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    Clinical Trial Results:
    A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled, Phase IIIb Study to Evaluate the Safety and Efficacy of Benralizumab 30 mg sc in Patients with Severe Asthma Uncontrolled on Standard of Care Treatment (ANDHI)

    Summary
    EudraCT number
    		 2017-001040-35
    Trial protocol
    		 DK   GB   FR   BE   SE   NL   AT   ES   FI   IT  
    Global end of trial date
    21 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Nov 2021
    First version publication date
    03 Nov 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D3250C00045
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03170271
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Södertälje, Södertälje, Sweden, SE 151 85
    Public contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 8772409479, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Sep 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The goal of this study was to evaluate the efficacy and safety of repeat dosing of benralizumab 30 milligrams (mg), administered subcutaneously (sc), compared to placebo on top of standard of care asthma therapy in patients with severe uncontrolled asthma. The primary objective was to determine the effect of benralizumab on the rate of asthma exacerbations (treatment period 24 weeks).
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation / Good Clinical Practice, applicable regulatory requirements, and the AstraZeneca policy on Bioethics.
    Background therapy
    		 Patients with a history of physician-diagnosed asthma must have been on treatment with medium-to-high dose inhaled corticosteroids (ICS) plus asthma controller, for at least 12 months prior to enrolment. Other acceptable asthma controllers included a long-acting bronchodilator, a leukotriene inhibitor, theophylline preparations or maintenance oral corticosteroids (OCS; maximum total daily dose 20 mg prednisone or equivalent).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jul 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 18 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: 221
    Country: Number of subjects enrolled
    Canada: 27
    Country: Number of subjects enrolled
    Italy: 109
    Country: Number of subjects enrolled
    France: 72
    Country: Number of subjects enrolled
    Spain: 68
    Country: Number of subjects enrolled
    United Kingdom: 47
    Country: Number of subjects enrolled
    Germany: 44
    Country: Number of subjects enrolled
    Sweden: 20
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Netherlands: 11
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Norway: 2
    Worldwide total number of subjects
    656
    EEA total number of subjects
    361
    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)
    529
    From 65 to 84 years
    127
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with severe uncontrolled asthma and peripheral blood eosinophil counts of ≥150 cells/microliter (μL) (with major subgroups of 150–300 cells/μL plus clinical features and ≥300 cells/μL) were recruited to 221 centers in 14 countries. Patients were randomized 2:1 to benralizumab or placebo. Results are reported for the double-blind period.

    Pre-assignment
    Screening details
    		 Severe eosinophilic patients were to have had ≥2 asthma exacerbations while on maintenance ICS plus another asthma controller requiring treatment with systemic corticosteroids in the 12 months prior to enrolment. 660 patients were randomized but 4 patients were withdrawn after randomization as screen failures. Thus, 656 patients received treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Benralizumab
    Arm description
    		 Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An End of Treatment (EOT) visit was performed at Week 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Benralizumab
    Investigational medicinal product code
    MEDI-563
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Benralizumab 30 mg/milliliter (mL) solution for injection in an accessorized pre-filled syringe, 1 mL fill volume.

    Arm title
    		 Placebo
    Arm description
    		 Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.
    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
    Matching placebo solution for injection in an accessorized pre-filled syringe, 1 mL fill volume.

    Number of subjects in period 1
    		Benralizumab Placebo
    Started
    427
    229
    Full Analysis Set (FAS)
    427
    229
    Completed
    398
    218
    Not completed
    29
    11
         Physician decision
    1
    -
         Consent withdrawn by subject
    17
    5
         Adverse event, non-fatal
    7
    2
         Protocol-specified withdrawal criterion
    2
    1
         Unspecified
    2
    2
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Benralizumab
    Reporting group description
    		 Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An End of Treatment (EOT) visit was performed at Week 24.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.

