by subject
    20
    17
    7
    1
         Eligibility criteria not fulfilled
    -
    2
    -
    -
         Adverse event, non-fatal
    3
    4
    -
    -
         Ongoing
    19
    58
    -
    -
         study specific discount. criteria
    1
    1
    -
    -
         Lost to follow-up
    5
    10
    1
    2
         eg. not made to the visit
    7
    4
    -
    1
         Protocol deviation
    1
    2
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: There are total 2133 enrolled, 10 patients were excluded from all analyses due to GCP breach. Thus there is a 10 patient difference.

    Baseline characteristics

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

    Reporting group title
    SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks
    Reporting group description
    		 Benralizumab administered subcutaneously every 8 weeks

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

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

    Reporting group values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks Total
    Number of subjects
    		 953 973 100 97 2123
    Age categorical
    Two separate summaries presented: Overall all randomized patients (excluding non-GCP compliant patients); Separately for Full analysis set, excluding patients enrolled in MELTEMI.
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 21 51 0 0 72
        Adults (18-64 years)
    		 773 790 86 83 1732
        From 65-84 years
    		 159 132 14 14 319
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Full analysis set, Excluding patients enrolled in MELTEMI
    Units: years
        arithmetic mean (standard deviation)
    		 51.1 ( 13.79 ) 48.9 ( 15.53 ) 49.7 ( 10.35 ) 52.7 ( 8.90 ) -
    Sex: Female, Male
    Two separate summaries presented: Overall all randomized patients (excluding non-GCP compliant patients); Separately for Full analysis set, excluding patients enrolled in MELTEMI.
    Units: Subjects
        Female
    		 612 584 58 61 1315
        Male
    		 341 389 42 36 808
    Race/Ethnicity, Customized
    Two separate summaries presented: Overall all randomized patients (excluding non-GCP compliant patients); Separately for Full analysis set, excluding patients enrolled in MELTEMI.
    Units: Subjects
        White
    		 753 774 96 88 1711
        Black and African American
    		 25 30 0 2 57
        Asian
    		 143 139 4 7 293
        Other
    		 32 30 0 0 62
    Subject analysis sets

    Subject analysis set title
    SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 4 weeks, predecessor study with benralizumab treatment

    Subject analysis set title
    SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 4 weeks, predecessor study with placebo treatment

    Subject analysis set title
    SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 8 weeks, predecessor study with benralizumab treatment

    Subject analysis set title
    SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 8 weeks, predecessor study with placebo treatment

    Subject analysis set title
    ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 4 weeks, predecessor study with benralizumab treatment

    Subject analysis set title
    ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 4 weeks, predecessor study with placebo treatment

    Subject analysis set title
    ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 8 weeks, predecessor study with benralizumab treatment

    Subject analysis set title
    ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 8 weeks, predecessor study with placebo treatment

    Subject analysis sets values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4 SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8 SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4 ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8 ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
    Number of subjects
    518
    265
    512
    281
    31
    18
    31
    18
    Age categorical
    Two separate summaries presented: Overall all randomized patients (excluding non-GCP compliant patients); Separately for Full analysis set, excluding patients enrolled in MELTEMI.
    Units: Subjects
        In utero
    0
    0
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    12
    9
    25
    26
    0
    0
    0
    0
        Adults (18-64 years)
    421
    213
    421
    211
    30
    16
    26
    17
        From 65-84 years
    85
    43
    66
    44
    1
    2
    5
    1
        85 years and over
    0
    0
    0
    0
    0
    0
    0
    0
    Age Continuous
    Full analysis set, Excluding patients enrolled in MELTEMI
    Units: years
        arithmetic mean (standard deviation)
    51.7 ( 13.26 )
    49.9 ( 14.73 )
    49.3 ( 14.81 )
    48.2 ( 16.77 )
    47.9 ( 10.42 )
    52.7 ( 9.77 )
    54.3 ( 8.39 )
    49.9 ( 9.30 )
    Sex: Female, Male
    Two separate summaries presented: Overall all randomized patients (excluding non-GCP compliant patients); Separately for Full analysis set, excluding patients enrolled in MELTEMI.
    Units: Subjects
        Female
    339
    164
    307
    163
    13
    14
    20
    9
        Male
    179
    101
    205
    118
    18
    4
    11
    9
    Race/Ethnicity, Customized
    Two separate summaries presented: Overall all randomized patients (excluding non-GCP compliant patients); Separately for Full analysis set, excluding patients enrolled in MELTEMI.
    Units: Subjects
        White
    398
    201
    388
    224
    28
    17
    26
    16
        Black and African American
    6
    10
    12
    7
    0
    0
    0
    1
        Asian
    94
    44
    92
    44
    3
    1
    5
    1
        Other
    20
    10
    20
    6
    0
    0
    0
    0

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks
    Reporting group description
    		 Benralizumab administered subcutaneously every 4 weeks

    Reporting group title
    SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks
    Reporting group description
    		 Benralizumab administered subcutaneously every 8 weeks

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

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

    Subject analysis set title
    SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 4 weeks, predecessor study with benralizumab treatment

    Subject analysis set title
    SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 4 weeks, predecessor study with placebo treatment

    Subject analysis set title
    SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 8 weeks, predecessor study with benralizumab treatment

    Subject analysis set title
    SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 8 weeks, predecessor study with placebo treatment

    Subject analysis set title
    ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 4 weeks, predecessor study with benralizumab treatment

    Subject analysis set title
    ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 4 weeks, predecessor study with placebo treatment

    Subject analysis set title
    ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 8 weeks, predecessor study with benralizumab treatment

    Subject analysis set title
    ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Benralizumab administered subcutaneously every 8 weeks, predecessor study with placebo treatment

    Primary: Change from baseline in lab variables, Full analysis set, Excluding MELTEMI patients

