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    Clinical Trial Results:
    A Phase 2b, Dose-ranging Study to Evaluate the Efficacy and Safety of MEDI-563 in Adults with Uncontrolled Asthma

    Summary
    EudraCT number
    2010-020126-17
    Trial protocol
    BG  
    Global end of trial date
    15 Aug 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    08 Dec 2016
    First version publication date
    20 Feb 2016
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    MI-CP220
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01238861
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    MedImmune, LLC, an affiliate of AstraZeneca AB
    Sponsor organisation address
    SE-151 85, Sodertalje, Sweden,
    Public contact
    Rene van der Merwe, MBChB, MFPM, Medical Officer, MedImmune, LLC, an affiliate of AstraZeneca AB, vandermerwer@medimmune.com
    Scientific contact
    Rene van der Merwe, MBChB, MFPM, Medical Officer, MedImmune, LLC, an affiliate of AstraZeneca AB, vandermerwer@medimmune.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
    15 Aug 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the effect of multiple-dose subcutaneous (SC) administration of benralizumab on the annual asthma exacerbation rate (AER) in adult participants with uncontrolled, suspected eosinophilic asthma.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Participating participant signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Dec 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    10 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 74
    Country: Number of subjects enrolled
    Russian Federation: 106
    Country: Number of subjects enrolled
    Brazil: 62
    Country: Number of subjects enrolled
    Bulgaria: 96
    Country: Number of subjects enrolled
    Poland: 61
    Country: Number of subjects enrolled
    Argentina: 70
    Country: Number of subjects enrolled
    Peru: 59
    Country: Number of subjects enrolled
    Mexico: 40
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Colombia: 32
    Worldwide total number of subjects
    609
    EEA total number of subjects
    157
    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)
    559
    From 65 to 84 years
    50
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Participants were stratified based on the protocol defined eosinophilic phenotype (EOS+ versus EOS-) and inhaled corticosteroid (ICS) use during a 3-week screening period. A total of 964 participants were screened out of which 609 were randomized in the study, and of which 606 participants received at least one dose of investigational product.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Eosinophilic phenotype (EOS+) Placebo
    Arm description
    EOS+ (defined as ELEN Index [proprietary mathematical algorithm to predict sputum eosinophil’s greater than or equal to 2 percent] positive and/or FeNO [fraction of exhaled nitric oxide] greater than or equal to [>=] 50 parts per billion [ppb]) participants received matching placebo subcutaneous injection every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.
    Arm type
    Placebo

    Investigational medicinal product name
    Eosinophilic phenotype (EOS+) Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    EOS+ participants received matching placebo injections subcutaneous injection every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Arm title
    EOS+ Benralizumab, 2 mg
    Arm description
    EOS+ participants received benralizumab 2 milligram (mg) subcutaneous injection every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.
    Arm type
    Experimental

    Investigational medicinal product name
    Benralizumab
    Investigational medicinal product code
    MEDI-563
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    EOS+ participants received single benralizumab 2 milligram (mg) injection followed by a single placebo injection subcutaneously.

    Arm title
    EOS+ Benralizumab, 20 mg
    Arm description
    EOS+ participants received benralizumab 20 mg subcutaneous injection every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.
    Arm type
    Experimental

    Investigational medicinal product name
    Benralizumab
    Investigational medicinal product code
    MEDI-563
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    EOS+ participants received single benralizumab 20 mg injection followed by a single placebo injection subcutaneously.

    Arm title
    EOS+ Benralizumab, 100 mg
    Arm description
    EOS+ participants received benralizumab 50 mg as two subcutaneous injections every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.
    Arm type
    Experimental

    Investigational medicinal product name
    Benralizumab
    Investigational medicinal product code
    MEDI-563
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    EOS+ participants received benralizumab 50 mg as two injections subcutaneously every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Arm title
    Non-eosinophil phenotype (EOS-) Placebo
    Arm description
    EOS- (defined as ELEN Index negative and FeNO <50 ppb) participants received matching placebo subcutaneous injections every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.
    Arm type
    Placebo

    Investigational medicinal product name
    Non-eosinophil phenotype (EOS-) Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    EOS- (defined as ELEN Index negative and FeNO <50 ppb) participants received matching placebo subcutaneous every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Arm title
    EOS- Benralizumab, 100 mg
    Arm description
    EOS- participants received benralizumab 50 mg as two subcutaneous injections every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.
    Arm type
    Experimental

    Investigational medicinal product name
    Benralizumab
    Investigational medicinal product code
    MEDI-563
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    EOS- participants received benralizumab 50 mg as two injections subcutaneously every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Number of subjects in period 1 [1]
    Eosinophilic phenotype (EOS+) Placebo EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg EOS+ Benralizumab, 100 mg Non-eosinophil phenotype (EOS-) Placebo EOS- Benralizumab, 100 mg
    Started
    80
    81
    81
    82
    142
    140
    Completed
    69
    73
    70
    69
    129
    125
    Not completed
    11
    8
    11
    13
    13
    15
         Did not meet entry ACQ-6 criteria
    -
    -
    1
    -
    1
    1
         Unable to continue visits
    -
    -
    -
    1
    -
    1
         Subject traveled to Argentina by 1 year
    -
    -
    1
    -
    -
    -
         Personal problems
    -
    -
    -
    1
    -
    -
         Lack of compliance
    -
    -
    -
    -
    -
    1
         Consent withdrawn by subject
    6
    5
    4
    8
    10
    9
         Subject moved out of state/area
    -
    -
    1
    1
    -
    -
         Strongyloides stercoralis antibodies +
    -
    -
    -
    1
    -
    -
         Unplanned surgery
    1
    -
    -
    -
    -
    -
         Incorrect enrollment/randomization
    -
    -
    1
    -
    1
    -
         Adverse event, non-fatal
    -
    1
    -
    -
    -
    -
         Lost to follow-up
    4
    2
    3
    1
    1
    2
         Serious adverse event
    -
    -
    -
    -
    -
    1
    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: Not all randomized subjects were treated with study drugs. Hence, the worldwide number enrolled in the trial, which is the same as the number randomized, differs from the number of subjects reported in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Eosinophilic phenotype (EOS+) Placebo
    Reporting group description
    EOS+ (defined as ELEN Index [proprietary mathematical algorithm to predict sputum eosinophil’s greater than or equal to 2 percent] positive and/or FeNO [fraction of exhaled nitric oxide] greater than or equal to [>=] 50 parts per billion [ppb]) participants received matching placebo subcutaneous injection every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Reporting group title
    EOS+ Benralizumab, 2 mg
    Reporting group description
    EOS+ participants received benralizumab 2 milligram (mg) subcutaneous injection every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Reporting group title
    EOS+ Benralizumab, 20 mg
    Reporting group description
    EOS+ participants received benralizumab 20 mg subcutaneous injection every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Reporting group title
    EOS+ Benralizumab, 100 mg
    Reporting group description
    EOS+ participants received benralizumab 50 mg as two subcutaneous injections every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Reporting group title
    Non-eosinophil phenotype (EOS-) Placebo
    Reporting group description
    EOS- (defined as ELEN Index negative and FeNO <50 ppb) participants received matching placebo subcutaneous injections every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Reporting group title
    EOS- Benralizumab, 100 mg
    Reporting group description
    EOS- participants received benralizumab 50 mg as two subcutaneous injections every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Reporting group values
    Eosinophilic phenotype (EOS+) Placebo EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg EOS+ Benralizumab, 100 mg Non-eosinophil phenotype (EOS-) Placebo EOS- Benralizumab, 100 mg Total
    Number of subjects
    80 81 81 82 142 140 606
    Age categorical
    Units: Subjects
        test
    0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    45.6 ± 11.7 47.1 ± 12.8 46.6 ± 13.2 47.8 ± 12.9 50 ± 12.3 50 ± 11.5 -
    Gender, Male/Female
    Units: participants
        Female
    53 58 48 60 100 98 417
        Male
    27 23 33 22 42 42 189

