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    Clinical Trial Results:
    A Multicentre, Randomised, Double-blind, Parallel Group, Placebo-controlled, Phase 3 Efficacy and Safety Study of Benralizumab (MEDI-563) Added to Medium to High-dose Inhaled Corticosteroid Plus Long-acting β2 Agonist in Patients with Uncontrolled Asthma

    Summary
    EudraCT number
    		 2017-000702-38
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    30 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Sep 2023
    First version publication date
    30 Sep 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D3250C00036
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03186209
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Vastra Malarehamnen 9, Sodertalje, Sweden, 151 85
    Public contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 18772409479, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Mar 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of benralizumab on asthma exacerbations in patients on medium- to high-dose ICS-LABA with uncontrolled asthma
    Protection of trial subjects
    The study is performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Conference on Harmonisation (ICH)/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological samples. Each PI is responsible for providing the ECs/institutional review boards (IRBs) with reports of any serious and unexpected adverse drug reactions from any other study conducted with the investigational product. AstraZeneca provides this information to the PI so that he/she can meet these reporting requirements. During the study, AstraZeneca representative have regular contacts with the study site, ie, monitoring the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Sep 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 522
    Country: Number of subjects enrolled
    Taiwan: 14
    Country: Number of subjects enrolled
    Philippines: 49
    Country: Number of subjects enrolled
    Korea, Republic of: 110
    Worldwide total number of subjects
    695
    EEA total number of subjects
    0
    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)
    1
    Adults (18-64 years)
    594
    From 65 to 84 years
    100
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 695 participants were randomized to received treatment in study D3250C00036 (MIRACLE) with Benralizumab or placebo. All the 695 randomized participants received treatment with study drug. Of the 695 dosed, 348 (50.1%) participants received Benralizumab and 347 (49.9%) pariticipants received placebo.

    Pre-assignment
    Screening details
    		 At the first visit, the enrollment visit 1, participants were evaluated regarding the protocol mandated inclusion and exclusion criteria. After enrollment, eligible participants were randomized to either placebo or Benralizumab 30 mg at a 1:1 ratio, administered subcutaneously every 4 weeks for the first 3 doses and then every 8 weeks thereafter.

    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, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Benralizumab 30 mg
    Arm description
    		 Benralizumab administered subcutaneously
    Arm type
    		 Experimental

    Investigational medicinal product name
    Benralizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    30 mg, administered every 4 weeks for the first 3 doses and then every 8 weeks after.

    Arm title
    		 Placebo
    Arm description
    		 Placebo administered subcutaneously
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    30 mg, administered every 4 weeks for the first 3 doses and then every 8 weeks after.

    Number of subjects in period 1
    		Benralizumab 30 mg Placebo
    Started
    348
    347
    Dosed
    348
    347
    Completed
    331
    321
    Not completed
    17
    26
         Consent withdrawn by subject
    11
    22
         V18 SKIPPED DUE TO LOGISTICS REASON
    1
    -
         Adverse event, non-fatal
    4
    -
         PI DECISION DUE TO LACK OF CRC RESOURCES
    -
    2
         Pregnancy
    1
    -
         Lost to follow-up
    -
    1
         Fail to meet randomization criteria
    -
    1

    Baseline characteristics

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

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered subcutaneously

    Reporting group values
    		 Benralizumab 30 mg Placebo Total
    Number of subjects
    		 348 347 695
    Age Categorical
    Units: Participants
        >=12 - <18 years
    		 1 0 1
        >=18 - <65 years
    		 299 295 594
        >=65 - <=75
    		 48 52 100
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.1 ( 11.56 ) 51.0 ( 12.56 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 221 207 428
        Male
    		 127 140 267
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Non-Hispanic or Latino
    		 348 347 695
    Race
    Units: Subjects
        Asian
    		 348 347 695

    End points

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

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered subcutaneously

    Primary: Annual asthma exacerbation rate in patients on medium to high-dose ICS-LABA with uncontrolled asthma for baseline eosinophils >=300/uL

