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    Clinical Trial Results:
    A multicenter, open-label, safety extension study with Benralizumab for asthmatic adults on inhaled corticosteroid plus long-acting Beta2 agonist

    Summary
    EudraCT number
    2015-005396-25
    Trial protocol
    GB   ES   DE   CZ   PL   BG   FR  
    Global end of trial date
    18 Jun 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Feb 2021
    First version publication date
    28 Feb 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D3250C00037
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02808819
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Vastra Malarehamnen 9, Sodertalje, Sweden,
    Public contact
    AstraZeneca Information Center, AstraZeneca, +1 8002369933, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Jul 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety and tolerability of 2 dosing regimens of benralizumab for adult patients
    Protection of trial subjects
    An independent adjudication committee was constituted to provide an independent, external, systematic and unbiased assessment of blinded data to confirm diagnosis of: 1) Investigator-reported non-fatal myocardial infarction, non-fatal stroke (hemorrhagic, ischemic, embolic), as well as cardiovascular deaths and 2) Investigator-reported malignancies during the phase 3 trials. The committee operated in accordance with an Adjudication Committee Charter/Manual of Operations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Jun 2016
    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: 11
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Bulgaria: 11
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    Chile: 8
    Country: Number of subjects enrolled
    Czechia: 7
    Country: Number of subjects enrolled
    France: 36
    Country: Number of subjects enrolled
    Germany: 60
    Country: Number of subjects enrolled
    Poland: 93
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Turkey: 10
    Country: Number of subjects enrolled
    Ukraine: 73
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 86
    Worldwide total number of subjects
    446
    EEA total number of subjects
    216
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    366
    From 65 to 84 years
    80
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    447 participants enrolled in MELTEMI, 1 participant from Czech Republic was not treated, thus 446 patients received at least 1 dose of IP. Among these treated participants, 347 were from studies SIROCCO/CALIMA and 99 were from study ZONDA.

    Pre-assignment
    Screening details
    170 participants from SIROCCO/CALIMA assigned to Benralizumab 30 mg every 4 weeks (q4w) with 1 participant not treated. 178 participants from SIROCCO/CALIMA received Benralizumab every 8 weeks (q8w). 51 participants from ZONDA received Benralizumab q4w. 48 participants from study ZONDA received Benralizumab q8w.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Benra 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
    Benra 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
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Started
    220
    226
    Treated
    220
    226
    Completed
    189
    195
    Not completed
    31
    31
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    10
    13
         Adverse event, non-fatal
    3
    4
         Site terminated by sponsor
    2
    -
         Pregnancy
    1
    -
         eg. no treatment efficacy on asthma
    5
    4
         Lost to follow-up
    1
    6
         Development of study-specific withdrawal criteria
    8
    3
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Benra 30 mg q.4 weeks
    Reporting group description
    Benralizumab administered subcutaneously every 4 weeks

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

    Reporting group values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks Total
    Number of subjects
    220 226 446
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    177 189 366
        From 65-84 years
    43 37 80
        85 years and over
    0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    53.5 ( 12.00 ) 53.0 ( 11.64 ) -
    Sex: Female, Male
    Units: Participants
        Female
    140 144 284
        Male
    80 82 162
    Race/Ethnicity, Customized
    Units: Subjects
        White
    204 206 410
        Black or African
    9 13 22
        American Asian
    5 3 8
        Other
    2 4 6

    End points

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

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

    Primary: Change from baseline in Basophils, Full analysis set

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    End point title
    Change from baseline in Basophils, Full analysis set [1]
    End point description
    Change from baseline in hematologic lab parameter of Basophils.
    End point type
    Primary
    End point timeframe
    End of Treatment
    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: It is a safety long-term extension study. No hypothesis testing planned for the study.
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    173
    178
    Units: 10^9 cells/L
        arithmetic mean (standard deviation)
    0.014 ( 0.0229 )
    0.012 ( 0.0243 )
    No statistical analyses for this end point

    Primary: Change from baseline in Leukocytes, Full analysis set

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    End point title
    Change from baseline in Leukocytes, Full analysis set [2]
    End point description
    Change from baseline in hematologic lab parameter of Leukocytes.
    End point type
    Primary
    End point timeframe
    End of Treatment
    Notes
    [2] - 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: It is a safety long-term extension study. No hypothesis testing planned for the study.
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    178
    182
    Units: 10^9 cells/L
        arithmetic mean (standard deviation)
    -0.254 ( 2.0446 )
    -0.498 ( 1.7217 )
    No statistical analyses for this end point