    End points

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    End points reporting groups
    Reporting group title
    Eosinophilic phenotype (EOS+) Placebo
    Reporting group description
    EOS+ (defined as ELEN Index [proprietary mathematical algorithm to predict sputum eosinophil’s greater than or equal to 2 percent] positive and/or FeNO [fraction of exhaled nitric oxide] greater than or equal to [>=] 50 parts per billion [ppb]) participants received matching placebo subcutaneous injection every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Reporting group title
    EOS+ Benralizumab, 2 mg
    Reporting group description
    EOS+ participants received benralizumab 2 milligram (mg) subcutaneous injection every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Reporting group title
    EOS+ Benralizumab, 20 mg
    Reporting group description
    EOS+ participants received benralizumab 20 mg subcutaneous injection every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Reporting group title
    EOS+ Benralizumab, 100 mg
    Reporting group description
    EOS+ participants received benralizumab 50 mg as two subcutaneous injections every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Reporting group title
    Non-eosinophil phenotype (EOS-) Placebo
    Reporting group description
    EOS- (defined as ELEN Index negative and FeNO <50 ppb) participants received matching placebo subcutaneous injections every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Reporting group title
    EOS- Benralizumab, 100 mg
    Reporting group description
    EOS- participants received benralizumab 50 mg as two subcutaneous injections every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Subject analysis set title
    EOS+ Placebo - Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    EOS+ participants received two placebo injections subcutaneously.

    Subject analysis set title
    EOS- Placebo - Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    EOS- participants received two placebo injections subcutaneously.

    Subject analysis set title
    EOS- Placebo - mITT Population
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    EOS- participants received two placebo injections subcutaneously.

    Subject analysis set title
    Benralizumab (100 mg) - mITT Population
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    EOS+ and EOS- participants received two benralizumab 50 mg injections subcutaneously.The modified intent-to-treat (mITT) population included all randomized participants who received any dose of investigational product.

    Subject analysis set title
    Placebo - mITT population
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    Participants received two placebo injections subcutaneously.

    Subject analysis set title
    EOS- Benralizumab, 100 mg - Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    EOS- participants received benralizumab 50 mg as two subcutaneous injections every 4 weeks for first 3 doses and then every 8 weeks for next 4 doses up to Week 40.

    Subject analysis set title
    Benralizumab, 100 mg - PK Population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    EOS+ and EOS- participants received two benralizumab 50 mg injections subcutaneously.he Pharmacokinetic (PK) Population included all participants who received at least one dose of benralizumab and had at least one quantifiable PK observation. One participant, randomized to the EOS- placebo group received a single dose of 100 mg benralizumab on Week 16 and was analyzed for PK in the 100 mg benralizumab group.

    Primary: Annual Asthma Exacerbation Rate (AER) for Eosinophilic Phenotype (EOS+) Participants

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    End point title
    Annual Asthma Exacerbation Rate (AER) for Eosinophilic Phenotype (EOS+) Participants [1]
    End point description
    The annual asthma exacerbation rate (AER) was calculated as the total number of observed exacerbations in each group up to week 52, divided by total duration of person-year follow-up in each group. An asthma exacerbation is defined as a progressive increase of asthma symptoms (cough, wheeze, chest tightness, and/or shortness of breath) that does not resolve after the initiation of rescue medications and remains troublesome for the participant resulting in either 1) use of systemic corticosteroids or increase of a stable systemic maintenance dose for a duration of at least 3 days as prescribed or administered by the investigator or healthcare provider; or 2) participant initiation of systemic corticosteroids for a duration of at least 3 days as outlined in the Asthma Action Plan provided to the participant by the investigator on Day 1. The modified intent-to-treat (mITT) population included all randomized participants who received any dose of investigational product.
    End point type
    Primary
    End point timeframe
    Week 1 up to Week 52
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The EOS- participants were only for exploratory analyses, and hence, data was reported for EOS+ participants in this endpoint.
    End point values
    Eosinophilic phenotype (EOS+) Placebo EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg EOS+ Benralizumab, 100 mg
    Number of subjects analysed
    80
    81
    81
    82
    Units: AER events/person-year
        number (not applicable)
    0.57
    0.65
    0.37
    0.34
    Statistical analysis title
    Statistical Analysis-1
    Comparison groups
    Eosinophilic phenotype (EOS+) Placebo v EOS+ Benralizumab, 2 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.781
    Method
    Poisson Regression Method
    Parameter type
    Rate Ratio
    Point estimate
    1.09
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.74
         upper limit
    1.59
    Statistical analysis title
    Statistical Analysis-3
    Comparison groups
    Eosinophilic phenotype (EOS+) Placebo v EOS+ Benralizumab, 100 mg
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.096
    Method
    Poisson Regression Method
    Parameter type
    Rate ratio
    Point estimate
    0.59
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    0.89
    Statistical analysis title
    Statistical Analysis-2
    Comparison groups
    Eosinophilic phenotype (EOS+) Placebo v EOS+ Benralizumab, 20 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.173
    Method
    Poisson Regression Method
    Parameter type
    Rate Ratio
    Point estimate
    0.64
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.42
         upper limit
    0.97

    Secondary: Dose Response in EOS+ Participants

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    End point title
    Dose Response in EOS+ Participants [2]
    End point description
    Due to change in planned analysis after unblinding of study data, dose response was not performed.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 66
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analyses for this end point.
    End point values
    Eosinophilic phenotype (EOS+) Placebo EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg EOS+ Benralizumab, 100 mg
    Number of subjects analysed
    0 [3]
    0 [4]
    0 [5]
    0 [6]
    Units: participants
    Notes
    [3] - Due to change in planned analysis, dose response was not analyzed.
    [4] - Due to change in planned analysis, dose response was not analyzed.
    [5] - Due to change in planned analysis, dose response was not analyzed.
    [6] - Due to change in planned analysis, dose response was not analyzed.
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Trough Concentration for Benralizumab at Steady-State (Ctrough, ss)