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    End point title
    		 Annual asthma exacerbation rate in patients on medium to high-dose ICS-LABA with uncontrolled asthma for baseline eosinophils >=300/uL
    End point description
    Annual asthma exacerbation rate over the 48-week treatment period among benralizumab and placebo groups
    End point type
    Primary
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    236
    237
    Units: events/patient-year
        least squares mean (confidence interval 95%)
    0.49 (0.33 to 0.72)
    1.88 (1.35 to 2.61)
    Statistical analysis title
    		 Negative Binomial Model
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 Negative binomial
    Parameter type
    		 Rate Ratio
    Point estimate
    0.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 0.36
    Notes
    [1] - Multiplicity protected by hierarchy testing procedure. First in line hypothesis testing, requiring p-value <0.05.

    Secondary: Change From Baseline at Week 48 in Pre-bronchodilator FEV1 (L) Value for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

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    End point title
    		 Change From Baseline at Week 48 in Pre-bronchodilator FEV1 (L) Value for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
    End point description
    Change from baseline at Week 48 in Pre-bronchodilator FEV1 (L)
    End point type
    Secondary
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    215
    204
    Units: Liter
        arithmetic mean (standard deviation)
    0.333 ( 0.4499 )
    0.103 ( 0.4841 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 0.34
    Notes
    [2] - Test after significant primary endpoint. Two secondary endpoints (change in FEV1 and total asthma symptom score) using Holm's procedure; smaller p-value to be <0.025, and larger p-value to be <0.05.

    Secondary: Change From Baseline at Week 48 in Total Asthma Symptom Score for for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

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    End point title
    		 Change From Baseline at Week 48 in Total Asthma Symptom Score for for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
    End point description
    Daytime and nighttime symptoms are reported using a response scale ranging from 0 to 3 where 0 indicates no asthma symptoms. The total asthma symptom score is the sum of the daytime and nighttime scores and ranges from 0 to 6; a decrease in score indicates symptom improvement.
    End point type
    Secondary
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    213
    206
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.07 ( 1.126 )
    -0.80 ( 1.129 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0126 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 -0.05
    Notes
    [3] - Test after significant primary endpoint. Two secondary endpoints (change in FEV1 and total asthma symptom score) using Holm's procedure; smaller p-value to be <0.025, and larger p-value to be <0.05.

    Secondary: Change from Baseline at Week 48 in Total Asthma Rescue Medication use for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

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    End point title
    		 Change from Baseline at Week 48 in Total Asthma Rescue Medication use for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
    End point description
    Change from baseline at week 48 in total rescue medication use (number of puffs/day)
    End point type
    Secondary
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    213
    206
    Units: Puffs/day
        arithmetic mean (standard deviation)
    -0.85 ( 1.865 )
    -0.89 ( 2.213 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1835 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.42
         upper limit
    		 0.08
    Notes
    [4] - Nominal p-value. Not multiplicity protected by testing procedure.

    Secondary: Change from Baseline at Week 48 in Morning Peak Expiratory Flow (PEF) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

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    End point title
    		 Change from Baseline at Week 48 in Morning Peak Expiratory Flow (PEF) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
    End point description
    Change from baseline at week 48 in morning PEF
    End point type
    Secondary
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    213
    207
    Units: L/min
        arithmetic mean (standard deviation)
    54.194 ( 86.3963 )
    12.995 ( 68.7947 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    420
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    38.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 24.24
         upper limit
    		 53.07
    Notes
    [5] - Nominal p-value. Not multiplicity protected by testing procedure.

    Secondary: Change From baseline at Week 48 in the Proportion of Night Awakening Due to Asthma and Requiring rescue medication for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

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    End point title
    		 Change From baseline at Week 48 in the Proportion of Night Awakening Due to Asthma and Requiring rescue medication for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
    End point description
    Change from baseline at Week 48 in proportion of night awakening due to asthma and requiring rescue medication
    End point type
    Secondary
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    217
    208
    Units: Proportion of nights
        arithmetic mean (standard deviation)
    -0.15 ( 0.220 )
    -0.15 ( 0.260 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    425
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3385 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.03
         upper limit
    		 0.01
    Notes
    [6] - Nominal p-value. Not multiplicity protected by testing procedure.