    Primary: Change from baseline in Lymphocytes, Full analysis set

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    End point title
    Change from baseline in Lymphocytes, Full analysis set [3]
    End point description
    Change from baseline in hematologic lab parameter of Lymphocytes.
    End point type
    Primary
    End point timeframe
    End of Treatment
    Notes
    [3] - 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: It is a safety long-term extension study. No hypothesis testing planned for the study.
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    173
    178
    Units: 10^9 cells/L
        arithmetic mean (standard deviation)
    -0.098 ( 0.5479 )
    -0.142 ( 0.6544 )
    No statistical analyses for this end point

    Primary: Change from baseline in Neutrophils, Full analysis set

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    End point title
    Change from baseline in Neutrophils, Full analysis set [4]
    End point description
    Change from baseline in hematologic lab parameter of Neutrophils.
    End point type
    Primary
    End point timeframe
    End of Treatment
    Notes
    [4] - 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: It is a safety long-term extension study. No hypothesis testing planned for the study.
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    173
    178
    Units: 10^9 cells/L
        arithmetic mean (standard deviation)
    -0.237 ( 1.8765 )
    -0.392 ( 1.4802 )
    No statistical analyses for this end point

    Primary: Change from baseline in Monocytes, Full analysis set

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    End point title
    Change from baseline in Monocytes, Full analysis set [5]
    End point description
    Change from baseline in hematologic lab parameter of Monocytes.
    End point type
    Primary
    End point timeframe
    End of Treatment
    Notes
    [5] - 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: It is a safety long-term extension study. No hypothesis testing planned for the study.
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    173
    179
    Units: 10^9 cells/L
        arithmetic mean (standard deviation)
    0.055 ( 0.1835 )
    0.056 ( 0.1766 )
    No statistical analyses for this end point

    Primary: Change from baseline in Platelets, Full analysis set

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    End point title
    Change from baseline in Platelets, Full analysis set [6]
    End point description
    Change from baseline in hematologic lab parameter of Platelets.
    End point type
    Primary
    End point timeframe
    End of Treatment
    Notes
    [6] - 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: It is a safety long-term extension study. No hypothesis testing planned for the study.
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    177
    179
    Units: 10^9 cells/L
        arithmetic mean (standard deviation)
    9.1 ( 41.72 )
    11.9 ( 36.13 )
    No statistical analyses for this end point

    Primary: Change from baseline in Hematocrit, Full analysis set

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    End point title
    Change from baseline in Hematocrit, Full analysis set [7]
    End point description
    Change from baseline in hematologic lab parameter of Hematocrit.
    End point type
    Primary
    End point timeframe
    End of Treatment
    Notes
    [7] - 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: It is a safety long-term extension study. No hypothesis testing planned for the study.
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    172
    177
    Units: [ratio]
        arithmetic mean (standard deviation)
    -0.002 ( 0.0269 )
    -0.003 ( 0.0260 )
    No statistical analyses for this end point

    Primary: Change from baseline in Erythrocytes, Full analysis set

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    End point title
    Change from baseline in Erythrocytes, Full analysis set [8]
    End point description
    Change from baseline in hematologic lab parameter of Erythrocytes.
    End point type
    Primary
    End point timeframe
    End of Treatment
    Notes
    [8] - 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: It is a safety long-term extension study. No hypothesis testing planned for the study.
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    178
    183
    Units: 10^12 cells/L
        arithmetic mean (standard deviation)
    -0.008 ( 0.2922 )
    -0.054 ( 0.2614 )
    No statistical analyses for this end point

    Primary: Change from baseline in Hemoglobin, Full analysis set

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    End point title
    Change from baseline in Hemoglobin, Full analysis set [9]
    End point description
    Change from baseline in hematologic lab parameter of Hemoglobin.
    End point type
    Primary
    End point timeframe
    End of Treatment
    Notes
    [9] - 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: It is a safety long-term extension study. No hypothesis testing planned for the study.
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    178
    183
    Units: g/L
        arithmetic mean (standard deviation)
    2.6 ( 8.92 )
    1.2 ( 8.37 )
    No statistical analyses for this end point

    Primary: Change from baseline in Alanine Aminotransferase (ALT), Full analysis set

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    End point title
    Change from baseline in Alanine Aminotransferase (ALT), Full analysis set [10]
    End point description
    Change from baseline in chemistry test ALT.
    End point type
    Primary
    End point timeframe
    End of Treatment
    Notes
    [10] - 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: It is a safety long-term extension study. No hypothesis testing planned for the study.
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    174
    175
    Units: ukat/L
        arithmetic mean (standard deviation)
    0.007 ( 0.2060 )
    0.004 ( 0.2118 )
    No statistical analyses for this end point