    Reporting group values
    		 Benralizumab Placebo Total
    Number of subjects
    		 427 229 656
    Age categorical
    Units: subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 345 184 529
        From 65-84 years
    		 82 45 127
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.5 ± 12.69 53.3 ± 12.52 -
    Sex: Female, Male
    Units: subjects
        Female
    		 263 136 399
        Male
    		 164 93 257
    Race
    Units: Subjects
        White
    		 314 168 482
        Black or African American
    		 35 18 53
        Asian
    		 11 7 18
        Native Hawaiian or other Pacific Islander
    		 0 1 1
        Other
    		 5 2 7
        Missing
    		 62 33 95
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 49 25 74
        Not Hispanic or Latino
    		 318 172 490
        Unknown or Not Reported
    		 60 32 92
    Screening eosinophil count group (cells/µL)
    Units: Subjects
        ≥ 150 – < 300
    		 129 63 192
        ≥ 300
    		 297 165 462
        Missing
    		 1 1 2
    Baseline eosinophil count group (cells/μL)
    Units: Subjects
        < 300
    		 146 74 220
        ≥ 300 – < 450
    		 105 56 161
        ≥ 450
    		 176 99 275

    End points

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    End points reporting groups
    Reporting group title
    Benralizumab
    Reporting group description
    		 Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An End of Treatment (EOT) visit was performed at Week 24.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.

    Primary: Annualized Rate of Asthma Exacerbations Over the Treatment Period (up to Week 24)

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    End point title
    		 Annualized Rate of Asthma Exacerbations Over the Treatment Period (up to Week 24)
    End point description
    An asthma exacerbation was defined as a worsening of asthma that led to any of the following: • Use of systemic corticosteroids (or temporary increase in stable OCS background dose) for ≥3 days; a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids. • An emergency room/urgent care visit (defined as evaluation and treatment for <24 hours in emergency department or urgent care center) due to asthma that required systemic corticosteroids (as per above). • An inpatient hospitalization (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥24 hours) due to asthma. Annual exacerbation rate=365.25*total number of exacerbations/total duration of follow-up within treatment group. Annual asthma exacerbation rate over the 24-week period was estimated using a negative binomial model. The FAS included all randomized patients who received ≥1 dose of investigational product (IP).
    End point type
    Primary
    End point timeframe
    Baseline (Week 0) up to Week 24
    End point values
    		 Benralizumab Placebo
    Number of subjects analysed
    427
    229
    Units: Events/year
        number (confidence interval 95%)
    0.94 (0.79 to 1.12)
    1.86 (1.54 to 2.24)
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Comparison of annual exacerbation rates for benralizumab versus (vs) placebo (rate ratio). Treatment group, region, number of exacerbations in previous year and maintenance OCS use at baseline were included in the negative binomial model as covariates. The log of each patient’s corresponding follow-up time was used as an offset variable in the model to adjust for patients having different follow-up times during which events occurred.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.0001
    Method
    		 Negative binomial
    Parameter type
    		 Rate ratio
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.65
    Notes
    [1] - The null hypothesis was that the exacerbation rate of benralizumab was equal to the exacerbation rate of placebo.

    Secondary: Change from Baseline in Saint George Respiratory Questionnaire (SGRQ) Total Score to the EOT (Week 24)

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    End point title
    		 Change from Baseline in Saint George Respiratory Questionnaire (SGRQ) Total Score to the EOT (Week 24)
    End point description
    The SGRQ is a 50-item patient-reported outcome instrument which measures the health status of patients with airway obstruction diseases. The questionnaire is divided into 2 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 SGRQ total score indicates the impact of disease on overall health status and is expressed as a percentage of overall impairment (scores range from 0 to100, with 100 representing worst possible health status and 0 indicating the best possible health status). The least squares (LS) mean change from baseline in SGRQ total score at Week 24 is presented. The FAS included all randomized patients who received ≥1 dose of IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 24
    End point values
    		 Benralizumab Placebo
    Number of subjects analysed
    364
    204
    Units: Scores on a scale
        least squares mean (standard error)
    -23.06 ± 1.00
    -14.94 ± 1.34
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in SGRQ total score at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a mixed-effect model for repeated measures (MMRM) analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    568
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean difference
    Point estimate
    -8.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.41
         upper limit
    		 -4.82
    Notes
    [2] - Model: Change from baseline in SGRQ total score = Treatment + baseline SGRQ total score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