    Secondary: Change from Baseline at Week 48 in Evening Peak Expiratory Flow (PEF) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

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    End point title
    		 Change from Baseline at Week 48 in Evening Peak Expiratory Flow (PEF) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
    End point description
    Change from baseline at week 48 in evening PEF
    End point type
    Secondary
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    217
    209
    Units: L/min
        arithmetic mean (standard deviation)
    45.661 ( 85.4642 )
    7.989 ( 68.0632 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    426
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    35.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 21.52
         upper limit
    		 50.18
    Notes
    [7] - Nominal p-value. Not multiplicity protected by testing procedure.

    Secondary: Change From Baseline at Week 48 in Asthma Control Questionnaire 6 (ACQ-6) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

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    End point title
    		 Change From Baseline at Week 48 in Asthma Control Questionnaire 6 (ACQ-6) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
    End point description
    ACQ-6 contains one bronchodilator question and 5 symptom questions. Questions are rated from 0 (totally controlled) to 6 (severely uncontrolled). Mean ACQ-6 score is the average of the responses.
    End point type
    Secondary
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    218
    212
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.22 ( 0.901 )
    -0.79 ( 0.962 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    430
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 -0.28
    Notes
    [8] - Nominal p-value. Not multiplicity protected by testing procedure.

    Secondary: Time to First Asthma Exacerbation for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

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    End point title
    		 Time to First Asthma Exacerbation for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
    End point description
    Time to first asthma exacerbation over 48-week treatment period
    End point type
    Secondary
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    236
    237
    Units: Participants
    55
    125
    Statistical analysis title
    		 Cox Regression Model
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [9]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 0.43
    Notes
    [9] - Nominal p-value. Not multiplicity protected by testing procedure.

    Secondary: Annual asthma exacerbation rate associated with an emergency room/urgent care visit or a hospitalization for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

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    End point title
    		 Annual asthma exacerbation rate associated with an emergency room/urgent care visit or a hospitalization for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
    End point description
    Annual asthma exacerbation rate associated with an emergency room/urgent care visit or a hospitalization over 48-week treatment period
    End point type
    Secondary
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    236
    237
    Units: events/patient-year
        least squares mean (confidence interval 95%)
    0.06 (0.04 to 0.11)
    0.14 (0.09 to 0.20)
    Statistical analysis title
    		 Negative Binomial Model
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0222 [10]
    Method
    		 Negative binomial
    Parameter type
    		 Rate ratio
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 0.9
    Notes
    [10] - Nominal p-value. Not multiplicity protected by testing procedure.

    Secondary: Number and Percentage of Patients With >=1 Asthma Exacerbations among patients who were on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

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    End point title
    		 Number and Percentage of Patients With >=1 Asthma Exacerbations among patients who were on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
    End point description
    Number and percentage of patients with at least one exacerbation over 48-week treatment period
    End point type
    Secondary
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    236
    237
    Units: participants
        Number of patients with >=1 asthma exacerbation
    55
    125
    Statistical analysis title
    		 Cochran-Mantel-Haenszel Test
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [11]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.19
         upper limit
    		 0.42
    Notes
    [11] - Nominal p-value. Not multiplicity protected by testing procedure.

    Secondary: Change From Baseline at Week 48 in Total score of St. George’s Respiratory Questionnaire (SGRQ) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

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    End point title
    		 Change From Baseline at Week 48 in Total score of St. George’s Respiratory Questionnaire (SGRQ) for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
    End point description
    The SGRQ is a 50-item PRO instrument developed to measure the HRQoL of patients with airway diseases. The questionnaire is divided into two parts: part 1 consists of 8 items pertaining to the severity of respiratory symptoms in the preceding 4 weeks; part 2 consists of 42 items related to the daily activity and psychosocial impacts of the individual’s respiratory condition. The total score indicates the impact of disease on overall HRQoL. This total score is expressed as a percentage of overall impairment, in which 100 represents the worst possible HRQoL and 0 indicates the best possible HRQoL.
    End point type
    Secondary
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    209
    200
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -23.24 ( 20.509 )
    -14.75 ( 21.838 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    409
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -9.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.79
         upper limit
    		 -5.6
    Notes
    [12] - Nominal p-value. Not multiplicity protected by testing procedure.

