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    Clinical Trial Results:
    SHAMAL: A Multicentre, Randomised, Open-Label, Parallel-Group, Active-Controlled, Phase IV Study to Assess the Reduction of Daily Maintenance ICS/LABA Treatment Towards Anti-Inflammatory Reliever Treatment in Patients with Severe Eosinophilic Asthma Treated with Benralizumab

    Summary
    EudraCT number
    		 2019-001924-37
    Trial protocol
    		 GB   DE   FR   IT  
    Global end of trial date
    31 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Feb 2024
    First version publication date
    14 Feb 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D3250C00072
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04159519
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca Clinical study Information Center
    Sponsor organisation address
    Södertälje, Södertälje, Sweden, 151 85
    Public contact
    AstraZeneca Clinical study Information Center, AstraZeneca Clinical study Information Center, +1 8772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca Clinical study Information Center, +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
    28 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the potential for benralizumab-treated patients to reduce Symbicort maintenance treatment while maintaining asthma symptom control.
    Protection of trial subjects
    The clinical study protocol (CSP) and participant informed consent documents were reviewed and approved by the institutional review board/independent ethics committee before the study was initiated. 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. The Principal Investigator at each study site explained the nature of the study to the patient and answered all questions regarding the study. Patients were informed that their participation was voluntary, and they were free to refuse to participate and withdraw their consent at any time and for any reason during the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jul 2020
    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
    France: 34
    Country: Number of subjects enrolled
    Germany: 72
    Country: Number of subjects enrolled
    Italy: 24
    Country: Number of subjects enrolled
    United Kingdom: 38
    Worldwide total number of subjects
    168
    EEA total number of subjects
    130
    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)
    114
    From 65 to 84 years
    54
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted between 27 July 2020 and 31 January 2023.

    Pre-assignment
    Screening details
    		 The study included a screening period and run-in period of 4-8 weeks . The 208 were enrolled and entered screening and run-in period, during which patients received benralizumab with high-dose Symbicort. At Week 0, patients meeting the randomization criteria were randomized into treatment reduction or reference arms.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment reduction
    Arm description
    		 Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), tapering to, medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Benralizumab
    Investigational medicinal product code
    Other name
    Fasenra®
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients received benralizumab 30 mg/mL, 1 mL fill volume via subcutaneous injection every 8 weeks during the study period.

    Investigational medicinal product name
    Ventolin®
    Investigational medicinal product code
    Other name
    Salbutamol
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Patients received salbutamol sulfate 100 μg per inhalation in the screening/run-in phase as needed.

    Investigational medicinal product name
    Symbicort®
    Investigational medicinal product code
    Other name
    Budesonide/formoterol
    Pharmaceutical forms
    Inhalation solution, Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Patients received budesonide 400 μg/formoterol fumarate 12 μg per inhalation (2 inhalations) BID as maintenance, and reducing to budesonide 200 μg/formoterol fumarate 6 μg per inhalation (1 or 2 inhalations) BID as maintenance and reliever as needed, or as reliever only.

    Arm title
    		 Reference
    Arm description
    		 Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Benralizumab
    Investigational medicinal product code
    Other name
    Fasenra®
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients received benralizumab 30 mg/mL, 1 mL fill volume via subcutaneous injection every 8 weeks during the study period.

    Investigational medicinal product name
    Ventolin®
    Investigational medicinal product code
    Other name
    Salbutamol
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Patients received salbutamol sulfate 100 μg per inhalation as needed.

    Investigational medicinal product name
    Symbicort®
    Investigational medicinal product code
    Other name
    Budesonide/formoterol
    Pharmaceutical forms
    Inhalation solution, Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Patients received budesonide 400 μg/formoterol fumarate 12 μg per inhalation (2 inhalations) BID as maintenance.

    Number of subjects in period 1
    		Treatment reduction Reference
    Started
    125
    43
    Completed
    117
    37
    Not completed
    8
    6
         Consent withdrawn by subject
    4
    4
         Adverse event, non-fatal
    1
    1
         Discontinued from study
    1
    -
         Lack of efficacy
    1
    -
         Protocol deviation
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment reduction
    Reporting group description
    		 Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), tapering to, medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.