    Primary: Change from baseline in Aspartate Aminotransferase (AST), Full analysis set

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    End point title
    Change from baseline in Aspartate Aminotransferase (AST), Full analysis set [11]
    End point description
    Change from baseline in chemistry test AST.
    End point type
    Primary
    End point timeframe
    End of Treatment
    Notes
    [11] - 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: It is a safety long-term extension study. No hypothesis testing planned for the study.
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    174
    175
    Units: ukat/L
        arithmetic mean (standard deviation)
    -0.021 ( 0.1258 )
    -0.018 ( 0.1280 )
    No statistical analyses for this end point

    Primary: Change from baseline in Bilirubin, Full analysis set

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    End point title
    Change from baseline in Bilirubin, Full analysis set [12]
    End point description
    Change from baseline in chemistry test Bilirubin.
    End point type
    Primary
    End point timeframe
    End of Treatment
    Notes
    [12] - 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: It is a safety long-term extension study. No hypothesis testing planned for the study.
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    172
    175
    Units: umol/L
        arithmetic mean (standard deviation)
    -0.451 ( 3.0980 )
    -0.297 ( 3.3972 )
    No statistical analyses for this end point

    Secondary: Number of participants with asthma exacerbations during study period

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    End point title
    Number of participants with asthma exacerbations during study period
    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 184 in study treatment period and through the follow up period (12 weeks from day of last dose)
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    220
    226
    Units: participants
        Patients with at least one exacerbation
    96
    97
    No statistical analyses for this end point

    Secondary: Number of participants who had health care encounter (ie, Hospitalization, Emergency department visits, urgent care visits, and all other outpatient visits due to asthma) during study period

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    End point title
    Number of participants who had health care encounter (ie, Hospitalization, Emergency department visits, urgent care visits, and all other outpatient visits due to asthma) during study period
    End point description
    Hospitalizations, Emergency department (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 184 in study treatment period and through the follow up period (12 weeks from day of last dose)
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    220
    226
    Units: participants
        All healthcare encounters combined
    25
    28
    No statistical analyses for this end point

    Secondary: Change of blood eosinophils count

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    End point title
    Change of blood eosinophils count
    End point description
    Change from Baseline to End of Treatment in blood eosinophils count.
    End point type
    Secondary
    End point timeframe
    End of Treatment
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    173
    178
    Units: cell/uL
        arithmetic mean (standard deviation)
    12.3 ( 50.24 )
    -12.9 ( 212.51 )
    No statistical analyses for this end point

    Secondary: Number of participants with Anti-drug antibodies (ADA) responses during the study

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    End point title
    Number of participants with Anti-drug antibodies (ADA) responses during the study
    End point description
    Assessments for the presence of ADA and neutralizing antibody (nAb) throughout study
    End point type
    Secondary
    End point timeframe
    From week 0 to week 184 in study treatment period and plus 12 weeks follow up period
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    220
    226
    Units: Participants
        Positive at any visit
    19
    28
        Both baseline and post-baseline positive
    11
    17
        Only post-baseline positive
    7
    10
        ADA Persistently Positive
    12
    21
        ADA Transiently Positive
    6
    6
        Only baseline positive
    1
    1
        nAb positive
    13
    24
        nAb positive in ADA positive participants
    13
    24
    No statistical analyses for this end point

    Secondary: Duration of exposure

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    End point title
    Duration of exposure
    End point description
    Duration of exposure
    End point type
    Secondary
    End point timeframe
    From week 0 to week 184 in study treatment period
    End point values
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Number of subjects analysed
    220
    226
    Units: months
        arithmetic mean (standard deviation)
    26.35 ( 10.112 )
    25.36 ( 9.939 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until last study visit
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Benra 30 mg q.4 weeks
    Reporting group description
    Benralizumab administered subcutaneously every 4 weeks