    Secondary: Change from Baseline in Pre-Bronchodilator (BD) Forced Expiratory Volume in First Second (FEV1) to the EOT (Week 24)

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    End point title
    		 Change from Baseline in Pre-Bronchodilator (BD) Forced Expiratory Volume in First Second (FEV1) to the EOT (Week 24)
    End point description
    Lung function was assessed by FEV1 which was measured by spirometry. Spirometry was performed by the Investigator or authorized delegate according to American Thoracic Society/European Respiratory Society guidelines. The LS mean change from baseline in pre-BD FEV1 at Week 24 is presented. The FAS included all randomized patients who received ≥1 dose of IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 24
    End point values
    		 Benralizumab Placebo
    Number of subjects analysed
    393
    213
    Units: Liters (L)
        least squares mean (standard error)
    0.30 ± 0.02
    0.14 ± 0.03
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in pre-BD FEV1 at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    606
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean difference
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.23
    Notes
    [3] - Model: Change from baseline in pre-BD FEV1 = Treatment + baseline pre-BD FEV1 + region + number of exacerbations in previous year + maintenance OCS use at baseline + gender + age + visit + treatment by visit.

    Secondary: Change from Baseline in Asthma Control Questionnaire 6 (ACQ-6) Score to the EOT (Week 24)

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    End point title
    		 Change from Baseline in Asthma Control Questionnaire 6 (ACQ-6) Score to the EOT (Week 24)
    End point description
    The ACQ-6 is a shortened version of the ACQ that assesses asthma symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath and wheezing) and short-acting β-2 receptor agonist use. Patients were asked to recall the status of their asthma during the previous week and respond to the questions of the ACQ-6 on a 7-point scale. Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ-6 score is computed as the mean of the responses from all the items in the questionnaire. Mean scores of ≤0.75 indicated well-controlled asthma, scores between 0.75 and <1.5 indicated partly-controlled asthma, and a score ≥1.5 indicated not well-controlled asthma. The LS mean change from baseline in ACQ-6 score at Week 24 is presented. The FAS included all randomized patients who received ≥1 dose of IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 24
    End point values
    		 Benralizumab Placebo
    Number of subjects analysed
    393
    216
    Units: Scores on a scale
        least squares mean (standard error)
    -1.47 ± 0.06
    -1.01 ± 0.08
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in ACQ-6 score at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    609
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.65
         upper limit
    		 -0.27
    Notes
    [4] - Model: Change from baseline in ACQ-6 score = Treatment + baseline ACQ-6 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

    Secondary: Time to First Asthma Exacerbation (up to Week 24)

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    End point title
    		 Time to First Asthma Exacerbation (up to Week 24)
    End point description
    Time to first asthma exacerbation was derived as follows: Start date of first asthma exacerbation − Date of randomization + 1. The time to first asthma exacerbation for patients who did not experience an asthma exacerbation during the treatment period was censored at the EOT visit (Week 24) for patients who completed the study. Patients who withdrew from the study or were lost to follow-up before the EOT visit were censored at the last visit date after which an exacerbation could not be assessed. The median time to first asthma exacerbation was not calculated, so the number of patients who experienced an asthma exacerbation is presented for the measured values. The FAS included all randomized patients who received ≥1 dose of IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 24
    End point values
    		 Benralizumab Placebo
    Number of subjects analysed
    427
    229
    Units: Patients
    123
    107
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Comparison of time to first asthma exacerbation for benralizumab vs placebo. Treatment group, region, number of exacerbations in previous year and maintenance OCS use at baseline were included in the Cox proportional hazard model as covariates.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 0.67
    Notes
    [5] - A hazard ratio < 1 favours benralizumab to be associated with a longer time from randomization to the first exacerbation than placebo.