    Reporting group title
    Reference
    Reporting group description
    		 Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

    Reporting group values
    		 Treatment reduction Reference Total
    Number of subjects
    		 125 43 168
    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)
    		 82 32 114
        From 65-84 years
    		 43 11 54
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 58.1 ( 12.44 ) 56.5 ( 11.70 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 69 20 89
        Male
    		 56 23 79

    End points

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    End points reporting groups
    Reporting group title
    Treatment reduction
    Reporting group description
    		 Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), tapering to, medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.

    Reporting group title
    Reference
    Reporting group description
    		 Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

    Primary: Proportion of patients who reduced their Symbicort® maintenance dose at the end of the reduction period

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    End point title
    		 Proportion of patients who reduced their Symbicort® maintenance dose at the end of the reduction period [1] [2]
    End point description
    Proportion of patients with non-missing Week 32 who reduced their Symbicort® maintenance dose at the end of the reduction period (Week 32) to: a) Medium-dose Symbicort® maintenance and reliever therapy (SMART), or b) Low-dose SMART, or c) Symbicort® anti-inflammatory reliever only. The full analysis set (FAS) population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study.
    End point type
    Primary
    End point timeframe
    At Week 32
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was performed.
    End point values
    		 Treatment reduction
    Number of subjects analysed
    119
    Units: Proportion
    number (confidence interval 95%)
        Medium-dose SMART
    0.151 (0.0922 to 0.2285)
        Low-dose SMART
    0.168 (0.1058 to 0.2476)
        Symbicort® reliever-only dose
    0.605 (0.5113 to 0.6934)
    No statistical analyses for this end point

    Secondary: Change from baseline in Asthma control questionnaire-5 item (ACQ-5) score at the end of the reduction period

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    End point title
    		 Change from baseline in Asthma control questionnaire-5 item (ACQ-5) score at the end of the reduction period
    End point description
    Change from baseline in the ACQ-5 patient reported outcome. This instrument contains 5 asthma symptom questions, rated from 0 (total control) to 6 (severely uncontrolled). The ACQ-5 score is the mean of the responses. Mean scores ≤0.75 indicate well controlled, >0.75 and <1.5 indicate partly controlled and ≥1.5 indicate not well controlled asthma. The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study.
    End point type
    Secondary
    End point timeframe
    Week 0 (baseline) and at Week 32
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    112
    38
    Units: Change from baseline in score
        least squares mean (standard error)
    0.1617 ( 0.0393 )
    0.0555 ( 0.0677 )
    Statistical analysis title
    		 Comparison with reference arm
    Statistical analysis description
    Comparison with reference arm
    Comparison groups
    Treatment reduction v Reference
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    Method
    		 Mixed model for repeated measure
    Parameter type
    		 Least square mean difference
    Point estimate
    0.1062
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0485
         upper limit
    		 0.2609
    Notes
    [3] - Mixed model for repeated measure (MMRM) with fixed effects for treatment arm, visit, baseline value, and treatment-by-visit interaction with an unstructured covariance structure.

    Secondary: Change from baseline in standardised asthma quality of life questionnaire for 12 years and older (AQLQ(S)+12) at the end of the reduction period

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    End point title
    		 Change from baseline in standardised asthma quality of life questionnaire for 12 years and older (AQLQ(S)+12) at the end of the reduction period
    End point description
    The AQLQ(S)+12 is a Patient-Reported Outcome (PRO) that measures the health-related quality of life experienced by asthma patients. The questionnaire comprises 4 separate domains (symptoms, activity limitations, emotional function, and environmental stimuli). Patients are asked to recall their experiences during the previous 2 weeks before each visit and to score each of the questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). The statistical test is mixed model for repeated measure (MMRM) with fixed effects for treatment arm, visit, baseline value, and treatment-by-visit interaction with an unstructured covariance structure. The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study.
    End point type
    Secondary
    End point timeframe
    Week 0 (baseline) and at Week 32
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    99
    35
    Units: Change from baseline in score
        least squares mean (standard error)
    -0.0279 ( 0.0559 )
    0.0064 ( 0.0950 )
    Statistical analysis title
    		 Comparison with reference arm
    Statistical analysis description
    Comparison with reference arm
    Comparison groups
    Treatment reduction v Reference
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    Method
    		 Mixed model for repeated measure
    Parameter type
    		 Least square mean difference
    Point estimate
    -0.0343
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2527
         upper limit
    		 0.1841
    Notes
    [4] - MMRM with fixed effects for treatment arm, visit, baseline value, and treatment-by-visit interaction with an unstructured covariance structure.