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    End point title
    		 Change from baseline in lab variables, Full analysis set, Excluding MELTEMI patients [1]
    End point description
    Change from baseline in hematologic (Basophils, Leukocytes, Lymphocytes, Neutrophils, Eosinophils) and chemistry tests (ALT, AST, Bilirubin).
    End point type
    Primary
    End point timeframe
    Week 56
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This study is safety follow-up study. All analyses are descriptive and no hypothesis testing was intended or planned.
    End point values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks
    Number of subjects analysed
    783
    793
    49
    49
    Units: SI unit
    arithmetic mean (standard deviation)
        Basophils (10**9/L)|
    -0.005 ( 0.0223 )
    -0.005 ( 0.0239 )
    -0.007 ( 0.0283 )
    -0.005 ( 0.0244 )
        Leukocytes (10**9/L)|
    -0.344 ( 2.0412 )
    -0.128 ( 1.8614 )
    -0.808 ( 1.8177 )
    -0.507 ( 3.3612 )
        Lymphocytes (10**9/L)|
    -0.032 ( 0.6242 )
    0.003 ( 0.5402 )
    -0.093 ( 0.6403 )
    0.007 ( 0.6864 )
        Neutrophils (10**9/L)|
    -0.171 ( 1.8746 )
    0.013 ( 1.7024 )
    -0.501 ( 1.7096 )
    -0.368 ( 3.2057 )
        Eosinophils (10**9/L)|
    -0.1220 ( 0.30599 )
    -0.1271 ( 0.26161 )
    -0.1451 ( 0.30766 )
    -0.1664 ( 0.35139 )
        Alanine Aminotransferase (ukat/L)|
    -0.007 ( 0.2102 )
    0.017 ( 0.4651 )
    -0.064 ( 0.3547 )
    -0.023 ( 0.1940 )
        Aspartate Aminotransferase (ukat/L)|
    -0.005 ( 0.1431 )
    0.004 ( 0.3303 )
    -0.027 ( 0.2291 )
    -0.026 ( 0.1178 )
        Bilirubin (umol/L)|
    0.187 ( 3.6261 )
    0.391 ( 3.9945 )
    0.146 ( 2.8094 )
    0.279 ( 3.8765 )
    No statistical analyses for this end point

    Secondary: Number of overall patients with asthma exacerbations during study period, Full analysis set, Excluding MELTEMI patients

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    End point title
    		 Number of overall patients with asthma exacerbations during study period, Full analysis set, Excluding MELTEMI patients
    End point description
    Annual asthma exacerbation rate, where an asthma exacerbation is defined by a worsening of asthma requiring the use of systemic corticosteroids for at least 3 days, and/or an in patient hospitalization, and/or an emergency department or urgent care visit
    End point type
    Secondary
    End point timeframe
    From week 0 to week 56 in study treatment period and through the follow up period (16 weeks from day of last dose)
    End point values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4 SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8 SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4 ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8 ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
    Number of subjects analysed
    783
    793
    49
    49
    518
    265
    512
    281
    31
    18
    31
    18
    Units: participants
        Sirocco/Calima eos>=300/μL|# exacerb.
    159
    170
    0
    0
    99
    60
    104
    66
    0
    0
    0
    0
        Sirocco/Calima eos<300/μL|# exacerb.
    113
    97
    0
    0
    69
    44
    65
    32
    0
    0
    0
    0
        Zonda|# of exacerbation
    0
    0
    17
    24
    0
    0
    0
    0
    12
    5
    13
    11
    No statistical analyses for this end point

    Secondary: Annual asthma exacerbation rate during on-treatment period, Full analysis set, Excluding MELTEMI patients

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    End point title
    		 Annual asthma exacerbation rate during on-treatment period, Full analysis set, Excluding MELTEMI patients
    End point description
    Annual asthma exacerbation rate, where an asthma exacerbation is defined by a worsening of asthma requiring the use of systemic corticosteroids for at least 3 days, and/or an in patient hospitalization, and/or an emergency department or urgent care visit.
    End point type
    Secondary
    End point timeframe
    From week 0 to week 56 in study treatment period.
    End point values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4 SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8 SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4 ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8 ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
    Number of subjects analysed
    783 [2]
    793 [3]
    49 [4]
    49 [5]
    518 [6]
    265 [7]
    512 [8]
    281 [9]
    31 [10]
    18 [11]
    31 [12]
    18 [13]
    Units: count per year
    number (confidence interval 95%)
        Sirocco/Calima patients with EOS>=300/µL
    0.5 (0.44 to 0.56)
    0.49 (0.44 to 0.56)
    0 (0 to 0)
    0 (0 to 0)
    0.48 (0.42 to 0.56)
    0.53 (0.43 to 0.56)
    0.59 (0.49 to 0.71)
    0.74 (0.59 to 0.94)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
        Sirocco/Calima patients with EOS<300/µL
    0.76 (0.66 to 0.87)
    0.64 (0.55 to 0.74)
    0 (0 to 0)
    0 (0 to 0)
    0.74 (0.62 to 0.88)
    0.8 (0.64 to 1)
    0.59 (0.49 to 0.71)
    0.74 (0.59 to 0.94)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
        Zonda patients
    0 (0 to 0)
    0 (0 to 0)
    0.63 (0.44 to 0.91)
    0.68 (0.48 to 0.95)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    0.6 (0.39 to 0.95)
    0.7 (0.38 to 1.3)
    0.64 (0.42 to 0.98)
    0.75 (0.44 to 1.3)
    Notes
    [2] - 519 for EOS>=300 264 for EOS<300
    [3] - 527 for EOS>=300 266 for EOS<300
    [4] - Over all EOS
    [5] - Over all EOS
    [6] - 347 for EOS>=300 171 for EOS<300
    [7] - 172 for EOS>=300 93 for EOS<300
    [8] - 339 for EOS>=300 173 for EOS<300
    [9] - 188 for EOS>=300 93 for EOS<300
    [10] - Over all EOS
    [11] - Over all EOS
    [12] - Over all EOS
    [13] - Over all EOS
    No statistical analyses for this end point

    Secondary: Change from baseline in pre-brochodilator FEV1 (L), Full analysis set, Excluding MELTEMI patients