    Secondary: The pharmacokinetics (PK) of benralizumab as assessed by trough concentration

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    End point title
    		 The pharmacokinetics (PK) of benralizumab as assessed by trough concentration
    End point description
    PK trough concentrations at each visit
    End point type
    Secondary
    End point timeframe
    week 0, week 24, week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    345
    0 [13]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Week 0
    0 ( 0 )
    ( )
        Week 24
    137.914 ( 432.419 )
    ( )
        Week 48
    123.476 ( 395.951 )
    ( )
    Notes
    [13] - Placebo treated patients are not having pharmacokinetics Benralizumab concentrations analyzed.
    No statistical analyses for this end point

    Secondary: Number and Percentages of Asthma specific Health Care Resource Utilization for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

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    End point title
    		 Number and Percentages of Asthma specific Health Care Resource Utilization for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
    End point description
    Asthma specific health care resource utilization over 48-week treatment period.
    End point type
    Secondary
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    236
    237
    Units: participants
        Hospitalisations
    6
    21
        Emergency Department Visits
    11
    12
        Unscheduled Outpatient Visits
    53
    99
        Home Visits
    1
    2
        Telephone Calls
    35
    71
        Ambulance Transports
    2
    2
        Advanced Pulmonary Function Test
    4
    8
    No statistical analyses for this end point

    Secondary: The immunogenicity of benralizumab as assessed by the presence of anti-drug antibodies (ADAs)

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    End point title
    		 The immunogenicity of benralizumab as assessed by the presence of anti-drug antibodies (ADAs)
    End point description
    Anti-drug antibodies (ADA) responses at baseline and post baseline.
    End point type
    Secondary
    End point timeframe
    Pre-treatment until end of 48-week end of treatment
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    348
    347
    Units: participants
        ADA positive at any time (ADA prevalence)
    58
    6
        Treatment-emergent ADA positive(induced/boosted)
    58
    2
        Treatment-induced ADA positive
    56
    2
        Treatment-boosted ADA positive
    2
    0
        ADA positive at both baseline and ≥1 post-baseline
    2
    2
        ADA positive at baseline only
    0
    2
        ADA persistently positive
    40
    1
        ADA transiently positive
    16
    1
        ADA positive with max titre > median max titre
    25
    2
        ADA positive with max titre ≤ median max titres
    33
    4
        nAb prevalence
    55
    1
        nAb incidence
    55
    1
    No statistical analyses for this end point

    Secondary: Percent change from baseline at week 48 in blood eosinophil levels for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL

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    End point title
    		 Percent change from baseline at week 48 in blood eosinophil levels for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils >=300/uL
    End point description
    Percent change from baseline at Week 48 in blood eosinophil levels
    End point type
    Secondary
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    213
    199
    Units: Percentage
        arithmetic mean (standard deviation)
    -80.6 ( 34.65 )
    42.3 ( 380.86 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    412
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -119.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -169.78
         upper limit
    		 -68.84
    Notes
    [14] - Nominal p-value. Not multiplicity protected by testing procedure.

    Other pre-specified: Annual asthma exacerbation rate in patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL

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    End point title
    		 Annual asthma exacerbation rate in patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL
    End point description
    Annual asthma exacerbation rate over the 48-week treatment period among benralizumab and placebo groups
    End point type
    Other pre-specified
    End point timeframe
    From randomization through Study Week 48.
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    112
    110
    Units: events/patient-year
        least squares mean (confidence interval 95%)
    0.72 (0.49 to 1.06)
    0.87 (0.61 to 1.24)
    Statistical analysis title
    		 Negative Binomial Model
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    222
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4519 [15]
    Method
    		 Negative binomial
    Parameter type
    		 Rate Ratio
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 1.35
    Notes
    [15] - Nominal p-value. Not multiplicity protected by testing procedure.