    Secondary: Number of patients with no deterioration in AQLQ(S)+12 at the end of the reduction period

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    End point title
    		 Number of patients with no deterioration in AQLQ(S)+12 at the end of the reduction period
    End point description
    The AQLQ(S)+12 is a PRO that measures the health-related quality of life experienced by asthma patients. The questionnaire comprises 4 separate domains (symptoms, activity limitations, emotional function, and environmental stimuli). Patients are asked to recall their experiences during the previous 2 weeks before each visit and to score each of the questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). AQLQ(S)+12 deterioration was defined as at least a 0.5 unit decrease in AQLQ(S)+12 total score from baseline. Patients with no deterioration include patients with improvement or no change. The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study.
    End point type
    Secondary
    End point timeframe
    At Week 32
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    125
    43
    Units: Participants
        Improvement
    12
    3
        No change
    73
    28
    No statistical analyses for this end point

    Secondary: Number of patients with no deterioration in ACQ-5 at the end of the reduction period

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    End point title
    		 Number of patients with no deterioration in ACQ-5 at the end of the reduction period
    End point description
    Change from baseline in the ACQ-5 patient reported outcome. This instrument contains 5 asthma symptom questions, rated from 0 (total control) to 6 (severely uncontrolled). The ACQ-5 score is the mean of the responses. Mean scores ≤0.75 indicating well controlled, >0.75 and <1.5 indicate partly controlled and ≥1.5 indicate not well controlled asthma. ACQ-5 deterioration is defined as at least a 0.5 unit increase in ACQ-5 score from baseline. Patients with no deterioration include patients with improvement or no change. The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study.
    End point type
    Secondary
    End point timeframe
    At Week 32
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    125
    43
    Units: Participants
        Improvement
    6
    2
        No change
    87
    28
    No statistical analyses for this end point

    Secondary: Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) during the study period

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    End point title
    		 Change from baseline in pre-bronchodilator forced expiratory volume in 1 second (FEV1) during the study period
    End point description
    The potential for benralizumab-treated patients to maintain lung function while stepping down Symbicort® maintenance treatment was assessed. The FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration, expressed in liters. Change from baseline pre-bronchodilator FEV1 calculated as post-baseline pre-bronchodilator FEV1 (L) minus baseline pre-bronchodilator FEV1 (L) for all post-baseline measurement points. The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, "n" represents the number of patients analyzed for each row of this endpoint.
    End point type
    Secondary
    End point timeframe
    At Week 0 (baseline), and at Weeks 8, 16, 24, 32, 40, and 48
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    125
    43
    Units: Liter
    least squares mean (standard error)
        Week 8 (n= 102; 33)
    0.0411 ( 0.0183 )
    0.0549 ( 0.0315 )
        Week 16 (n= 97; 34)
    0.0299 ( 0.0215 )
    0.0115 ( 0.0363 )
        Week 24 (n= 92; 31)
    -0.0536 ( 0.0317 )
    0.0644 ( 0.0540 )
        Week 32 (n= 89; 31)
    -0.0824 ( 0.0285 )
    -0.0016 ( 0.0482 )
        Week 40 (n= 93; 32)
    -0.0953 ( 0.0280 )
    0.0428 ( 0.0476 )
        Week 48 (n= 92; 29)
    -0.0889 ( 0.0272 )
    0.0059 ( 0.0475 )
    No statistical analyses for this end point