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    End point title
    		 Change from baseline in pre-brochodilator FEV1 (L), Full analysis set, Excluding MELTEMI patients
    End point description
    Change from baseline to Week 56 in Pre-bronchodilator Forced expiratory volume in 1 second (FEV1).
    End point type
    Secondary
    End point timeframe
    Week 56
    End point values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4 SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8 SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4 ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8 ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
    Number of subjects analysed
    665 [14]
    660 [15]
    38 [16]
    43 [17]
    444 [18]
    221 [19]
    440 [20]
    220 [21]
    27 [22]
    11 [23]
    28 [24]
    15 [25]
    Units: Liter
    arithmetic mean (standard deviation)
        Sirocco/Calima patients with EOS>=300/μL
    0.038 ( 0.346 )
    0.040 ( 0.356 )
    0 ( 0 )
    0 ( 0 )
    -0.006 ( 0.295 )
    0.131 ( 0.422 )
    0.019 ( 0.317 )
    0.081 ( 0.419 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
        Sirocco/Calima patients with EOS<300/μL
    -0.017 ( 0.345 )
    -0.001 ( 0.312 )
    0 ( 0 )
    0 ( 0 )
    -0.021 ( 0.376 )
    -0.011 ( 0.280 )
    -0.015 ( 0.293 )
    0.030 ( 0.350 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
        Zonda patients
    0 ( 0 )
    0 ( 0 )
    0.057 ( 0.412 )
    -0.012 ( 0.314 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0.013 ( 0.354 )
    0.167 ( 0.533 )
    -0.093 ( 0.280 )
    0.138 ( 0.329 )
    Notes
    [14] - 439 for EOS>=300 226 for EOS<300
    [15] - 442 for EOS>=300 218 for EOS<300
    [16] - Over all EOS
    [17] - Over all EOS
    [18] - 297 for EOS>=300 147 for EOS<300
    [19] - 142 for EOS>=300 79 for EOS<300
    [20] - 291 for EOS>=300 149 for EOS<300
    [21] - 151 for EOS>=300 69 for EOS<300
    [22] - Over all EOS
    [23] - Over all EOS
    [24] - Over all EOS
    [25] - Over all EOS
    No statistical analyses for this end point

    Secondary: Change from baseline in post-brochodilator FEV1 (L), Full analysis set, Excluding MELTEMI patients

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    End point title
    		 Change from baseline in post-brochodilator FEV1 (L), Full analysis set, Excluding MELTEMI patients [26]
    End point description
    Change from baseline to Week 56 in Post-bronchodilator Forced expiratory volume in 1 second (FEV1).
    End point type
    Secondary
    End point timeframe
    Week 56
    Notes
    [26] - 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: Patients in two arms from study ZONDA were not required to collect post-bronchodilator FEV1, thus this endpoint was not analyzed for those two arms.
    End point values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4 SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8 SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo
    Number of subjects analysed
    659 [27]
    652 [28]
    439 [29]
    220 [30]
    438 [31]
    214 [32]
    Units: Liter
    arithmetic mean (standard deviation)
        Sirocco/Calima patients with eos>=300/μL
    -0.015 ( 0.354 )
    -0.004 ( 0.329 )
    -0.066 ( 0.280 )
    0.089 ( 0.455 )
    -0.029 ( 0.281 )
    0.045 ( 0.401 )
        Sirocco/Calima patients with eos<300/μL
    -0.046 ( 0.350 )
    -0.015 ( 0.316 )
    -0.058 ( 0.379 )
    -0.024 ( 0.289 )
    -0.043 ( 0.273 )
    0.049 ( 0.394 )
    Notes
    [27] - 440 for EOS>=300 219 for EOS<300
    [28] - 443 for EOS>=300 209 for EOS<300
    [29] - 296 for EOS>=300 143 for EOS<300
    [30] - 144 for EOS>=300 76 for EOS<300
    [31] - 292 for EOS>=300 146 for EOS<300
    [32] - 151 for EOS>=300 63 for EOS<300
    No statistical analyses for this end point

    Secondary: Change from baseline in Asthma Control Questionnaire (ACQ) as a measure of asthma control in overall patients, Full analysis set, Excluding MELTEMI patients

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    End point title
    		 Change from baseline in Asthma Control Questionnaire (ACQ) as a measure of asthma control in overall patients, Full analysis set, Excluding MELTEMI patients
    End point description
    Asthma Control Questionnaire 6 (ACQ-6) contains 1 bronchodilator use question and 5 symptom questions. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ-6 score was the mean of the responses.
    End point type
    Secondary
    End point timeframe
    Week 56
    End point values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4 SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8 SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4 ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8 ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
    Number of subjects analysed
    671 [33]
    664 [34]
    39 [35]
    43 [36]
    447 [37]
    224 [38]
    444 [39]
    220 [40]
    28 [41]
    11 [42]
    28 [43]
    15 [44]
    Units: Scale of score
    arithmetic mean (standard deviation)
        Sirocco/Calima patients with eos>=300/μL
    -0.09 ( 0.91 )
    -0.12 ( 0.91 )
    0 ( 0 )
    0 ( 0 )
    -0.04 ( 0.83 )
    -0.20 ( 1.04 )
    -0.06 ( 0.82 )
    -0.25 ( 1.06 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
        Sirocco/Calima patients with eos<300/μL
    -0.15 ( 0.86 )
    -0.10 ( 0.90 )
    0 ( 0 )
    0 ( 0 )
    -0.16 ( 0.90 )
    -0.12 ( 0.80 )
    -0.10 ( 0.83 )
    -0.09 ( 1.06 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
        Zonda patients
    0 ( 0 )
    0 ( 0 )
    -0.21 ( 0.87 )
    -0.05 ( 1.04 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    -0.05 ( 0.89 )
    -0.61 ( 0.74 )
    0.15 ( 1.02 )
    -0.43 ( 1.00 )
    Notes
    [33] - 444 for EOS>=300 227 for EOS<300
    [34] - 447 for EOS>=300 217 for EOS<300
    [35] - Over all EOS
    [36] - Over all EOS
    [37] - 298 for EOS>=300 149 for EOS<300
    [38] - 146 for EOS>=300 78 for EOS<300
    [39] - 294 for EOS>=300 150 for EOS<300
    [40] - 153 for EOS>=300 67 for EOS<300
    [41] - Over all EOS
    [42] - Over all EOS
    [43] - Over all EOS
    [44] - Over all EOS
    No statistical analyses for this end point