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    End point title
    Minimum Observed Serum Trough Concentration for Benralizumab at Steady-State (Ctrough, ss) [7]
    End point description
    The Pharmacokinetic (PK) Population included all participants who received at least one dose of benralizumab and had at least one quantifiable PK observation. One participant, randomized to the EOS- placebo group received a single dose of 100 mg benralizumab on Week 16 and was analyzed for PK in the 100 mg benralizumab group.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour), Post-dose on Day 1, 6, Week 4, 16, 24, 32, 40, and 52
    Notes
    [7] - 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: The EOS- participants were only for exploratory analyses, and hence, data was reported for EOS+ participants in this endpoint.
    End point values
    EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg Benralizumab, 100 mg - PK Population
    Number of subjects analysed
    81
    81
    223
    Units: microgram per milliliter
        arithmetic mean (standard deviation)
    34.7 ± 131
    182 ± 180
    869 ± 665
    No statistical analyses for this end point

    Secondary: Dose-Normalized Minimum Observed Serum Trough Concentration for Benralizumab at Steady-State (Ctrough, ssD)

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    End point title
    Dose-Normalized Minimum Observed Serum Trough Concentration for Benralizumab at Steady-State (Ctrough, ssD) [8]
    End point description
    The PK Population included all participants who received at least one dose of benralizumab and had at least one quantifiable PK observation. One participant, randomized to the EOS- placebo group received a single dose of 100 mg benralizumab on Week 16 and was analyzed for PK in the 100 mg benralizumab group.
    End point type
    Secondary
    End point timeframe
    Pre-dose (0 hour), Post-dose on Day 1, 6, Week 4, 16, 24, 32, 40, and 52
    Notes
    [8] - 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: The EOS- participants were only for exploratory analyses, and hence, data was reported for EOS+ participants in this endpoint.
    End point values
    EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg Benralizumab, 100 mg - PK Population
    Number of subjects analysed
    81
    81
    223
    Units: microgram per milliliter
        arithmetic mean (standard deviation)
    17.3 ± 65.3
    9.1 ± 9.02
    8.69 ± 6.65
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Anti-Drug Antibodies (ADA) to Benralizumab in Eosinophilic Phenotype (EOS+) Participants

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    End point title
    Percentage of Participants with Anti-Drug Antibodies (ADA) to Benralizumab in Eosinophilic Phenotype (EOS+) Participants [9]
    End point description
    Immunogenicity assessment included determination of anti-drug (benralizumab) antibodies in serum samples. ADA positive was defined as a titer >=50 at any point in the study. It was observed at baseline and any visit during the study. The mITT population included all randomized participants who received any dose of investigational product.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 92
    Notes
    [9] - 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: The EOS- participants were only for exploratory analyses, and hence, data was reported for EOS+ participants in this endpoint.
    End point values
    EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg EOS+ Benralizumab, 100 mg EOS+ Placebo - Safety population
    Number of subjects analysed
    81
    81
    82
    80
    Units: percentage of participants
        number (not applicable)
    42
    30.9
    25.6
    3.8
    No statistical analyses for this end point

    Secondary: Change from Baseline in Asthma Control Questionnaire (6-items) (ACQ-6) Score at Week 52

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    End point title
    Change from Baseline in Asthma Control Questionnaire (6-items) (ACQ-6) Score at Week 52
    End point description
    Asthma Control Questionnaire (ACQ) is a participant-reported questionnaire to assess the asthma control with 6 items assessing night-time waking, symptoms on waking, activity limitation, shortness of breath, wheeze, and rescue short-acting beta agonist use. Each item was rated on a 7-point Likert scale ranging from 0 (no impairment) to 6 (maximum impairment). Overall ACQ score was the mean of the 6 item scores with a score range of 0 (well controlled) to 6 (extremely poor controlled). Data collected on Day 1 prior to dosing was considered as baseline. Results were reported for overall ACQ score. ACQ-6 score was summarized together for all participants. The mITT population included all randomized participants who received any dose of investigational product. Here "n" signifies participants who were evaluable for this measure for the specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    Eosinophilic phenotype (EOS+) Placebo EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg EOS+ Benralizumab, 100 mg Non-eosinophil phenotype (EOS-) Placebo EOS- Benralizumab, 100 mg
    Number of subjects analysed
    80
    81
    81
    82
    142
    140
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=80,80,80,82,142,140)
    2.7479 ± 0.9762
    2.6479 ± 0.9908
    2.475 ± 0.9106
    2.5346 ± 0.9728
    2.4742 ± 0.8408
    2.6381 ± 0.833
        Change at Week 52 (n=34,42,40,39,64,73)
    -0.8922 ± 1.1969
    -1.1032 ± 1.1207
    -1.25 ± 1.2247
    -1.1239 ± 1.2852
    -0.8418 ± 1.1343
    -1.1295 ± 1.1301
    Statistical analysis title
    Statistical Analysis-1
    Comparison groups
    Eosinophilic phenotype (EOS+) Placebo v EOS+ Benralizumab, 2 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.125
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical Analysis-2
    Comparison groups
    Eosinophilic phenotype (EOS+) Placebo v EOS+ Benralizumab, 20 mg
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.074
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical Analysis-3
    Comparison groups
    Eosinophilic phenotype (EOS+) Placebo v EOS+ Benralizumab, 100 mg
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.057
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical analysis 4
    Comparison groups
    Non-eosinophil phenotype (EOS-) Placebo v EOS- Benralizumab, 100 mg
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.01 [10]
    Method
    ANCOVA
    Confidence interval
    Notes
    [10] - P-value was calculated by ANCOVA with treatment, baseline inhaled steroid status and baseline observed value as covariates.

    Secondary: Change From Baseline in Mean Total Nasal Symptoms Score (TNSS) at Week 52

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    End point title
    Change From Baseline in Mean Total Nasal Symptoms Score (TNSS) at Week 52 [11]
    End point description
    Total Nasal Symptoms Score (TNSS) is a 3-item questionnaire, the sum of nasal symptoms, namely, nasal obstruction (rhinorrhea), nasal congestion, and nasal itching/sneezing. Each symptom was rated on a scale from 0-3, with 0 representing no symptoms, 1 mild, 2 moderate, and 3 severe symptoms. TNSS score was a summation of the 3 individual nasal symptom. TNSS score could range from 0 to 9 where higher score indicates worsening. Data was summarized by each treatment group. In addition, data was summarized together for “EOS+ and EOS- Placebo” arms and “EOS+ and EOS- benralizumab 100 mg” arms. The mITT population included all randomized participants who received any dose of investigational product. Here "n" signifies participants who were evaluable for this measure for the specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    Notes
    [11] - 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: The EOS- participants were only for exploratory analyses, and hence, data was reported for EOS+ participants in this endpoint.
    End point values
    EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg Benralizumab (100 mg) - mITT Population Placebo - mITT population
    Number of subjects analysed
    81
    81
    222
    222
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=71,27,25,81))
    4.8 ± 2
    5.3 ± 1.8
    4.4 ± 2.1
    4.3 ± 2
        Change at Week 52 (n=89,39,39,106)
    -0.8 ± 2.01
    -1 ± 2.96
    -0.8 ± 2.24
    -0.4 ± 2.9
    No statistical analyses for this end point