    Secondary: Change from Run-in Baseline Home Peak Expiratory Flow (PEF) (Morning and Evening) to the EOT (Week 24)

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    End point title
    		 Change from Run-in Baseline Home Peak Expiratory Flow (PEF) (Morning and Evening) to the EOT (Week 24)
    End point description
    Home PEF testing was performed by the patient each morning after awakening and before taking their morning asthma medications, and each evening using a peak flow meter. Measurements were taken at approximately the same time each day and recorded in the Asthma Daily Diary. The maximum of the 3 measurements performed every morning and evening were used in the calculation of the weekly means. A weekly mean was calculated as the sum of all non-missing daily measures over the 7 sequential days divided by the number of non-missing daily measures. If more than 3 daily measures (> 50%) within a period were missing, then the weekly mean for that period was set to ‘missing’. Change from run-in baseline in weekly means for morning PEF and evening PEF are presented. Baseline was the average for data collected over the last 7 days of the run-in period prior to randomization. The FAS included all randomized patients who received ≥1 dose of IP.
    End point type
    Secondary
    End point timeframe
    Run-in baseline (from Day -28 to Day 0) and Week 24
    End point values
    		 Benralizumab Placebo
    Number of subjects analysed
    427 [6]
    229 [7]
    Units: L/minute
    least squares mean (standard error)
        Morning (n=276, 142)
    27.17 ± 3.98
    7.06 ± 5.49
        Evening (n=256, 144)
    16.47 ± 4.04
    -6.61 ± 5.54
    Notes
    [6] - 'n' in category title denotes number of patients analyzed for that category.
    [7] - 'n' in category title denotes number of patients analyzed for that category.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from run-in baseline in morning PEF at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.0031
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean difference
    Point estimate
    20.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.79
         upper limit
    		 33.44
    Notes
    [8] - Model: Change from baseline in PEF = Treatment + baseline PEF + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from run-in baseline in evening PEF at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.0008
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    23.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.62
         upper limit
    		 36.55
    Notes
    [9] - Model: Change from baseline in PEF = Treatment + baseline PEF + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

    Secondary: Change from Baseline in Short Form 36-item Health Survey, version 2 (SF-36v2) to the EOT (Week 24)