    Other pre-specified: Change From Baseline at Week 48 in Total Asthma Symptom Score for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL

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    End point title
    		 Change From Baseline at Week 48 in Total Asthma Symptom Score for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL
    End point description
    Daytime and nighttime symptoms are reported using a response scale ranging from 0 to 3 where 0 indicates no asthma symptoms. The total asthma symptom score is the sum of the daytime and nighttime scores and ranges from 0 to 6; a decrease in score indicates symptom improvement.
    End point type
    Other pre-specified
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    101
    94
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -0.97 ( 1.260 )
    -0.75 ( 1.105 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1589 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 0.08
    Notes
    [16] - Nominal p-value. Not multiplicity protected by testing procedure.

    Other pre-specified: Change From Baseline at Week 48 in Pre-bronchodilator FEV1 (L) Value for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL

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    End point title
    		 Change From Baseline at Week 48 in Pre-bronchodilator FEV1 (L) Value for patients on medium to high-dose ICS-LABA with uncontrolled asthma and baseline eosinophils <300/uL
    End point description
    Change from baseline at Week 48 in Pre-bronchodilator FEV1 (L)
    End point type
    Other pre-specified
    End point timeframe
    From randomization through Study Week 48
    End point values
    		 Benralizumab 30 mg Placebo
    Number of subjects analysed
    101
    97
    Units: Liter
        arithmetic mean (standard deviation)
    0.178 ( 0.4068 )
    0.045 ( 0.3626 )
    Statistical analysis title
    		 Mixed Effect Model Repeated Measurement
    Comparison groups
    Benralizumab 30 mg v Placebo
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0214 [17]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.22
    Notes
    [17] - Nominal p-value. Not multiplicity protected by testing procedure.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until last study visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered subcutaneously

    Reporting group title
    Benra 30 mg
    Reporting group description
    		 Benralizumab administered subcutaneously

    Serious adverse events
    		 Placebo Benra 30 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    63 / 347 (18.16%)
    44 / 348 (12.64%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenolymphoma
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal papilloma of breast
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian adenoma
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian germ cell teratoma benign
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    2 / 347 (0.58%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Neurogenic shock
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Food allergy
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    33 / 347 (9.51%)
    12 / 348 (3.45%)
         occurrences causally related to treatment / all
    0 / 37
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung opacity
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 347 (0.29%)
    3 / 348 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus polyp
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord polyp
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 347 (0.86%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Reflux gastritis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic gastritis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic mass
         subjects affected / exposed
    1 / 347 (0.29%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal mass
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibromyalgia
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 347 (0.58%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthropathy
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 347 (0.00%)
    2 / 348 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis allergic
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 347 (0.00%)
    2 / 348 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic infection
         subjects affected / exposed
    1 / 347 (0.29%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 347 (1.73%)
    3 / 348 (0.86%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    3 / 347 (0.86%)
    3 / 348 (0.86%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asymptomatic COVID-19
         subjects affected / exposed
    0 / 347 (0.00%)
    1 / 348 (0.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 347 (0.58%)
    0 / 348 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Placebo Benra 30 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    269 / 347 (77.52%)
    261 / 348 (75.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    13 / 347 (3.75%)
    7 / 348 (2.01%)
         occurrences all number
    14
    7
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 347 (2.31%)
    11 / 348 (3.16%)
         occurrences all number
    14
    11
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    9 / 347 (2.59%)
    18 / 348 (5.17%)
         occurrences all number
    9
    22
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic
         subjects affected / exposed
    15 / 347 (4.32%)
    22 / 348 (6.32%)
         occurrences all number
    17
    41
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    27 / 347 (7.78%)
    11 / 348 (3.16%)
         occurrences all number
    40
    15
    COVID-19
         subjects affected / exposed
    6 / 347 (1.73%)
    11 / 348 (3.16%)
         occurrences all number
    6
    11
    Nasopharyngitis
         subjects affected / exposed
    33 / 347 (9.51%)
    28 / 348 (8.05%)
         occurrences all number
    48
    36
    Otitis media
         subjects affected / exposed
    8 / 347 (2.31%)
    11 / 348 (3.16%)
         occurrences all number
    9
    11
    Pharyngitis
         subjects affected / exposed
    13 / 347 (3.75%)
    13 / 348 (3.74%)
         occurrences all number
    14
    13
    Rhinitis
         subjects affected / exposed
    6 / 347 (1.73%)
    13 / 348 (3.74%)
         occurrences all number
    9
    14
    Upper respiratory tract infection
         subjects affected / exposed
    120 / 347 (34.58%)
    120 / 348 (34.48%)
         occurrences all number
    230
    200
    Urinary tract infection
         subjects affected / exposed
    12 / 347 (3.46%)
    9 / 348 (2.59%)
         occurrences all number
    14
    10
    Pneumonia
         subjects affected / exposed
    16 / 347 (4.61%)
    9 / 348 (2.59%)
         occurrences all number
    19
    13