    Secondary: Change from baseline in Mean Asthma Symptom Diary Score at Week 51-52

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    End point title
    Change from baseline in Mean Asthma Symptom Diary Score at Week 51-52 [12]
    End point description
    Asthma Symptom Diary included 7 questions about the participant symptom and the overall impact of treatment on the disease during the study period. Mean scores of the 7 questions were calculated to identify asthma symptom-free days. Asthma Symptom Diary Scores were analyzed on a bi-weekly basis and compared to baseline scores. Overall symptom score=(daytime frequency score + daytime severity score + nighttime severity score)/3, where total score ranges from 0 to 9. Higher score represents worsening. Mean asthma symptom diary score were summarized together for all participants. Data was summarized by each treatment group. In addition, data was summarized together for “EOS+ and EOS- Placebo” arms and “EOS+ and EOS- benralizumab 100 mg” arms. The mITT population included all randomized participants who received any dose of investigational product. Here "n" signifies participants who were evaluable for this measure for the specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 51-52
    Notes
    [12] - 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: The EOS- participants were only for exploratory analyses, and hence, data was reported for EOS+ participants in this endpoint.
    End point values
    EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg Benralizumab (100 mg) - mITT Population Placebo - mITT population
    Number of subjects analysed
    81
    81
    222
    222
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=204,72,74,210)
    1.65 ± 0.65
    1.6 ± 0.61
    1.6 ± 0.62
    1.58 ± 0.6
        Change at Week 51-52 (n=111,36,39,111)
    -0.56 ± 0.76
    -0.56 ± 0.69
    -0.53 ± 0.67
    -0.37 ± 0.61
    Statistical analysis title
    Statistical Analysis-1
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.131
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.182
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.336
         upper limit
    -0.028
    Statistical analysis title
    Statistical Analysis-2
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.126
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.173
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.317
         upper limit
    -0.028
    Statistical analysis title
    Statistical Analysis-3
    Comparison groups
    Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.097
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.14
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.247
         upper limit
    -0.032

    Secondary: Change from Baseline in Rescue Medication Use at Week 51-52

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    End point title
    Change from Baseline in Rescue Medication Use at Week 51-52 [13]
    End point description
    Participants were provided inhalers of the same dose (medium- or high-dose) inhaled corticosteroid (ICS) plus long-acting beta antagonist (LABA) combination product as baseline prophylactic medication and continued with same dose throughout the study. Rescue medications such as short-term beta2 agonists were used as first-line treatment for worsening asthma symptoms. Investigator prescribed additional short term asthma controller medications included additional ICS, theophylline, inhaled cromones or antimuscarinics; if asthma symptoms remained mild but not resolved. If asthma symptoms worsened, received an oral corticosteroid burst. All rescue medications use with prophylactic medication (+ prophylactic) and without prophylactic medication (- prophylactic) was recorded in asthma symptom dairy and analyzed on a bi-weekly basis and compared to baseline scores. Data summarized for “EOS+ and EOS- Placebo” and “EOS+ and EOS- benralizumab 100 mg” arms.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 51-52
    Notes
    [13] - 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: The EOS- participants were only for exploratory analyses, and hence, data was reported for EOS+ participants in this endpoint.
    End point values
    EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg Benralizumab (100 mg) - mITT Population Placebo - mITT population
    Number of subjects analysed
    81 [14]
    81 [15]
    222 [16]
    222 [17]
    Units: rescue medication per 2 weeks
    arithmetic mean (standard deviation)
        Baseline without prophylactic (n=204,72,74,210)
    3.57 ± 3.67
    3.82 ± 4.34
    3.16 ± 2.82
    3.09 ± 2.55
        Baseline with prophylactic (n=204,72,74,210)
    4.71 ± 5.56
    5.24 ± 6.4
    4.22 ± 3.9
    4.07 ± 3.34
        Change Week 51-52 -prophylactic(n=111,36,39,111)
    -1.4116 ± 2.8722
    -1.8804 ± 5.3129
    -1.1589 ± 2.0086
    -1.254 ± 2.4571
        Change Week 51-52 +prophylactic(n=111,36,39,111)
    -1.681 ± 4.2247
    -2.5118 ± 7.6814
    -1.4693 ± 2.5603
    -1.6855 ± 3.2875
    Notes
    [14] - mITT population. Here "n" = evaluable participants for the specified time point for each arm.
    [15] - mITT population. Here "n" = evaluable participants for the specified time point for each arm.
    [16] - mITT population
    [17] - mITT population
    Statistical analysis title
    Statistical Analysis-1
    Statistical analysis description
    Analysis reported for rescue medication use without prophylactic at Week 51-52.
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.642
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.174
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.654
         upper limit
    0.306
    Statistical analysis title
    Statistical Analysis-2
    Statistical analysis description
    Analysis reported for rescue medication use without prophylactic at Week 51-52.
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.824
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.111
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.533
         upper limit
    0.756
    Statistical analysis title
    Statistical Analysis-3
    Statistical analysis description
    Analysis reported for rescue medication use without prophylactic at Week 51-52.
    Comparison groups
    Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.91
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.029
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.297
         upper limit
    0.355
    Statistical analysis title
    Statistical Analysis-4
    Statistical analysis description
    Analysis reported for rescue medication use with prophylactic at Week 51-52.
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.992
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.004
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.602
         upper limit
    0.593
    Statistical analysis title
    Statistical Analysis-5
    Statistical analysis description
    Analysis reported for rescue medication use with prophylactic at Week 51-52.
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.624
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.337
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.548
         upper limit
    1.222
    Statistical analysis title
    Statistical Analysis-6
    Statistical analysis description
    Analysis reported for rescue medication use with prophylactic at Week 51-52.
    Comparison groups
    Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.645
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.15
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.267
         upper limit
    0.567

    Secondary: Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 52

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    End point title
    Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Week 52 [18]
    End point description
    FEV1 was the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. Data was summarized by each treatment group. In addition, data was summarized together for “EOS+ and EOS- Placebo” arms and “EOS+ and EOS- benralizumab 100 mg” arms. The mITT population included all randomized participants who received any dose of investigational product. Here "n" signifies participants who were evaluable for this measure for the specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    Notes
    [18] - 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: The EOS- participants were only for exploratory analyses, and hence, data was reported for EOS+ participants in this endpoint.
    End point values
    EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg Benralizumab (100 mg) - mITT Population Placebo - mITT population
    Number of subjects analysed
    81
    81
    222
    222
    Units: liters
    arithmetic mean (standard deviation)
        Baseline (n=215,80,81,218)
    1.978 ± 0.701
    2.08 ± 0.751
    2.012 ± 0.672
    2.033 ± 0.669
        Change at Week 52 (n=150,51,58,160)
    0.1631 ± 0.4691
    0.1847 ± 0.5234
    0.0998 ± 0.3541
    0.0098 ± 0.3615
    Statistical analysis title
    Statistical Analysis-1
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.014
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.157
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.076
         upper limit
    0.237
    Statistical analysis title
    Statistical Analysis-2
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Benralizumab (100 mg) - mITT Population v Placebo - mITT population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.004
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.184
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.102
         upper limit
    0.266
    Statistical analysis title
    Statistical Analysis-3
    Comparison groups
    Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.026
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.091
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.039
         upper limit
    0.143