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    End point title
    		 Change from Baseline in Short Form 36-item Health Survey, version 2 (SF-36v2) to the EOT (Week 24)
    End point description
    The SF-36v2 is a quality of life scale comprising 8 domains of health status: physical functioning, role limitations due to physical health, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. The physical and mental health component summary scores are computed from subscale scores to give a broader metric of physical and mental health-related quality of life. Each domain score, as well as the physical and mental component scores, were scored on a scale from 0-100 (worst health possible to best health possible); higher scores indicate better health status. Norm-based scoring was used to calculate the 8 SF-36v2 subscales and the 2 component scores. The LS mean change from baseline in each of the SF-36 subscale and component summary scores at Week 24 are presented. The FAS included all randomized patients who received ≥1 dose of IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 24
    End point values
    		 Benralizumab Placebo
    Number of subjects analysed
    287
    169
    Units: Scores on a scale
    least squares mean (standard error)
        Physical functioning
    17.76 ± 1.21
    12.42 ± 1.59
        Role limitations due to physical health
    17.62 ± 1.34
    10.82 ± 1.76
        Bodily pain
    6.44 ± 1.37
    3.37 ± 1.79
        General health perceptions
    12.92 ± 1.01
    7.29 ± 1.34
        Vitality
    12.04 ± 1.10
    6.53 ± 1.44
        Social functioning
    12.44 ± 1.34
    9.32 ± 1.75
        Role limitations due to emotional problems
    8.23 ± 1.18
    5.79 ± 1.55
        Mental health
    5.57 ± 0.90
    3.89 ± 1.18
        Physical health component summary score
    6.09 ± 0.46
    3.77 ± 0.60
        Mental health component summary score
    2.87 ± 0.48
    1.99 ± 0.64
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in SF-36v2 subscale score for physical functioning at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.0077
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean difference
    Point estimate
    5.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.42
         upper limit
    		 9.28
    Notes
    [10] - Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in SF-36v2 subscale score for role limitations due to physical health at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.0022
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    6.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.45
         upper limit
    		 11.14
    Notes
    [11] - Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in SF-36v2 subscale score for bodily pain at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.1741
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.36
         upper limit
    		 7.5
    Notes
    [12] - Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in SF-36v2 subscale score for general health perceptions at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.0009
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    5.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.32
         upper limit
    		 8.92
    Notes
    [13] - Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in SF-36v2 subscale score for vitality at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.0025
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    5.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.95
         upper limit
    		 9.08
    Notes
    [14] - Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in SF-36v2 subscale score for social functioning at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.1583
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    3.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.22
         upper limit
    		 7.46
    Notes
    [15] - Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in SF-36v2 subscale score for role limitations due to emotional problems at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.2103
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.38
         upper limit
    		 6.27
    Notes
    [16] - Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in SF-36v2 subscale score for mental health at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.2581
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    1.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.23
         upper limit
    		 4.59
    Notes
    [17] - Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in SF-36v2 physical health component summary score at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.0022
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    2.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 3.81
    Notes
    [18] - Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in SF-36v2 mental health component summary score at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    456
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.2751
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean Difference
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 2.44
    Notes
    [19] - Model: Change from baseline in SF-36v2 score = Treatment + baseline SF-36v2 score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

    Secondary: Patient Global Impression of Severity (PGI-S): Responder Status at the EOT (Week 24)

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    End point title
    		 Patient Global Impression of Severity (PGI-S): Responder Status at the EOT (Week 24)
    End point description
    The PGI-S is a single question asking the patient to rate the overall severity of their symptoms using a 6-point categorical response scale from 0 to 5 where 0=no symptoms and 5=very severe symptoms. Higher scores indicate a worse outcome. Improvement was defined as a PGI-S at EOT (Week 24) better than PGI-S at baseline. Important improvement was defined as PGI-S at baseline = moderate symptoms or severe symptoms or very severe symptoms shifting to PGI-S at EOT = no symptoms or very mild symptoms or mild symptoms. Patients with missing data at the EOT visit who did not complete the study were considered non-responders. For patients who completed the study with missing data at EOT (Week 24), their last evaluable post-baseline score was used to define responder status. The percentage of patients for each of the indicated PGI-S responder categories are presented. The FAS included all randomized patients who received ≥1 dose of IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 24
    End point values
    		 Benralizumab Placebo
    Number of subjects analysed
    345
    187
    Units: Percentage of patients
    number (not applicable)
        Improvement
    61.7
    53.5
        Important improvement
    45.5
    38.0
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Estimate of the log odds of being a responder classified as type ‘Important Improvement’ at Week 24 in the benralizumab group compared to the placebo group using a logistic regression.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    532
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.0401
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.02
         upper limit
    		 2.16
    Notes
    [20] - Model: ln (1/(1-p)) = Treatment + baseline score + region + number of exacerbations in previous year + maintenance OCS use at baseline, where p is the proportion of patients being a responder.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Estimate of the log odds of being a responder classified as type ‘Improvement’ at Week 24 in the benralizumab group compared to the placebo group using a logistic regression.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    532
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.0233
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.06
         upper limit
    		 2.25
    Notes
    [21] - Model: ln (1/(1-p)) = Treatment + baseline score + region + number of exacerbations in previous year + maintenance OCS use at baseline, where p is the proportion of patients being a responder.