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Nov 2016
    1. The SGRQ replaced the AQLQ(s)+12 2. Amended inclusion criteria #8, #13, and #14 3. Amended exclusion criteria #18, #19, #24, and #30 4. Updated text about visit dates and medication restrictions in Section 4, Table 1 5. In Section 7.6.1.1 (background medication), added “medium to high dose” for ICS, and revised duration for ICS-LABA treatment to at least 6 months prior to Visit 1 and during the study 6. Removed the independent adjudication for asthma-related exacerbation 7. Removed the safety objective “Physical Examination”
    25 Apr 2018
    In Section 1.4, replaced “Approximately 834 patients will be randomised, among which at least 666 patients (333 patients/arm) patients will be recruited from China” with “Approximately 666 patients will be randomised, among which approximately 534 patients (267 patients/arm) will be recruited from China.” Related changes to stratum language in Sections 3.3, 3.10.2, and 8.2 due to the patient sample size change. The sample size justification was also updated.
    17 Dec 2019
    1. Amended inclusion criteria #3, #5, and #7 2. Added inclusion criteria #14 (“Pre-bronchodilator FEV1 of < 80% predicted [<90% predicted for patients aged 12 to 17 year] at Visit 2”) and #16 (“ACQ-6 score ≥ 1.5 at Visit 2”) 3. In Section 3.8.1 and Section 5.1.2, amended language about background medications and about withholding ICS-LABA therapy on the day of scheduled spirometry visits 4. New Section 3.10.5 (“withdrawal due to repeat exacerbations during screening”) was added 5. In Section 4, updated ACQ-6 assessment timing 6. In Section 6.3.3, SAE variables were added 7. In Section 7.6.1.1, adjusted language about changing the ICS-LABA dose and documentation
    18 Dec 2020
    1. In Sections 1.4 and 3.3, changed percentage of China patients from approximately 80% to at least 70%, and removed specific regions 2. In Sections 3.9 and 7.4, removed the criteria of 2 consecutive doses IP missed for discontinuation; and added statement of how to deal with the cases of a patient missing more than 2 doses within a calendar year, respectively 3. In Section 4.4, new wording added to give guidance on how the study could continue in the event of a serious disruption with details of mitigation that could be employed to ensure study continuity. Language in Appendix G was updated in a similar way 4. In Section 5.3.8, added language to include the possibility of patient testing performed during public health crisis 5. In Section 8.5, added additional analyses to address possible impact of study disruption 6. In Appendix D for anaphylaxis: definition, signs, symptoms and management introduction: changed the wording of appropriate drugs at study sites and updated monitoring timeframe 7. In Appendix G: Changes Related to Mitigation of Study Disruptions Due to Cases of Civil Crisis, Natural Disaster, or Public Health Crisis: new wording was added which gave guidance on how the study could continue in the event of a serious disruption with details of mitigation that could be employed to ensure study continuity

    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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