    Secondary: Cumulative total daily inhaled corticosteroids (ICS) dose, by period

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    End point title
    		 Cumulative total daily inhaled corticosteroids (ICS) dose, by period
    End point description
    The cumulative total daily ICS dose (maintenance +reliever) for: a) reduction period; b) maintenance period; c) study period was assessed. The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, "n" represents the number of patients analyzed for each row of this endpoint.
    End point type
    Secondary
    End point timeframe
    Reduction period (From Week 0 up to Week 32); maintenance period (From Week 32 up to Week 48); Study period (Week 0 up to end of maintenance period/ end of study)
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    125
    42
    Units: Microgram
    arithmetic mean (standard deviation)
        Reduction period (n= 125; 42)
    115956.8 ( 73223.93 )
    312857.1 ( 81251.22 )
        Maintenance period (n= 102; 38)
    50984.3 ( 51148.59 )
    150400.0 ( 42180.46 )
        Study period (n= 125; 42)
    157560.0 ( 114123.69 )
    448933.3 ( 131247.22 )
    No statistical analyses for this end point

    Secondary: Annualised asthma exacerbation rate during the study period

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    End point title
    		 Annualised asthma exacerbation rate during the study period
    End point description
    Asthma exacerbation rate was assessed. An asthma exacerbation was defined as a worsening of asthma symptoms that led to any of the following: a) Temporary bolus/burst of systemic corticosteroids (≥3 consecutive days); b) Single depo-injectable dose of corticosteroids (equivalent to a 3-day bolus/burst); c) Visit to emergency room/urgent care (treatment <24 hours) requiring systemic corticosteroids; d) Hospitalization (admission/evaluation ≥24 hours) due to asthma. The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study.
    End point type
    Secondary
    End point timeframe
    From Week 0 up to Week 48
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    125
    43
    Units: Rate
        number (confidence interval 95%)
    0.14 (0.09 to 0.23)
    0.14 (0.06 to 0.31)
    No statistical analyses for this end point

    Secondary: Total daily ICS dose (maintenance + reliever) at the end of the reduction period

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    End point title
    		 Total daily ICS dose (maintenance + reliever) at the end of the reduction period
    End point description
    The mean total daily ICS dose (maintenance + reliever) during the 8 weeks prior to end of the reduction period was assessed. The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study.
    End point type
    Secondary
    End point timeframe
    At Week 32
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    120
    39
    Units: Microgram
        arithmetic mean (standard deviation)
    380.028 ( 440.4995 )
    1401.796 ( 316.9718 )
    No statistical analyses for this end point

    Secondary: Proportion of participants using the same Symbicort® daily dose at the end of the maintenance period (Week 48) that they achieved at the end of the reduction period (Week 32)

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    End point title
    		 Proportion of participants using the same Symbicort® daily dose at the end of the maintenance period (Week 48) that they achieved at the end of the reduction period (Week 32) [5]
    End point description
    Proportion of patients using the same Symbicort daily dose at the end of the maintenance period that they achieved at the end of the reduction period. Proportions were based on patients with non-missing Week 32 and Week 48 Symbicort doses. The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study.
    End point type
    Secondary
    End point timeframe
    At Week 48
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was performed.
    End point values
    		 Treatment reduction
    Number of subjects analysed
    118
    Units: Proportion
        number (confidence interval 95%)
    0.958 (0.9039 to 0.9861)
    No statistical analyses for this end point

    Secondary: Number of patients with at least 1 exacerbation occurring from end of the reduction period to end of the maintenance period

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    End point title
    		 Number of patients with at least 1 exacerbation occurring from end of the reduction period to end of the maintenance period
    End point description
    Number of patients with at least 1 exacerbation occurring from end of the reduction period to end of the maintenance period. The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study.
    End point type
    Secondary
    End point timeframe
    From Week 32 to Week 48
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    125
    43
    Units: Participants
    5
    4
    No statistical analyses for this end point

    Secondary: Total daily ICS dose from the end of the reduction period to the end of the maintenance period

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    End point title
    		 Total daily ICS dose from the end of the reduction period to the end of the maintenance period
    End point description
    Total daily ICS dose from the end of the reduction period to the end of the maintenance period. The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, "n" represents the number of patients analyzed for each row of this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 32, Week 40, and Week 48
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    119
    38
    Units: Microgram
    arithmetic mean (standard deviation)
        Week 32 (n= 119; 38)
    383.221 ( 440.9649 )
    1438.685 ( 220.6355 )
        Week 40 (n= 119; 38)
    408.458 ( 475.6986 )
    1424.624 ( 321.5752 )
        Week 48 (n= 117; 38)
    376.356 ( 449.6614 )
    1265.356 ( 472.5244 )
    No statistical analyses for this end point