    Secondary: Change from baseline in total score of asthma related and general health-related quality of life questionnaire (AQLQ(S)+12), Full analysis set, Excluding MELTEMI patients

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    End point title
    		 Change from baseline in total score of asthma related and general health-related quality of life questionnaire (AQLQ(S)+12), Full analysis set, Excluding MELTEMI patients
    End point description
    Standardised Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) comprises 4 separate domains (symptoms, activity limitations, emotional function, and environmental stimuli). An increase in score indicates improvement.
    End point type
    Secondary
    End point timeframe
    Week 56
    End point values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4 SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8 SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4 ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8 ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
    Number of subjects analysed
    668 [45]
    662 [46]
    37 [47]
    43 [48]
    444 [49]
    224 [50]
    442 [51]
    220 [52]
    26 [53]
    11 [54]
    28 [55]
    15 [56]
    Units: Scale of score
    arithmetic mean (standard deviation)
        Sirocco/Calima patients with eos>=300/μL
    0.08 ( 0.87 )
    0.15 ( 0.94 )
    0 ( 0 )
    0 ( 0 )
    0.02 ( 0.80 )
    0.21 ( 0.98 )
    0.08 ( 0.91 )
    0.26 ( 1.00 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
        Sirocco/Calima patients with eos<300/μL
    0.09 ( 0.85 )
    0.11 ( 0.95 )
    0 ( 0 )
    0 ( 0 )
    0.11 ( 0.84 )
    0.03 ( 0.89 )
    0.15 ( 0.90 )
    0.02 ( 1.06 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
        Zonda patients|
    0 ( 0 )
    0 ( 0 )
    0.22 ( 0.92 )
    0.11 ( 0.98 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0.13 ( 0.93 )
    0.43 ( 0.91 )
    -0.04 ( 0.94 )
    0.40 ( 1.03 )
    Notes
    [45] - 442 for EOS>=300 226 for EOS<300
    [46] - 446 for EOS>=300 216 for EOS<300
    [47] - Over all EOS
    [48] - Over all EOS
    [49] - 296 for EOS>=300 148 for EOS<300
    [50] - 146 for EOS>=300 78 for EOS<300
    [51] - 293 for EOS>=300 149 for EOS<300
    [52] - 153 for EOS>=300 67 for EOS<300
    [53] - Over all EOS
    [54] - Over all EOS
    [55] - Over all EOS
    [56] - Over all EOS
    No statistical analyses for this end point

    Secondary: Change of blood eosinophil levels' measurement in overall patients, Full analysis set, Excluding MELTEMI patients

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    End point title
    		 Change of blood eosinophil levels' measurement in overall patients, Full analysis set, Excluding MELTEMI patients
    End point description
    Change from baseline to Week 56 in Blood eosinophils
    End point type
    Secondary
    End point timeframe
    Week 56
    End point values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4 SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8 SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4 ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8 ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
    Number of subjects analysed
    691 [57]
    703 [58]
    39 [59]
    42 [60]
    454 [61]
    237 [62]
    461 [63]
    242 [64]
    28 [65]
    11 [66]
    27 [67]
    15 [68]
    Units: cell/µL
    arithmetic mean (standard deviation)
        Sirocco/Calima patients with eos>=300/μL
    -148.6 ( 332.91 )
    -154.1 ( 297.34 )
    0 ( 0 )
    0 ( 0 )
    4.9 ( 177.42 )
    -449.6 ( 360.6 )
    -10.1 ( 134.7 )
    -422.5 ( 330.01 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
        Sirocco/Calima patients with eos<300/μL
    -68.4 ( 234.40 )
    -74.7 ( 160.29 )
    0 ( 0 )
    0 ( 0 )
    15.7 ( 87.04 )
    -222.1 ( 325.03 )
    -2.9 ( 59.11 )
    -217.4 ( 198.56 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
        Zonda patients
    0 ( 0 )
    0 ( 0 )
    -145.1 ( 307.66 )
    -166.4 ( 351.39 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    0 ( 0 )
    2.5 ( 69.85 )
    -520.9 ( 360.79 )
    -17.0 ( 107.48 )
    -435.3 ( 468.64 )
    Notes
    [57] - 462 for EOS>=300 229 for EOS<300
    [58] - 464 for EOS>=300 239 for EOS<300
    [59] - Over all EOS
    [60] - Over all EOS
    [61] - 306 for EOS>=300 148 for EOS<300
    [62] - 156 for EOS>=300 81 for EOS<300
    [63] - 302 for EOS>=300 159 for EOS<300
    [64] - 162 for EOS>=300 80 for EOS<300
    [65] - Over all EOS
    [66] - Over all EOS
    [67] - Over all EOS
    [68] - Over all EOS
    No statistical analyses for this end point

    Secondary: Change from baseline in EQ-5D-5L visual analog scale, Full analysis set, Excluding MELTEMI patients

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    End point title
    		 Change from baseline in EQ-5D-5L visual analog scale, Full analysis set, Excluding MELTEMI patients
    End point description
    The questionnaire included a VAS, where the patient was asked to rate current health status on a scale of 0 to 100, with 0 being the worst imaginable health state; thus, an increase in VAS score indicated improvement.
    End point type
    Secondary
    End point timeframe
    Week 56
    End point values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks
    Number of subjects analysed
    682 [69]
    709 [70]
    21 [71]
    28 [72]
    Units: Scale of score
    arithmetic mean (standard deviation)
        Sirocco/Calima patients with eos>=300/μL
    6.08 ( 15.68 )
    6.02 ( 17.68 )
    0 ( 0 )
    0 ( 0 )
        Sirocco/Calima patients with eos<300/μL
    4.38 ( 14.99 )
    6.69 ( 15.96 )
    0 ( 0 )
    0 ( 0 )
        Zonda patients
    0 ( 0 )
    0 ( 0 )
    5.00 ( 10.35 )
    1.36 ( 13.58 )
    Notes
    [69] - 454 for EOS>=300 228 for EOS<3000
    [70] - 468 for EOS>=300 241 for EOS<300
    [71] - Over all EOS
    [72] - Over all EOS
    No statistical analyses for this end point