    Secondary: Change From Baseline in Mean Forced Vital Capacity (FVC) at Week 52

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    End point title
    Change From Baseline in Mean Forced Vital Capacity (FVC) at Week 52 [19]
    End point description
    Forced Vital Capacity (FVC) was the volume of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. The mITT population included all randomized participants who received any dose of investigational product. Here "n" signifies participants who were evaluable for this measure for the specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    Notes
    [19] - 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: The EOS- participants were only for exploratory analyses, and hence, data was reported for EOS+ participants in this endpoint.
    End point values
    EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg EOS+ Benralizumab, 100 mg Non-eosinophil phenotype (EOS-) Placebo EOS- Benralizumab, 100 mg EOS+ Placebo - Safety population
    Number of subjects analysed
    81
    81
    82
    142
    140
    80
    Units: liters
    arithmetic mean (standard deviation)
        Baseline (n=80,80,81,82,135,136)
    3.069 ± 0.957
    3.285 ± 1.028
    3.11 ± 0.851
    3.043 ± 0.864
    3.126 ± 0.981
    3.282 ± 1.03
        Change at Week 52 (n=51,51,58,59,99,101)
    0.129 ± 0.565
    0.19 ± 0.586
    0.166 ± 0.445
    -0.03 ± 0.426
    0.056 ± 0.371
    0.029 ± 0.514
    Statistical analysis title
    Statistical Analysis-1
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v EOS+ Benralizumab, 100 mg v EOS+ Placebo - Safety population
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.384
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical Analysis-2
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v EOS+ Benralizumab, 100 mg v EOS+ Placebo - Safety population
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.092
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical Analysis-3
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v EOS+ Benralizumab, 100 mg v EOS+ Placebo - Safety population
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.134
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Statistical analysis-4
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v EOS+ Benralizumab, 100 mg v EOS+ Placebo - Safety population
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.129 [20]
    Method
    ANCOVA
    Confidence interval
    Notes
    [20] - P-value was calculated by ANCOVA with treatment, baseline inhaled steroid status and baseline observed value as covariates.

    Secondary: Change From Baseline in Peak Expiratory Flow (PEF) at Week 52

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    End point title
    Change From Baseline in Peak Expiratory Flow (PEF) at Week 52 [21]
    End point description
    The PEF is a participant’s maximum speed of expiration, as measured with a peak flow meter. Peak flow testing for PEF was performed while sitting or standing prior to using any medication (if needed) for asthma. Home PEF was determined separately for morning and evening, and were averaged for each participant. Data was summarized by each treatment group. In addition, data was summarized together for “EOS+ and EOS- Placebo” arms and “EOS+ and EOS- benralizumab 100 mg” arms. The mITT population included all randomized participants who received any dose of investigational product. Here "n" signifies participants who were evaluable for this measure for the specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    Notes
    [21] - 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: The EOS- participants were only for exploratory analyses, and hence, data was reported for EOS+ participants in this endpoint.
    End point values
    EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg Benralizumab (100 mg) - mITT Population Placebo - mITT population
    Number of subjects analysed
    81
    81
    222
    222
    Units: liters per minute
    arithmetic mean (standard deviation)
        Baseline (n=215,80,81,218)
    325.5 ± 101.6
    323.1 ± 100.8
    323.8 ± 101.7
    319.3 ± 104.7
        Change at Week 52 (n=150,51,58,160)
    29 ± 64.1
    45.9 ± 95.5
    26.6 ± 66.3
    13 ± 64.6
    No statistical analyses for this end point

    Secondary: Change From Baseline in Asthma Quality of Life Questionnaire (Standardized Version) (AQLQ[S]) Score at Week 52

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    End point title
    Change From Baseline in Asthma Quality of Life Questionnaire (Standardized Version) (AQLQ[S]) Score at Week 52 [22]
    End point description
    AQLQ: a 32-item questionnaire evaluating quality of life of participants with asthma including 4 domains (symptoms, activity limitations, emotional function, and environmental stimuli). Participants were asked to recall their experiences during the previous 2 weeks and to score each of the 32 questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment) and mean response was calculated as overall score. The 4 domain scores were the means of the responses to the questions in each of the domains. Overall AQLQ score and 4 domain scores ranged from 7 (no impairment) to 1 (severe impairment). The AQLQ(S) responses were categorized as improvement (defined as change from baseline >=0.5), no change (defined as change from baseline >= -0.5 to < 0.5), and worse (defined as change from baseline < -0.5). Data summarized for “EOS+ and EOS- Placebo” and “EOS+ and EOS- benralizumab 100 mg” arms.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    Notes
    [22] - 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: The EOS- participants were only for exploratory analyses, and hence, data was reported for EOS+ participants in this endpoint.
    End point values
    EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg Benralizumab (100 mg) - mITT Population Placebo - mITT population
    Number of subjects analysed
    81 [23]
    81 [24]
    222 [25]
    222 [26]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=214,78,80,217)
    3.72 ± 1.17
    3.79 ± 1.06
    3.72 ± 1.01
    3.72 ± 1.04
        Change at Week 52 (n=88,39,38,105)
    1.2612 ± 1.2082
    1.4474 ± 1.4262
    1.1223 ± 1.2636
    0.9634 ± 1.3342
    Notes
    [23] - mITT population. Here "n" = evaluable participants for the specified time point for each arm.
    [24] - mITT population. Here "n" = evaluable participants for the specified time point for each arm.
    [25] - mITT population
    [26] - mITT population
    Statistical analysis title
    Statistical Analysis-1
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.069
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.404
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.121
         upper limit
    0.687
    Statistical analysis title
    Statistical Analysis-2
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.049
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.462
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.163
         upper limit
    0.761
    Statistical analysis title
    Statistical Analysis-3
    Comparison groups
    Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.168
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.238
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.017
         upper limit
    0.459

    Secondary: Change From Baseline in European Quality of Life - 5 Dimensions (EQ-5D) Health State Evaluation at Week 52