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

    Serious adverse events
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 220 (20.00%)
    47 / 226 (20.80%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Silicon granuloma
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarteritis nodosa
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 220 (0.91%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal complication associated with device
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterovaginal prolapse
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    9 / 220 (4.09%)
    13 / 226 (5.75%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal turbinate hypertrophy
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood lactic acid increased
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 220 (0.00%)
    2 / 226 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    2 / 220 (0.91%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural nausea
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma complication
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve stenosis
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery aneurysm
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient global amnesia
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Hypochromic anaemia
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal stenosis
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral hernia incarcerated
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone deformity
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc degeneration
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament laxity
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 220 (0.45%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft infection
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    3 / 220 (1.36%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 220 (0.45%)
    2 / 226 (0.88%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis bacterial
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 220 (0.45%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    0 / 220 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    Benra 30 mg q.4 weeks Benra 30 mg q.8 weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    195 / 220 (88.64%)
    172 / 226 (76.11%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    14 / 220 (6.36%)
    24 / 226 (10.62%)
         occurrences all number
    23
    31
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 220 (3.18%)
    2 / 226 (0.88%)
         occurrences all number
    9
    2
    Headache
         subjects affected / exposed
    32 / 220 (14.55%)
    21 / 226 (9.29%)
         occurrences all number
    56
    41
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    7 / 220 (3.18%)
    8 / 226 (3.54%)
         occurrences all number
    9
    10
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 220 (3.64%)
    6 / 226 (2.65%)
         occurrences all number
    12
    6
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    16 / 220 (7.27%)
    20 / 226 (8.85%)
         occurrences all number
    21
    40
    Nasal polyps
         subjects affected / exposed
    7 / 220 (3.18%)
    4 / 226 (1.77%)
         occurrences all number
    10
    4
    Rhinitis allergic
         subjects affected / exposed
    4 / 220 (1.82%)
    8 / 226 (3.54%)
         occurrences all number
    8
    12
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 220 (3.18%)
    8 / 226 (3.54%)
         occurrences all number
    7
    9
    Back pain
         subjects affected / exposed
    11 / 220 (5.00%)
    10 / 226 (4.42%)
         occurrences all number
    14
    10
    Osteoarthritis
         subjects affected / exposed
    10 / 220 (4.55%)
    3 / 226 (1.33%)
         occurrences all number
    14
    3
    Infections and infestations
    Acute sinusitis
         subjects affected / exposed
    13 / 220 (5.91%)
    8 / 226 (3.54%)
         occurrences all number
    20
    10
    Bronchitis
         subjects affected / exposed
    23 / 220 (10.45%)
    22 / 226 (9.73%)
         occurrences all number
    33
    26
    Bronchitis bacterial
         subjects affected / exposed
    12 / 220 (5.45%)
    9 / 226 (3.98%)
         occurrences all number
    17
    13
    Influenza
         subjects affected / exposed
    6 / 220 (2.73%)
    10 / 226 (4.42%)
         occurrences all number
    6
    10
    Nasopharyngitis
         subjects affected / exposed
    67 / 220 (30.45%)
    64 / 226 (28.32%)
         occurrences all number
    126
    112
    Pharyngitis
         subjects affected / exposed
    10 / 220 (4.55%)
    3 / 226 (1.33%)
         occurrences all number
    19
    3
    Rhinitis
         subjects affected / exposed
    11 / 220 (5.00%)
    3 / 226 (1.33%)
         occurrences all number
    18
    3
    Sinusitis
         subjects affected / exposed
    17 / 220 (7.73%)
    10 / 226 (4.42%)
         occurrences all number
    26
    16
    Sinusitis bacterial
         subjects affected / exposed
    4 / 220 (1.82%)
    7 / 226 (3.10%)
         occurrences all number
    6
    10
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 220 (6.36%)
    8 / 226 (3.54%)
         occurrences all number
    20
    12
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    10 / 220 (4.55%)
    8 / 226 (3.54%)
         occurrences all number
    19
    10
    Urinary tract infection
         subjects affected / exposed
    7 / 220 (3.18%)
    7 / 226 (3.10%)
         occurrences all number
    9
    7
    Viral upper respiratory tract infection
         subjects affected / exposed
    29 / 220 (13.18%)
    19 / 226 (8.41%)
         occurrences all number
    38
    21

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jul 2017
    1. Clarify that for the Q8W regimen, in case one dose was skipped, the next dose must be given within the visit window. If this was not possible, the patient was to be discontinued. 2. Clarify that if a patient chose to discontinue taking investigational product but agreed to return for the IPD and FU visits, then this was not considered a main consent withdrawal and data continued to be collected. If the main informed consent was withdrawn, no further study data and samples were collected. 3. Clarify that withdrawal of informed consent for the use of donated samples by the patient would result in the patient being withdrawn from further study participation. 4. Implement an independent adjudication committee for MACE and malignancies. 5. Multiple revisions were made to the list of restricted and prohibited medications to align with updates made to the BORA protocol.
    14 Oct 2019
    Text was updated to reflect that medications would be classified according to the terminology in the latest version of WHODrug Global B3 Format instead of the AstraZeneca Drug Dictionary.

    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 the values prior to first Benralizumab dose.
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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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