    Secondary: Work Productivity loss in adults, using Work Productivity and Activity Impairment Questionnaire (WPAI), Full analysis set, Excluding MELTEMI patients

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    End point title
    		 Work Productivity loss in adults, using Work Productivity and Activity Impairment Questionnaire (WPAI), Full analysis set, Excluding MELTEMI patients
    End point description
    The WPAI+CIQ is a 10-item questionnaire that assesses productivity and activity impairment over the previous week. The questionnaire includes hours missed from work/school due to asthma, degree health affected productivity while at work/school, as well as the degree to which health affected regular activities other than work or school. The questionnaire related to the previous 7 days.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 68
    End point values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks
    Number of subjects analysed
    783 [73]
    793 [74]
    49 [75]
    49 [76]
    Units: percentage
    arithmetic mean (standard deviation)
        Sirocco/Calima patients with eos>=300/μL-baseline
    25.3 ( 24.70 )
    25.0 ( 24.15 )
    0 ( 0 )
    0 ( 0 )
        Sirocco/Calima patients with eos>=300/μL-wk 68
    23.3 ( 26.18 )
    21.0 ( 25.54 )
    0 ( 0 )
    0 ( 0 )
        Sirocco/Calima patients with eos<300/μL-baseline
    31.0 ( 27.06 )
    32.6 ( 26.29 )
    0 ( 0 )
    0 ( 0 )
        Sirocco/Calima patients with eos<300/μL-wk 68
    32.7 ( 27.55 )
    25.8 ( 24.05 )
    0 ( 0 )
    0 ( 0 )
        Zonda Patients-baseline
    0 ( 0 )
    0 ( 0 )
    23.5 ( 25.13 )
    7.1 ( 10.47 )
        Zonda Patients-wk 68
    0 ( 0 )
    0 ( 0 )
    18.9 ( 24.94 )
    21.0 ( 27.13 )
    Notes
    [73] - BS: 234 for EOS>=300 WK68: 236 for EOS>=300 BS: 101 for EOS<300 WK68: 97 for EOS<300
    [74] - BS: 217 for EOS>=300 WK68: 217 for EOS>=300 BS: 93 for EOS<300 WK68: 96 for EOS<300
    [75] - BS: 16 WK68: 19
    [76] - BS: 17 WK68: 20
    No statistical analyses for this end point

    Secondary: Classroom Productivity loss in adolescents, using Classroom Impairment Questionnaire (CIQ), Full analysis set, Excluding MELTEMI patients

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    End point title
    		 Classroom Productivity loss in adolescents, using Classroom Impairment Questionnaire (CIQ), Full analysis set, Excluding MELTEMI patients [77]
    End point description
    The WPAI (+CIQ) is a 10-item questionnaire that assesses productivity and activity impairment over the previous week. The questionnaire includes hours missed from work/school due to asthma, degree health affected productivity while at work/school, as well as the degree to which health affected regular activities other than work or school. The questionnaire related to the previous 7 days.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 56
    Notes
    [77] - 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: Since two arms from study ZONDA, for which does not have adolescent patients, thus this endpoint was not analyzed for those two arms.
    End point values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks
    Number of subjects analysed
    25 [78]
    61 [79]
    Units: Percentage
    arithmetic mean (standard deviation)
        Sirocco/Calima patients with eos>=300/μL-Baseline
    13.0 ( 19.14 )
    30.7 ( 31.41 )
        Sirocco/Calima patients with eos>=300/μL-wk 56
    3.8 ( 7.44 )
    15.2 ( 20.69 )
        Sirocco/Calima patients with eos<300/μL-Baseline
    42.1 ( 32.50 )
    35.4 ( 23.92 )
        Sirocco/Calima patients with eos<300/μL-wk 56
    5.0 ( 7.07 )
    17.1 ( 20.06 )
    Notes
    [78] - BS: 11 for EOS>=300 WK56: 8 for EOS>=300 BS: 4 for EOS<300 WK56: 2 for EOS<300
    [79] - BS: 23 for EOS>=300 WK56: 24 for EOS>=300 BS: 19 for EOS<300 WK56: 24 for EOS<300
    No statistical analyses for this end point

    Secondary: Activity impairment (%), using Work Productivity and Activity Impairment Questionnaire (WPAI), Full analysis set, Excluding MELTEMI patients

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    End point title
    		 Activity impairment (%), using Work Productivity and Activity Impairment Questionnaire (WPAI), Full analysis set, Excluding MELTEMI patients
    End point description
    The WPAI+CIQ is a 10-item questionnaire that assesses productivity and activity impairment over the previous week. The questionnaire includes hours missed from work/school due to asthma, degree health affected productivity while at work/school, as well as the degree to which health affected regular activities other than work or school. The questionnaire related to the previous 7 days. The WPAI+CIQ outcomes are expressed as impairment percentages, with higher numbers indicating greater impairment and less productivity.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 68
    End point values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks
    Number of subjects analysed
    783 [80]
    793 [81]
    49 [82]
    49 [83]
    Units: percentage
    arithmetic mean (standard deviation)
        Sirocco/Calima patients with eos>=300/μL-baseline
    31.3 ( 26.44 )
    31.2 ( 25.63 )
    0 ( 0 )
    0 ( 0 )
        Sirocco/Calima patients with eos>=300/μL-wk 68
    26.6 ( 26.14 )
    24.4 ( 25.26 )
    0 ( 0 )
    0 ( 0 )
        Sirocco/Calima patients with eos<300/μL-baseline
    39.6 ( 25.75 )
    36.3 ( 25.72 )
    0 ( 0 )
    0 ( 0 )
        Sirocco/Calima patients with eos<300/μL-wk 68
    33.6 ( 26.55 )
    32.7 ( 26.58 )
    0 ( 0 )
    0 ( 0 )
        Zonda Patients-baseline
    0 ( 0 )
    0 ( 0 )
    31.5 ( 29.49 )
    24.5 ( 29.08 )
        Zonda Patients-wk 68
    0 ( 0 )
    0 ( 0 )
    28.4 ( 27.85 )
    39.0 ( 34.36 )
    Notes
    [80] - BS: 518 for EOS>=300 WK68: 458 for EOS>=300 BS: 261 for EOS<300 WK68: 239 for EOS<300
    [81] - BS: 524 for EOS>=300 WK68: 454 for EOS>=300 BS: 264 for EOS<300 WK68: 220 for EOS<300
    [82] - BS: 26 WK68: 38
    [83] - BS: 31 WK68: 41
    No statistical analyses for this end point