    Secondary: Change in ACQ-5 from the end of the reduction period to the end of the maintenance period

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    End point title
    		 Change in ACQ-5 from the end of the reduction period to the end of the maintenance period
    End point description
    Change in ACQ-5 score from end of reduction to end of maintenance is reported. The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study.
    End point type
    Secondary
    End point timeframe
    From Week 32 to Week 48
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    110
    34
    Units: Change in score
        arithmetic mean (standard deviation)
    -0.07 ( 0.575 )
    -0.20 ( 0.814 )
    No statistical analyses for this end point

    Secondary: Change in FEV1 from the end of the reduction period to the end of the maintenance period

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    End point title
    		 Change in FEV1 from the end of the reduction period to the end of the maintenance period
    End point description
    The change from the end of the reduction period to the end of the maintenance period for pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1) was calculated as Week 48 pre-bronchodilator FEV1 (Liter [L]) minus the maintenance period baseline pre-bronchodilator FEV1 (L). The FEV1 is the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration, expressed in liters. The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study.
    End point type
    Secondary
    End point timeframe
    From Week 32 to Week 48
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    100
    30
    Units: Liter
        arithmetic mean (standard deviation)
    0.0089 ( 0.2320 )
    0.0040 ( 0.2264 )
    No statistical analyses for this end point

    Secondary: Change in AQLQ(S)+12 from the end of the reduction period to the end of the maintenance period

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    End point title
    		 Change in AQLQ(S)+12 from the end of the reduction period to the end of the maintenance period
    End point description
    Change in AQLQ(S)+12 from the end of the reduction period to the end of the maintenance period is reported. The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study.
    End point type
    Secondary
    End point timeframe
    From Week 32 to Week 48
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    97
    31
    Units: Change in score
        arithmetic mean (standard deviation)
    -0.008 ( 0.4720 )
    0.060 ( 0.5658 )
    No statistical analyses for this end point

    Secondary: Number of patients that met each composite endpoint defining clinical remission

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    End point title
    		 Number of patients that met each composite endpoint defining clinical remission
    End point description
    Clinical remission in patients at end of the reduction and maintenance periods was assessed. A remission score, based on the number of remission criteria achieved at week 32 or week 48, was calculated for patients who met 0, 1, 2, and all 3 remission criteria (zero exacerbations, ACQ-5 < 1.5, or ACQ-5 <= 0.75, < 10% FEV1 deterioration). The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, "n" represents the number of patients analyzed for each row of this endpoint.
    End point type
    Secondary
    End point timeframe
    At Week 32 and Week 48
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    119
    38
    Units: Participants
        No asthma exacerbation at Week 32 (n= 119; 38)
    108
    37
        No asthma exacerbation at Week 48 (n= 117; 37)
    101
    32
        ACQ-5 <1.5 at Week 32 (n= 115; 35)
    106
    32
        ACQ-5 <1.5 at Week 48 (n= 113; 35)
    103
    32
        ACQ-5 ≤ 0.75 at Week 32 (n= 115; 35)
    65
    21
        ACQ-5 ≤ 0.75 at Week 48 (n= 113; 35)
    68
    21
        FEV1<10% decrease at Week 32 (n= 89; 31)
    59
    26
        FEV1 < 10% decrease at Week 48 (n= 92; 29)
    66
    23
    No statistical analyses for this end point

    Secondary: Number of patients that met 0, 1, 2, and all 3 composite remission endpoints