    Secondary: Clinician Global Impression of Change (CGI-C) and Patient Global Impression of Change (PGI-C): Responder Status at the EOT (Week 24)

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    End point title
    		 Clinician Global Impression of Change (CGI-C) and Patient Global Impression of Change (PGI-C): Responder Status at the EOT (Week 24)
    End point description
    The Investigator and the patient were asked separately to rate the degree of change in the overall asthma status compared to the start of treatment, i.e. baseline visit. A 7-point rating scale was used for CGI-C (rated by Investigator) and PGI-C (rated by patient) where: 1=Very Much Improved; 2=Much Improved; 3=Minimally Improved; 4=No Changes; 5=Minimally Worse; 6=Much Worse, and 7=Very Much Worse. Higher scores indicate a worse outcome. Responder category definitions: Much improved=(Much improved, Very much improved); Very much improved=(Very much improved). Patients with missing data at the EOT visit who did not complete the study were considered non-responders. For patients who completed the study with missing data at EOT (Week 24), their last evaluable post-baseline score was used to define responder status. The percentage of patients for each of the indicated CGI-C and PGI-C responder categories are presented. The FAS included all randomized patients who received ≥1 dose of IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 24
    End point values
    		 Benralizumab Placebo
    Number of subjects analysed
    427 [22]
    229 [23]
    Units: Percentage of patients
    number (not applicable)
        CGI-C: Much improved (n=420, 227)
    52.9
    35.2
        CGI-C: Very much improved (n=420, 227)
    15.0
    4.8
        PGI-C: Much improved (n=424, 228)
    55.9
    38.2
        PGI-C: Very much improved (n=424, 228)
    37.7
    16.7
    Notes
    [22] - 'n' in category title denotes number of patients analyzed for that category.
    [23] - 'n' in category title denotes number of patients analyzed for that category.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Estimate of the log odds of being a CGI-C responder classified as type ‘Much improved’ at Week 24 in the benralizumab group compared to the placebo group using a logistic regression.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.47
         upper limit
    		 2.86
    Notes
    [24] - Model: ln (1/(1-p)) = Treatment + region + number of exacerbations in previous year + maintenance OCS use at baseline, where p is the proportion of patients being a responder.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Estimate of the log odds of being a CGI-C responder classified as type ‘Very much improved’ at Week 24 in the benralizumab group compared to the placebo group using a logistic regression.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.0003
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.77
         upper limit
    		 6.7
    Notes
    [25] - Model: ln (1/(1-p)) = Treatment + region + number of exacerbations in previous year + maintenance OCS use at baseline, where p is the proportion of patients being a responder.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Estimate of the log odds of being a PGI-C responder classified as type ‘Much improved’ at Week 24 in the benralizumab group compared to the placebo group using a logistic regression.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.48
         upper limit
    		 2.87
    Notes
    [26] - Model: ln (1/(1-p)) = Treatment + region + number of exacerbations in previous year + maintenance OCS use at baseline, where p is the proportion of patients being a responder.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Estimate of the log odds of being a PGI-C responder classified as type ‘Very much improved’ at Week 24 in the benralizumab group compared to the placebo group using a logistic regression.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    656
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 < 0.0001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.02
         upper limit
    		 4.51
    Notes
    [27] - Model: ln (1/(1-p)) = Treatment + region + number of exacerbations in previous year + maintenance OCS use at baseline, where p is the proportion of patients being a responder.

    Secondary: Change from Baseline in Predominant Symptom and Impairment Assessment (PSIA) Severity Score for Average of Top 3 Ranked Symptoms/Impairments and for Top Ranked Symptom/Impairment at the EOT (Week 24)