    Secondary: Health care encounters in overall patients on study period, Full analysis set, Excluding MELTEMI patients

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    End point title
    		 Health care encounters in overall patients on study period, Full analysis set, Excluding MELTEMI patients
    End point description
    Hospitalizations, ED visits, urgent care visits and all other outpatient visits due to asthma
    End point type
    Secondary
    End point timeframe
    From week 0 to week 68 in study treatment period and through the follow up period (16 weeks from day of last dose)
    End point values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks
    Number of subjects analysed
    519 [84]
    527 [85]
    49 [86]
    49 [87]
    Units: Participants
        Sirocco/Calima patients with eos>=300/μL
    193
    198
    0
    0
        Sirocco/Calima patients with eos<300/μL
    118
    102
    0
    0
        Zonda patients
    0
    0
    20
    25
    Notes
    [84] - 519 for EOS>=300 264 for EOS<300
    [85] - 527 for EOS>=300 266 for EOS<300
    [86] - Over all EOS
    [87] - Over all EOS
    No statistical analyses for this end point

    Secondary: Pre-dose benralizumab concentration in serum during the treatment phase of the safety study

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    End point title
    		 Pre-dose benralizumab concentration in serum during the treatment phase of the safety study
    End point description
    Endpoint: Pharmacokinetic (PK) parameters
    End point type
    Secondary
    End point timeframe
    Week 0 and Week 56
    End point values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Pre Benra q.4 SIROCCO/CALIMA - Benralizumab 30 mg q.4 - Predecessor Placebo SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Pre Benra q.8 SIROCCO/CALIMA - Benralizumab 30 mg q.8 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.4 - Pre Benra q.4 ZONDA - Benralizumab 30 mg q.4 - Predecessor Placebo ZONDA - Benralizumab 30 mg q.8 - Pre Benra q.8 ZONDA - Benralizumab 30 mg q.8 - Predecessor Placebo
    Number of subjects analysed
    514 [88]
    263 [89]
    511 [90]
    279 [91]
    31 [92]
    16 [93]
    31 [94]
    17 [95]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Baseline
    714.25 ( 311.38 )
    0 ( 0 )
    142.92 ( 353.94 )
    0 ( 0 )
    964.21 ( 224.01 )
    0 ( 0 )
    692.91 ( 205.97 )
    0 ( 0 )
        Week 56
    930.04 ( 200.59 )
    865.93 ( 242.55 )
    173.95 ( 269.62 )
    162.03 ( 295.05 )
    823.62 ( 239.39 )
    1160.58 ( 48.82 )
    247.26 ( 133.0 )
    139.35 ( 274.98 )
    Notes
    [88] - 507 for Baseline 442 for Week 56
    [89] - 260 for Baseline 225 for Week 56
    [90] - 503 for Baseline 440 for Week 56
    [91] - 275 for Baseline 215 for Week 56
    [92] - 31 for Baseline 27 for Week 56
    [93] - 16 for Baseline 10 for Week 56
    [94] - 30 for Baseline 27 for Week 56
    [95] - 17 for Baseline 15 for Week 56
    No statistical analyses for this end point

    Secondary: Anti-drug antibodies (ADA) responses over all patients, Full analysis set, Excluding MELTEMI patients

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    End point title
    		 Anti-drug antibodies (ADA) responses over all patients, Full analysis set, Excluding MELTEMI patients
    End point description
    Assessments for the presence of ADA and nAb throughout study
    End point type
    Secondary
    End point timeframe
    From week 0 to week 56 in study treatment period (adults) and plus 16 weeks the follow up period; From week 0 to week 108-week in study treatment period (adolescents) and plus 16 weeks the follow up period
    End point values
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks
    Number of subjects analysed
    783
    793
    49
    49
    Units: Participants
        Positive at any visit|
    80
    93
    4
    8
        Base- and Post-baseline Positive
    23
    41
    2
    4
        Newly Persistently Positive
    28
    34
    1
    3
        Stable persistently positive
    21
    29
    2
    2
        Newly treatment-induced positive
    38
    41
    2
    2
        ADA treatment boosted positive
    6
    6
    0
    1
        Decreased in titre
    17
    9
    2
    1
        Only post-baseline positive
    48
    48
    2
    1
        ADA incidence
    44
    47
    2
    3
        Transiently Positive
    22
    26
    1
    3
        Only baseline positive
    9
    4
    0
    0
        nAb positive
    57
    75
    3
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adults participants collected events during the entire study period. Adolescents data collection up to last adolescent completed Week 56 visit, which is April 20, 2017.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks
    Reporting group description
    		 Benralizumab administered subcutaneously every 4 weeks

    Reporting group title
    SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks
    Reporting group description
    		 Benralizumab administered subcutaneously every 8 weeks