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    End point title
    Change From Baseline in European Quality of Life - 5 Dimensions (EQ-5D) Health State Evaluation at Week 52 [27]
    End point description
    The utility-based EQ-5D questionnaire comprises of two parts and provides a generic measure of health for clinical and economic appraisal. The health state valuation was the summary score of mobility, self-care, usual activities, pain/discomfort and anxiety/depression on a 3 category scale (no problem, moderate problem, severe problems). Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state. Data was summarized by each treatment group. In addition, data was summarized together for “EOS+ and EOS- Placebo” arms and “EOS+ and EOS- benralizumab 100 mg” arms. The mITT population included all randomized participants who received any dose of investigational product. Here "n" signifies participants who were evaluable for this measure for the specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    Notes
    [27] - 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: The EOS- participants were only for exploratory analyses, and hence, data was reported for EOS+ participants in this endpoint.
    End point values
    EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg Benralizumab (100 mg) - mITT Population Placebo - mITT population
    Number of subjects analysed
    81
    81
    222
    222
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=213,79,74,209)
    0.7418 ± 0.2376
    0.7877 ± 0.1878
    0.7679 ± 0.1623
    0.7629 ± 0.2153
        Change at Week 52 (n=148,58,53,161)
    0.0822 ± 0.3137
    0.1223 ± 0.2132
    0.0824 ± 0.2179
    0.0853 ± 0.2096
    Statistical analysis title
    Statistical Analysis-1
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.51
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.058
         upper limit
    0.019
    Statistical analysis title
    Statistical Analysis-2
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.113
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.041
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    0.008
         upper limit
    0.074
    Statistical analysis title
    Statistical Analysis-3
    Comparison groups
    Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.599
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.011
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.016
         upper limit
    0.038

    Secondary: Change From Baseline in EQ-5D Visual Analog Scale (VAS) at Week 52

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    End point title
    Change From Baseline in EQ-5D Visual Analog Scale (VAS) at Week 52 [28]
    End point description
    The utility-based EQ-5D questionnaire comprises of two parts and provides a generic measure of health for clinical and economic appraisal. The EQ-5D VAS was measured from 0 (worst imaginable health state) to 100 (best imaginable health state). Data was summarized by each treatment group. In addition, data was summarized together for “EOS+ and EOS- Placebo” arms and “EOS+ and EOS- benralizumab 100 mg” arms. The mITT population included all randomized participants who received any dose of investigational product. Here "n" signifies participants who were evaluable for this measure for the specified time point for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    Notes
    [28] - 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: The EOS- participants were only for exploratory analyses, and hence, data was reported for EOS+ participants in this endpoint.
    End point values
    EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg Benralizumab (100 mg) - mITT Population Placebo - mITT population
    Number of subjects analysed
    81
    81
    222
    222
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=213,79,74,208)
    65.4937 ± 18.5063
    64.3378 ± 18.1427
    64.625 ± 19.7778
    65.0798 ± 17.8903
        Change at Week 52 (n=148,58,53,161)
    12.5517 ± 20.8008
    15.4906 ± 21.7297
    13.7391 ± 20.5139
    12.8041 ± 19.1036
    Statistical analysis title
    Statistical Analysis-1
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.871
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.373
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -3.333
         upper limit
    2.586
    Statistical analysis title
    Statistical Analysis-2
    Comparison groups
    EOS+ Benralizumab, 20 mg v EOS+ Benralizumab, 2 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.227
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    2.857
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.175
         upper limit
    5.889
    Statistical analysis title
    Statistical Analysis-3
    Comparison groups
    Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    444
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.503
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.139
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -1.041
         upper limit
    3.319

    Secondary: Change From Baseline in Percentage of Nocturnal Awakening-Free Nights at Week 51-52

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    End point title
    Change From Baseline in Percentage of Nocturnal Awakening-Free Nights at Week 51-52 [29]
    End point description
    Percentage of nocturnal awakening-free nights were analyzed on a bi-weekly basis and compared to baseline scores. Data was summarized by each treatment group. In addition, data was summarized together for “EOS+ and EOS- Placebo” arms and “EOS+ and EOS- benralizumab 100 mg” arms.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 51-52
    Notes
    [29] - 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: The EOS- participants were only for exploratory analyses, and hence, data was reported for EOS+ participants in this endpoint.
    End point values
    EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg Benralizumab (100 mg) - mITT Population Placebo - mITT population
    Number of subjects analysed
    81
    81
    222
    222
    Units: percent nocturnal awakening-free nights
    arithmetic mean (standard deviation)
        Baseline (n=204,72,74,210)
    45.07 ± 40.04
    51.57 ± 39.72
    50.92 ± 37.72
    52.05 ± 36.96
        Change at Week 51-52 (n=111,36,39,111)
    27.1749 ± 41.7342
    29.6181 ± 38.4315
    23.3054 ± 36.2761
    19.7595 ± 39.1388
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Placebo, EOS+ Benralizumab, 2 mg
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.55 [30]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    3.907
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -4.483
         upper limit
    12.297
    Notes
    [30] - P-value was calculated by ANCOVA with treatment, baseline inhaled steroid status and baseline observed value as covariates.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Placebo, EOS+ Benralizumab, 20 mg
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.215 [31]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    7.659
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.262
         upper limit
    15.579
    Notes
    [31] - P-value was calculated by ANCOVA with treatment, baseline inhaled steroid status and baseline observed value as covariates.
    Statistical analysis title
    Statistical analysis 3
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.413 [32]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    3.54
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -2.006
         upper limit
    9.086
    Notes
    [32] - P-value was calculated by ANCOVA with treatment, baseline inhaled steroid status and baseline observed value as covariates.

    Secondary: Change From Baseline in Mean Fraction Exhaled Nitric Oxide (FeNO) at Week 52

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    End point title
    Change From Baseline in Mean Fraction Exhaled Nitric Oxide (FeNO) at Week 52 [33]
    End point description
    Data was summarized by each treatment group. In addition, data was summarized together for “EOS+ and EOS- Placebo” arms and “EOS+ and EOS- benralizumab 100 mg” arms.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 52
    Notes
    [33] - 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: The EOS- participants were only for exploratory analyses, and hence, data was reported for EOS+ participants in this endpoint.
    End point values
    EOS+ Benralizumab, 2 mg EOS+ Benralizumab, 20 mg Benralizumab (100 mg) - mITT Population Placebo - mITT population
    Number of subjects analysed
    81
    81
    222
    222
    Units: parts per billion
    arithmetic mean (standard deviation)
        Baseline (n=222,81,81,222)
    39.52 ± 32.67
    40.79 ± 31.03
    26.68 ± 23.1
    26.88 ± 23.57
        Change at Week 52 (n=148,57,56,157)
    -3.2222 ± 33.2543
    -6.1905 ± 30.1103
    1.4384 ± 28.909
    1.2523 ± 16.02
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Placebo, EOS+ Benralizumab, 2 mg
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.896 [34]
    Method
    ANCOVA
    Confidence interval
    Notes
    [34] - P-value was calculated by ANCOVA with treatment, baseline inhaled steroid status and baseline observed value as covariates.
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    Placebo, Benralizumab (100 mg)
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.667 [35]
    Method
    ANCOVA
    Confidence interval
    Notes
    [35] - P-value was calculated by ANCOVA with treatment, baseline inhaled steroid status and baseline observed value as covariates.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Placebo, EOS+ Benralizumab, 20 mg
    Comparison groups
    EOS+ Benralizumab, 2 mg v EOS+ Benralizumab, 20 mg v Placebo - mITT population v Benralizumab (100 mg) - mITT Population
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.944 [36]
    Method
    ANCOVA
    Confidence interval
    Notes
    [36] - P-value was calculated by ANCOVA with treatment, baseline inhaled steroid status and baseline observed value as covariates.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From initiation of investigational product administration up to Week 92
    Adverse event reporting additional description
    The safety population included all participants who received any investigational product and had safety data available for analysis. One participant, randomized to the EOS- placebo group received a single dose of 100 mg benralizumab on Week 16 and was analyzed for safety in the 100 mg benralizumab group .
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    EOS POS Placebo
    Reporting group description
    EOS+ participants received two placebo injections subcutaneously.