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    End point title
    		 Change from Baseline in Predominant Symptom and Impairment Assessment (PSIA) Severity Score for Average of Top 3 Ranked Symptoms/Impairments and for Top Ranked Symptom/Impairment at the EOT (Week 24)
    End point description
    For part 1 of the PSIA only administered at baseline, patients reviewed 8 concepts (including cardinal asthma symptoms, activities, awakenings, triggers) and selected those which were typically bothersome. Based on part 1 selections, part 2 of the PSIA produced a rank ordered list of bothersome concepts individualized per the patient for subsequent evaluation. For part 3 of the PSIA assessed at baseline and during the study, patients recorded the severity of each selected symptom or impairment using an 11-point numeric rating scale where: 0=Did not experience and 10=Worst I can imagine. The LS mean change from baseline in PSIA severity score for the indicated categories at Week 24 are presented. A negative change from baseline indicates an improvement in symptoms. Note: Average PSIA was calculated only where all of top 3 ranked symptoms/impairments were available, otherwise average was set to missing. The FAS included all randomized patients who received ≥1 dose of IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 24
    End point values
    		 Benralizumab Placebo
    Number of subjects analysed
    319 [28]
    180 [29]
    Units: Scores on a scale
    least squares mean (standard error)
        Average of top 3 ranked (n=302, 172)
    -2.97 ± 0.14
    -1.82 ± 0.19
        Top ranked (n=319, 180)
    -3.02 ± 0.15
    -1.87 ± 0.20
    Notes
    [28] - 'n' in category title denotes number of patients analyzed for that category.
    [29] - 'n' in category title denotes number of patients analyzed for that category.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in PSIA severity score of top ranked symptom/impairment at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean difference
    Point estimate
    -1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.64
         upper limit
    		 -0.66
    Notes
    [30] - Model: Change from baseline in PSIA score (top ranked) =Treatment + baseline PSIA score (top ranked) + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in PSIA severity score for the average of top 3 ranked symptoms/impairments at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 < 0.0001
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean difference
    Point estimate
    -1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.62
         upper limit
    		 -0.68
    Notes
    [31] - Model: Change from baseline in average PSIA score (top 3 ranked) =Treatment + baseline average PSIA score (top 3 ranked) + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

    Secondary: Change From Baseline in the Sino-Nasal Outcome Test Item 22 (SNOT-22) Total Score to the EOT (Week 24)

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    End point title
    		 Change From Baseline in the Sino-Nasal Outcome Test Item 22 (SNOT-22) Total Score to the EOT (Week 24)
    End point description
    The 22-item SNOT 22 questionnaire was used to assess the rhinosinusitis health status and quality of life of patients with baseline chronic rhinosinusitis with nasal polyposis. The 22-question SNOT-22 is scored as 0 (no problem) to 5 (problem as bad as it can be) with a total range from 0 to 110. Higher scores indicate poorer outcomes. The LS mean changes from baseline in SNOT-22 total score in patients in the chronic rhinosinusitis with nasal polyposis sub-study analysis set at Week 24 are presented. The chronic rhinosinusitis with nasal polyposis sub-study analysis set was defined as the subset of patients with doctor-diagnosed chronic rhinosinusitis and nasal polyposis included in their medical history who had signed the informed consent to participate in the sub-study and who had received ≥1 dose of IP.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 24
    End point values
    		 Benralizumab Placebo
    Number of subjects analysed
    92
    50
    Units: Scores on a scale
        least squares mean (standard error)
    -19.02 ± 2.27
    -10.11 ± 3.04
    Statistical analysis title
    		 Comparison between treatments
    Statistical analysis description
    Change from baseline in SNOT-22 total score at Week 24 was compared between the benralizumab group and placebo group using a restricted maximum likelihood based on a MMRM analysis.
    Comparison groups
    Benralizumab v Placebo
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [32]
    P-value
    		 = 0.0204
    Method
    		 Repeated measures analysis
    Parameter type
    		 LS Mean difference
    Point estimate
    -8.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.42
         upper limit
    		 -1.4
    Notes
    [32] - Model: Change from baseline in SNOT-22 total score = Treatment + baseline SNOT-22 total score + region + number of exacerbations in previous year + maintenance OCS use at baseline + visit + treatment by visit.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event (AE) data is reported for the on-treatment period + follow-up (up to a maximum of 24 weeks). Assessed until 12 Sep 2019 analysis cut-off date for completion of the double-blind period of the study.
    Adverse event reporting additional description
    AE definition for on-treatment period: onset date ≥ first dose of IP and ≤ scheduled EOT visit, or IP discontinuation visit for patients prematurely discontinuing IP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients received matching placebo solution administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.