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

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

    Serious adverse events
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    101 / 783 (12.90%)
    93 / 793 (11.73%)
    10 / 49 (20.41%)
    9 / 49 (18.37%)
         number of deaths (all causes)
    5
    4
    0
    1
         number of deaths resulting from adverse events
    1
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    B-cell lymphoma
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Basal cell carcinoma
         subjects affected / exposed
    2 / 783 (0.26%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Benign neoplasm of eyelid
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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 neoplasm of thyroid gland
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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 myeloid leukaemia
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Colon cancer stage 0
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Diffuse large B-cell lymphoma stage II
         subjects affected / exposed
    2 / 783 (0.26%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Large intestine benign neoplasm
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Lipoma
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Nasal cavity cancer
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Osteochondroma
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Ovarian germ cell teratoma benign
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         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
    Prostate cancer
         subjects affected / exposed
    0 / 783 (0.00%)
    2 / 793 (0.25%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Solid pseudopapillary tumour of the pancreas
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Thymoma
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Uterine leiomyoma
         subjects affected / exposed
    1 / 783 (0.13%)
    2 / 793 (0.25%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive emergency
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Phlebitis
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Death
         subjects affected / exposed
    2 / 783 (0.26%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Food allergy
         subjects affected / exposed
    0 / 783 (0.00%)
    2 / 793 (0.25%)
    0 / 49 (0.00%)
    0 / 49 (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
    Reproductive system and breast disorders
    Cervical polyp
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Ovarian cyst
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Vaginal fistula
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    35 / 783 (4.47%)
    26 / 793 (3.28%)
    3 / 49 (6.12%)
    2 / 49 (4.08%)
         occurrences causally related to treatment / all
    0 / 39
    1 / 31
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Asthmatic crisis
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Interstitial lung disease
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Middle lobe syndrome
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Nasal polyps
         subjects affected / exposed
    2 / 783 (0.26%)
    2 / 793 (0.25%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Pulmonary hypertension
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Status asthmaticus
         subjects affected / exposed
    1 / 783 (0.13%)
    2 / 793 (0.25%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Investigations
    Endocrine test abnormal
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Arthropod bite
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Bone contusion
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Clavicle fracture
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 793 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (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
    Fall
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         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 / 1
    Femur fracture
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Head injury
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Humerus fracture
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Incisional hernia
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Ligament rupture
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Limb injury
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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 limb fracture
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Multiple fractures
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Patella fracture
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Radius fracture
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Rib fracture
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Road traffic accident
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Subdural haemorrhage
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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 limb fracture
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Acute myocardial infarction
         subjects affected / exposed
    1 / 783 (0.13%)
    2 / 793 (0.25%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 783 (0.13%)
    2 / 793 (0.25%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Cardiac arrest
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Cardiac failure congestive
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Coronary artery disease
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Coronary artery insufficiency
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Nervous system disorders
    Diabetic neuropathy
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Dysarthria
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    0 / 783 (0.00%)
    2 / 793 (0.25%)
    0 / 49 (0.00%)
    0 / 49 (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
    Lumbosacral radiculopathy
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Syncope
         subjects affected / exposed
    1 / 783 (0.13%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Blood and lymphatic system disorders
    Hypochromic anaemia
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 793 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (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
    Neutropenia
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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 lower
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Barrett's oesophagus
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Colitis ulcerative
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         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
    Duodenal ulcer
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Femoral hernia strangulated
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Gastritis
         subjects affected / exposed
    2 / 783 (0.26%)
    0 / 793 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Ileus
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Inguinal hernia
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         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
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 783 (0.13%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Oesophageal ulcer
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Oesophagitis
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Pancreatitis acute
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Cholecystitis
         subjects affected / exposed
    1 / 783 (0.13%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Cholecystitis acute
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Cholelithiasis
         subjects affected / exposed
    2 / 783 (0.26%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Skin and subcutaneous tissue disorders
    Erythema nodosum
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Pemphigoid
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         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
    Rosacea
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Urticaria papular
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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 kidney disease
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Ureterolithiasis
         subjects affected / exposed
    2 / 783 (0.26%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Hyperparathyroidism
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Arthralgia
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 783 (0.13%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Jaw cyst
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 793 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (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
    Muscular weakness
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Osteoarthritis
         subjects affected / exposed
    0 / 783 (0.00%)
    2 / 793 (0.25%)
    0 / 49 (0.00%)
    0 / 49 (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
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         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
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Bronchitis
         subjects affected / exposed
    2 / 783 (0.26%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Diverticulitis
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 793 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (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