    Reporting group title
    EOS POS Benralizumab 2 mg
    Reporting group description
    EOS+ participants received single benralizumab 2 milligram (mg) injection followed by a single placebo injection subcutaneously.

    Reporting group title
    EOS POS Benralizumab 20 mg
    Reporting group description
    EOS+ participants received single benralizumab 20 mg injection followed by a single placebo injection subcutaneously.

    Reporting group title
    EOS POS Benralizumab 100 mg
    Reporting group description
    EOS+ participants received two benralizumab 50 mg injections subcutaneously.

    Reporting group title
    EOS NEG Placebo
    Reporting group description
    EOS- participants received two placebo injections subcutaneously.

    Reporting group title
    EOS NEG Benralizumab 100 mg
    Reporting group description
    EOS- participants received two benralizumab 50 mg injections subcutaneously.

    Serious adverse events
    EOS POS Placebo EOS POS Benralizumab 2 mg EOS POS Benralizumab 20 mg EOS POS Benralizumab 100 mg EOS NEG Placebo EOS NEG Benralizumab 100 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 80 (8.75%)
    10 / 81 (12.35%)
    6 / 81 (7.41%)
    6 / 82 (7.32%)
    16 / 141 (11.35%)
    18 / 141 (12.77%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyarteritis nodosa
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Fibrous histiocytoma
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    1 / 81 (1.23%)
    1 / 82 (1.22%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 141 (0.71%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 141 (0.71%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 141 (0.71%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Abdominal wound dehiscen
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 81 (1.23%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarct
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 141 (0.71%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    2 / 81 (2.47%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachyca
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 80 (2.50%)
    2 / 81 (2.47%)
    0 / 81 (0.00%)
    2 / 82 (2.44%)
    8 / 141 (5.67%)
    5 / 141 (3.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 3
    0 / 14
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthmatic crisis
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 81 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 141 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 141 (0.71%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung diseas
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 81 (1.23%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 81 (1.23%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 141 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 141 (0.71%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 141 (0.71%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 80 (1.25%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 141 (0.71%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema nodosum
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 141 (0.71%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 81 (2.47%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 81 (1.23%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 81 (1.23%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 141 (0.71%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    1 / 81 (1.23%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 141 (0.71%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eczema infected
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 141 (0.71%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 141 (0.71%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis viral
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 81 (1.23%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    1 / 141 (0.71%)
    3 / 141 (2.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    1 / 141 (0.71%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural cellulit
         subjects affected / exposed
    0 / 80 (0.00%)
    1 / 81 (1.23%)
    0 / 81 (0.00%)
    0 / 82 (0.00%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infe
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis bacterial
         subjects affected / exposed
    0 / 80 (0.00%)
    0 / 81 (0.00%)
    0 / 81 (0.00%)
    1 / 82 (1.22%)
    0 / 141 (0.00%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    EOS POS Placebo EOS POS Benralizumab 2 mg EOS POS Benralizumab 20 mg EOS POS Benralizumab 100 mg EOS NEG Placebo EOS NEG Benralizumab 100 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 80 (55.00%)
    54 / 81 (66.67%)
    57 / 81 (70.37%)
    68 / 82 (82.93%)
    94 / 141 (66.67%)
    93 / 141 (65.96%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 80 (1.25%)
    3 / 81 (3.70%)
    0 / 81 (0.00%)
    3 / 82 (3.66%)
    4 / 141 (2.84%)
    10 / 141 (7.09%)
         occurrences all number
    2
    3
    0
    3
    4
    12
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    30 / 80 (37.50%)
    28 / 81 (34.57%)
    24 / 81 (29.63%)
    26 / 82 (31.71%)
    42 / 141 (29.79%)
    42 / 141 (29.79%)
         occurrences all number
    51
    59
    42
    36
    67
    77
    Rhinitis allergic
         subjects affected / exposed
    3 / 80 (3.75%)
    3 / 81 (3.70%)
    8 / 81 (9.88%)
    6 / 82 (7.32%)
    4 / 141 (2.84%)
    5 / 141 (3.55%)
         occurrences all number
    3
    5
    13
    8
    8
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 80 (10.00%)
    8 / 81 (9.88%)
    6 / 81 (7.41%)
    9 / 82 (10.98%)
    8 / 141 (5.67%)
    13 / 141 (9.22%)
         occurrences all number
    13
    13
    10
    10
    9
    17
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    0 / 80 (0.00%)
    2 / 81 (2.47%)
    2 / 81 (2.47%)
    8 / 82 (9.76%)
    0 / 141 (0.00%)
    10 / 141 (7.09%)
         occurrences all number
    0
    2
    4
    17
    0
    17
    Injection site pain
         subjects affected / exposed
    0 / 80 (0.00%)
    6 / 81 (7.41%)
    4 / 81 (4.94%)
    2 / 82 (2.44%)
    6 / 141 (4.26%)
    2 / 141 (1.42%)
         occurrences all number
    0
    6
    17
    3
    12
    4
    Pyrexia
         subjects affected / exposed
    1 / 80 (1.25%)
    4 / 81 (4.94%)
    3 / 81 (3.70%)
    1 / 82 (1.22%)
    1 / 141 (0.71%)
    2 / 141 (1.42%)
         occurrences all number
    1
    4
    3
    1
    1
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 80 (2.50%)
    3 / 81 (3.70%)
    2 / 81 (2.47%)
    1 / 82 (1.22%)
    2 / 141 (1.42%)
    2 / 141 (1.42%)
         occurrences all number
    3
    3
    2
    1
    2
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 80 (1.25%)
    4 / 81 (4.94%)
    5 / 81 (6.17%)
    3 / 82 (3.66%)
    1 / 141 (0.71%)
    3 / 141 (2.13%)
         occurrences all number
    1
    5
    6
    3
    1
    3
    Back pain
         subjects affected / exposed
    3 / 80 (3.75%)
    4 / 81 (4.94%)
    2 / 81 (2.47%)
    2 / 82 (2.44%)
    1 / 141 (0.71%)
    3 / 141 (2.13%)
         occurrences all number
    3
    4
    2
    4
    1
    3
    Myalgia
         subjects affected / exposed
    1 / 80 (1.25%)
    2 / 81 (2.47%)
    3 / 81 (3.70%)
    2 / 82 (2.44%)
    1 / 141 (0.71%)
    5 / 141 (3.55%)
         occurrences all number
    1
    2
    3
    3
    1
    5
    Infections and infestations
    Influenza
         subjects affected / exposed
    4 / 80 (5.00%)
    3 / 81 (3.70%)
    7 / 81 (8.64%)
    6 / 82 (7.32%)
    10 / 141 (7.09%)
    6 / 141 (4.26%)
         occurrences all number
    4
    5
    7
    6
    11
    6
    Sinusitis
         subjects affected / exposed
    3 / 80 (3.75%)
    4 / 81 (4.94%)
    3 / 81 (3.70%)
    2 / 82 (2.44%)
    2 / 141 (1.42%)
    0 / 141 (0.00%)
         occurrences all number
    6
    7
    3
    3
    2
    0
    Acute sinusitis
         subjects affected / exposed
    3 / 80 (3.75%)
    4 / 81 (4.94%)
    2 / 81 (2.47%)
    3 / 82 (3.66%)
    2 / 141 (1.42%)
    6 / 141 (4.26%)
         occurrences all number
    7
    6
    2
    3
    4
    8
    Bronchitis
         subjects affected / exposed
    3 / 80 (3.75%)
    8 / 81 (9.88%)
    6 / 81 (7.41%)
    3 / 82 (3.66%)
    13 / 141 (9.22%)
    9 / 141 (6.38%)
         occurrences all number
    4
    10
    8
    4
    20
    11
    Nasopharyngitis
         subjects affected / exposed
    8 / 80 (10.00%)
    11 / 81 (13.58%)
    7 / 81 (8.64%)
    13 / 82 (15.85%)
    5 / 141 (3.55%)
    13 / 141 (9.22%)
         occurrences all number
    13
    19
    13
    16
    6
    17
    Pharyngitis
         subjects affected / exposed
    3 / 80 (3.75%)
    8 / 81 (9.88%)
    3 / 81 (3.70%)
    7 / 82 (8.54%)
    5 / 141 (3.55%)
    6 / 141 (4.26%)
         occurrences all number
    3
    10
    3
    9
    5
    6
    Rhinitis
         subjects affected / exposed
    3 / 80 (3.75%)
    3 / 81 (3.70%)
    3 / 81 (3.70%)
    2 / 82 (2.44%)
    5 / 141 (3.55%)
    3 / 141 (2.13%)
         occurrences all number
    3
    3
    3
    3
    5
    7
    Upper respiratory tract
         subjects affected / exposed
    4 / 80 (5.00%)
    7 / 81 (8.64%)
    7 / 81 (8.64%)
    5 / 82 (6.10%)
    10 / 141 (7.09%)
    11 / 141 (7.80%)
         occurrences all number
    6
    12
    8
    6
    12
    14
    Urinary tract infection
         subjects affected / exposed
    4 / 80 (5.00%)
    2 / 81 (2.47%)
    1 / 81 (1.23%)
    3 / 82 (3.66%)
    5 / 141 (3.55%)
    3 / 141 (2.13%)
         occurrences all number
    4
    3
    1
    4
    5
    3