    Reporting group title
    Benralizumab
    Reporting group description
    		 Patients received benralizumab 30 mg administered sc in an accessorized pre-filled syringe at Week 0 (initial dose), Week 4 (loading dose), Week 8 and Week 16. An EOT visit was performed at Week 24.

    Serious adverse events
    		 Placebo Benralizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 229 (10.92%)
    23 / 427 (5.39%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 427 (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
    Anti-neutrophil cytoplasmic antibody positive vasculitis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    9 / 229 (3.93%)
    9 / 427 (2.11%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 229 (0.87%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 427 (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
    Cerebrovascular accident
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Mydriasis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Food poisoning
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 427 (0.23%)
         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
    0 / 229 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 427 (0.23%)
         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
    Costochondritis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 427 (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
    2 / 229 (0.87%)
    2 / 427 (0.47%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 229 (0.00%)
    1 / 427 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 229 (0.44%)
    0 / 427 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Benralizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    78 / 229 (34.06%)
    136 / 427 (31.85%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 229 (3.06%)
    37 / 427 (8.67%)
         occurrences all number
    11
    50
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 229 (2.18%)
    26 / 427 (6.09%)
         occurrences all number
    8
    29
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 229 (5.68%)
    14 / 427 (3.28%)
         occurrences all number
    17
    16
    Dyspnoea
         subjects affected / exposed
    13 / 229 (5.68%)
    7 / 427 (1.64%)
         occurrences all number
    19
    9
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    18 / 229 (7.86%)
    22 / 427 (5.15%)
         occurrences all number
    22
    23
    Nasopharyngitis
         subjects affected / exposed
    17 / 229 (7.42%)
    30 / 427 (7.03%)
         occurrences all number
    23
    36
    Sinusitis
         subjects affected / exposed
    12 / 229 (5.24%)
    28 / 427 (6.56%)
         occurrences all number
    17
    32
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 229 (5.24%)
    17 / 427 (3.98%)
         occurrences all number
    13
    19

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Jan 2018
    The protocol was amended to: • Reduce the total estimated number of patients to be randomized and sample size estimate; the change preserved number of patients receiving benralizumab and reduced number exposed to placebo, while retaining statistical power to detect a treatment difference for both asthma exacerbation reduction and SGRQ improvement. • Update inclusion criteria to specify additional indicators of variable lung function and to allow inclusion of patients with blood eosinophil count of ≥150 to <300 cells/μL (if they met other required clinical criteria at time of enrolment). • Update eligibility criteria assessed at Visit 4 to allow randomization of patients with either a pre-BD FEV1 that remained <80% of predicted, or that was not increased from the qualifying pre-BD FEV1 value at Visit 2 by more than 20%. • Reduce interim biomarker assessments. • Add rationale text for Sino-Nasal Outcome Test 22 Item.
    18 Jul 2018
    The protocol was amended for inclusion of a 56-week open-label ANDHI in-Practice (AiP) sub-study. Applicable sections were updated throughout the study protocol.
    01 May 2020
    The protocol was amended to: • Provide more recent Global Initiative for Asthma step guidelines. • Update the main outcome measures and supportive measures for the AiP sub-study to better characterize the extent of reduction in asthma controller medications, provide further information on the type and extent of background medication that has been reduced, to provide predictive baseline characteristics of patients who were unlikely to achieve medication reductions and those likely to achieve meaningful reduction, and to include patients receiving OCS in reduction analyses. • Define 2 additional efficacy analysis sets for inclusion of patients receiving OCS in reduction analyses and patients transitioning directly from ANDHI main study to ANDHI IP sub-study. • Add text to address the possible need for alternative study conduct procedures due to COVID-19.

    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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