    Erysipelas
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Influenza
         subjects affected / exposed
    2 / 783 (0.26%)
    2 / 793 (0.25%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    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 / 783 (0.00%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         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
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Lung infection
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Pneumonia
         subjects affected / exposed
    2 / 783 (0.26%)
    4 / 793 (0.50%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 783 (0.13%)
    5 / 793 (0.63%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 783 (0.13%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Sepsis
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Sinusitis
         subjects affected / exposed
    1 / 783 (0.13%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Sinusitis bacterial
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 783 (0.00%)
    1 / 793 (0.13%)
    0 / 49 (0.00%)
    0 / 49 (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
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Urosepsis
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Dehydration
         subjects affected / exposed
    1 / 783 (0.13%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Obesity
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 793 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (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
    Type 2 diabetes mellitus
         subjects affected / exposed
    2 / 783 (0.26%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (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
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 SIROCCO/CALIMA - Benralizumab 30 mg q.4 weeks SIROCCO/CALIMA - Benralizumab 30 mg q.8 weeks ZONDA - Benralizumab 30 mg q.4 weeks ZONDA - Benralizumab 30 mg q.8 weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    404 / 783 (51.60%)
    392 / 793 (49.43%)
    33 / 49 (67.35%)
    38 / 49 (77.55%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 783 (0.00%)
    0 / 793 (0.00%)
    0 / 49 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    0
    0
    0
    2
    Blood pressure increased
         subjects affected / exposed
    4 / 783 (0.51%)
    3 / 793 (0.38%)
    1 / 49 (2.04%)
    2 / 49 (4.08%)
         occurrences all number
    5
    3
    1
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    31 / 783 (3.96%)
    28 / 793 (3.53%)
    0 / 49 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    32
    32
    0
    2
    Peripheral venous disease
         subjects affected / exposed
    1 / 783 (0.13%)
    3 / 793 (0.38%)
    0 / 49 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    1
    3
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    38 / 783 (4.85%)
    40 / 793 (5.04%)
    2 / 49 (4.08%)
    4 / 49 (8.16%)
         occurrences all number
    54
    54
    2
    4
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    26 / 783 (3.32%)
    28 / 793 (3.53%)
    3 / 49 (6.12%)
    1 / 49 (2.04%)
         occurrences all number
    38
    32
    3
    1
    Injection site bruising
         subjects affected / exposed
    0 / 783 (0.00%)
    2 / 793 (0.25%)
    0 / 49 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    0
    4
    0
    2
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 783 (0.26%)
    4 / 793 (0.50%)
    0 / 49 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    2
    6
    0
    3
    Oedema peripheral
         subjects affected / exposed
    4 / 783 (0.51%)
    6 / 793 (0.76%)
    0 / 49 (0.00%)
    4 / 49 (8.16%)
         occurrences all number
    4
    7
    0
    6
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    13 / 783 (1.66%)
    8 / 793 (1.01%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
         occurrences all number
    15
    8
    2
    0
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    4 / 783 (0.51%)
    8 / 793 (1.01%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
         occurrences all number
    5
    8
    3
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    12 / 783 (1.53%)
    9 / 793 (1.13%)
    1 / 49 (2.04%)
    2 / 49 (4.08%)
         occurrences all number
    14
    9
    1
    2
    Gastritis
         subjects affected / exposed
    6 / 783 (0.77%)
    7 / 793 (0.88%)
    2 / 49 (4.08%)
    1 / 49 (2.04%)
         occurrences all number
    6
    8
    2
    1
    Large intestine polyp
         subjects affected / exposed
    1 / 783 (0.13%)
    1 / 793 (0.13%)
    2 / 49 (4.08%)
    1 / 49 (2.04%)
         occurrences all number
    1
    1
    2
    1
    Nausea
         subjects affected / exposed
    10 / 783 (1.28%)
    5 / 793 (0.63%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
         occurrences all number
    11
    13
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    62 / 783 (7.92%)
    53 / 793 (6.68%)
    4 / 49 (8.16%)
    7 / 49 (14.29%)
         occurrences all number
    98
    72
    4
    9
    Dyspnoea
         subjects affected / exposed
    6 / 783 (0.77%)
    9 / 793 (1.13%)
    3 / 49 (6.12%)
    1 / 49 (2.04%)
         occurrences all number
    6
    9
    3
    1
    Nasal congestion
         subjects affected / exposed
    2 / 783 (0.26%)
    12 / 793 (1.51%)
    0 / 49 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    2
    12
    0
    2
    Nasal polyps
         subjects affected / exposed
    5 / 783 (0.64%)
    4 / 793 (0.50%)
    2 / 49 (4.08%)
    2 / 49 (4.08%)
         occurrences all number
    6
    4
    2
    2
    Rhinitis allergic
         subjects affected / exposed
    38 / 783 (4.85%)
    22 / 793 (2.77%)
    0 / 49 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    43
    31
    0
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    11 / 783 (1.40%)
    8 / 793 (1.01%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
         occurrences all number
    12
    8
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    26 / 783 (3.32%)
    20 / 793 (2.52%)
    5 / 49 (10.20%)
    0 / 49 (0.00%)
         occurrences all number
    32
    20
    5
    0
    Back pain
         subjects affected / exposed
    24 / 783 (3.07%)
    21 / 793 (2.65%)
    2 / 49 (4.08%)
    4 / 49 (8.16%)
         occurrences all number
    25
    21
    2
    4
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    27 / 783 (3.45%)
    44 / 793 (5.55%)
    2 / 49 (4.08%)
    2 / 49 (4.08%)
         occurrences all number
    45
    57
    5
    4
    Bronchitis
         subjects affected / exposed
    49 / 783 (6.26%)
    50 / 793 (6.31%)
    3 / 49 (6.12%)
    10 / 49 (20.41%)
         occurrences all number
    65
    73
    7
    16
    Bronchitis bacterial
         subjects affected / exposed
    18 / 783 (2.30%)
    15 / 793 (1.89%)
    3 / 49 (6.12%)
    2 / 49 (4.08%)
         occurrences all number
    23
    21
    3
    2
    Chronic sinusitis
         subjects affected / exposed
    12 / 783 (1.53%)
    10 / 793 (1.26%)
    1 / 49 (2.04%)
    2 / 49 (4.08%)
         occurrences all number
    13
    17
    1
    7
    Herpes zoster
         subjects affected / exposed
    8 / 783 (1.02%)
    2 / 793 (0.25%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
         occurrences all number
    8
    2
    2
    0
    Oral candidiasis
         subjects affected / exposed
    14 / 783 (1.79%)
    12 / 793 (1.51%)
    1 / 49 (2.04%)
    2 / 49 (4.08%)
         occurrences all number
    20
    15
    1
    2
    Respiratory tract infection viral
         subjects affected / exposed
    8 / 783 (1.02%)
    12 / 793 (1.51%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
         occurrences all number
    8
    13
    2
    0
    Sinusitis
         subjects affected / exposed
    21 / 783 (2.68%)
    18 / 793 (2.27%)
    3 / 49 (6.12%)
    4 / 49 (8.16%)
         occurrences all number
    23
    22
    3
    4
    Upper respiratory tract infection
         subjects affected / exposed
    60 / 783 (7.66%)
    55 / 793 (6.94%)
    0 / 49 (0.00%)
    7 / 49 (14.29%)
         occurrences all number
    94
    81
    0
    8
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    15 / 783 (1.92%)
    22 / 793 (2.77%)
    1 / 49 (2.04%)
    2 / 49 (4.08%)
         occurrences all number
    17
    27
    1
    2
    Urinary tract infection
         subjects affected / exposed
    14 / 783 (1.79%)
    7 / 793 (0.88%)
    0 / 49 (0.00%)
    2 / 49 (4.08%)
         occurrences all number
    17
    7
    0
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    121 / 783 (15.45%)
    129 / 793 (16.27%)
    14 / 49 (28.57%)
    13 / 49 (26.53%)
         occurrences all number
    181
    187
    22
    19

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Sep 2015
    Update study objectives; Remove requirement of continuing regular study visits after discontinuation of treatment; and other administrative changes.
    13 Jan 2016
    Add MELTEMI study as an extension of treatment study; Adjust unblinding language.
    16 Dec 2016
    Add Japanese interim analysis

    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.
    Patients in this study had to complete treatment in predecessor studies. Therefore selection bias may exist. Baseline is defined for this study’s entry value, not all values are prior to active treatment due to some patients being treated previously.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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