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Apr 2011
    The exclusion criteria for mitigation of parasitic infection associated with eosinophil depletion due to benralizumab were modified. Added an exploratory objective to analyse the performance of different helminth serology assays. Exclusion criterion 1 was revised to exclude subjects with allergic bronchopulmonary aspergillosis from participation. Exclusion criterion 27 was revised to ensure subjects were able to perform spirometry during the study. Exclusion criterion 28 was added to exclude subjects who used any oral or ophthalmic β-adrenergic antagonist. Withdrawal criterion was added that a subject would be discontinued from further investigational product administration based on an AE as determined by the sponsor. Withdrawal criterion added that the development of S stercoralis in subjects with chronic OCS-dependent asthma. Schedule of study procedures: The hepatitis A antibody test was removed from screening. Added that unblinded staff must not administer investigational product to the subject to maintain the integrity of the study blind. Added Asthma Symptom Diary Anchoring Questions. Schedule of study procedures: Hepatitis A antibody test was removed from screening. Schedule of study procedures: An early discontinuation visit was added and added serology testing for S stercoralis in subjects with chronic oral corticosteroiddependent asthma at Weeks 16, 32, 52, and 66. Added 4-day window to Screening Visit. Added collection of time of administration of the first injection of investigational product. Added Early Discontinuation Visit for subjects who discontinued the study prematurely. Added footnote under list of serum chemistries to conduct and assess tests for AST, ALT, ALP, and total bilirubin concurrently. Added procedures for parasite serology testing of S stercoralis, and for collection and analysis of stool samples. Added section on hepatic function abnormality as a measure of safety. Changed interim analysis to primary analysis.
    14 Nov 2011
    Changed total number of subjects to be randomized to 522 and total number of EOS+ subjects to be randomized to 280; changed number of EOS+ subjects in each treatment regimen from 60 to 70. Changed number of months for expected enrollment to 15-18. Changed number of weeks that subjects should return to the study site for peripheral blood eosinophil counts to 8. Changed study-stopping reason to reflect the occurrence of confirmed immune complex disease in a subject treated with benralizumab. Changes in inclusion and exclusion criteria. Added that a major deviation from the study protocol as judged by the investigator and/or the sponsor a reason for withdrawal. Modified procedures for following subjects for safety who were permanently discontinued from receiving investigational product. Changed procedures to allow for replacement of subjects who had not met major eligibility criteria and were withdrawn after receiving at least one dose of investigational product in error. Specified 21-gauge needle to be used. Specified when investigational product should not be administered. Updated text describing medium and high doses of ICS/LABA combination inhalers; added that subjects on high-dose ICS/LABA who used a secondary ICS inhaler were to be classified as high-dose subjects. Text describing rescreening procedures was modified. Removed sentence and reference citation regarding minimally clinical important difference in the TNSS-3. Changed the significance level to 0.2; changed the two-sided confidence interval to 80%; changed the sample size of the eosinophil-positive cohort and provided justification to augment the probability that the primary objective of detecting a reduction in asthma exacerbations in active versus placebo with adequate statistical power will be achieved; updated references as needed.
    16 Jul 2012
    Added section describing potential reason for stopping study for futility. Added interim analysis and a section describing unblinding for the interim analysis. Changed references to Week 52 analysis to Stage I analysis; Clarified the Stage I and Stage II analyses that will be conducted. Changed the primary endpoint analysis from Cochran-Mantel-Haenszel method to Poisson regression with overdispersion adjustment factor. Cochran-Mantel- Haenszel and negative binomial regression were considered sensitivity analyses. Removed weighted mean rate of asthma exacerbations as an exploratory endpoint.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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