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    End point title
    		 Number of patients that met 0, 1, 2, and all 3 composite remission endpoints
    End point description
    Clinical remission in patients at end of the reduction and maintenance periods was assessed. A remission score, based on the number of remission criteria achieved at week 32 or week 48, was calculated for patients who met 0, 1, 2, and all 3 remission criteria (zero exacerbations, ACQ-5 < 1.5, or ACQ-5 <= 0.75, < 10% FEV1 deterioration). The FAS population included for this endpoint, all randomised patients, irrespective of their protocol adherence and continued participation in the study. Here, #1a is defined as zero exacerbation, ACQ-5 ≤ 0.75, FEV1 < 10% decrease from baseline, and #1b as zero exacerbation, ACQ-5 < 1.5, FEV1 < 10% decrease from baseline. Also "n" represents the number of patients analyzed for each row of this endpoint.
    End point type
    Secondary
    End point timeframe
    At Week 32 and Week 48
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    89
    28
    Units: Participants
        Remission score (0) #1a at week 32 (n= 86; 28)
    2
    0
        Remission score (1) #1a at week 32 (n= 86; 28)
    15
    5
        Remission score (2) #1a at week 32 (n= 86; 28)
    40
    8
        Remission score (3) #1a at week 32 (n= 86; 28)
    29
    15
        Remission score (0) #1a at week 48 (n= 89; 28)
    1
    1
        Remission score (1) #1a at week 48 (n= 89; 28)
    15
    4
        Remission score (2) #1a at week 48 (n= 89; 28)
    41
    9
        Remission score (3) #1a at week 48 (n= 89; 28)
    32
    14
        Remission score (0) #1b at week 32 (n= 86; 28)
    1
    0
        Remission score (1) #1b at week 32 (n= 86; 28)
    5
    2
        Remission score (2) #1b at week 32 (n= 86; 28)
    32
    5
        Remission score (3) #1b at week 32 (n= 86; 28)
    48
    21
        Remission score (0) #1b at week 48 (n= 89; 28)
    0
    0
        Remission score (1) #1b at week 48 (n= 89; 28)
    5
    2
        Remission score (2) #1b at week 48 (n= 89; 28)
    36
    7
        Remission score (3) #1b at week 48 (n= 89; 28)
    48
    19
    No statistical analyses for this end point

    Secondary: Number of patients with adverse events or serious adverse events

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    End point title
    		 Number of patients with adverse events or serious adverse events
    End point description
    The safety and tolerability of benralizumab in patients with severe asthma, while stepping down Symbicort® maintenance treatment and maintaining asthma symptom control was assessed. The safety analysis set (SAF) included for this endpoint, all patients from the FAS who receive any amount of study treatment and will be used for all safety analyses.
    End point type
    Secondary
    End point timeframe
    From Week 0 (randomization) to Week 48 or end of treatment (total period of study is 2.5 years)
    End point values
    		 Treatment reduction Reference
    Number of subjects analysed
    125
    42
    Units: Participants
        Any adverse event (AE)
    91
    35
        Any AE with outcome = death
    0
    0
        Serious adverse events, including deaths.
    12
    5
        Any AE leading to discontinuation of benralizumab
    3
    1
        Any AE leading to discontinuation of Symbicort
    3
    1
        Any AE leading to discontinuation of Ventolin
    2
    1
        Any AE leading to withdrawal from study
    3
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Week 0 (randomization) to Week 48 or end of treatment (total period of study is 2.5 years)
    Adverse event reporting additional description
    The safety analysis set (SAF) included all patients from the FAS who receive any amount of study treatment and will be used for all safety analyses.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Reference
    Reporting group description
    		 Patients received benralizumab 30 mg Q8W + high-dose Symbicort® 400/12 μg maintenance × 2 inhalations BID + Ventolin® (salbutamol 100 μg) reliever PRN therapy. Eligible patients randomised to the reference arm continued on high-dose Symbicort® maintenance treatment and Ventolin® reliever treatment.

    Reporting group title
    Treatment reduction
    Reporting group description
    		 Patients received benralizumab 30 mg every 8 weeks (Q8W) during the study period, and high-dose Symbicort maintenance 400/12 μg ×2 inhalations BID + Ventolin (salbutamol 100 μg) reliever as needed (PRN), tapering to, medium-dose Symbicort 200/6 μg ×2 inhalations BID maintenance + Symbicort 200/6 μg reliever PRN, low dose Symbicort 200/6 μg x 1 inhalation BID maintenance + Symbicort 200/6 μg reliever PRN; or Symbicort 200/6 μg reliever only, as per tapering scheme and depending on the degree of asthma control). The reduction period in this arm lasted for 32 weeks.

    Serious adverse events
    		 Reference Treatment reduction
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 42 (11.90%)
    12 / 125 (9.60%)
         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)
    Gallbladder adenocarcinoma
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Spinal compression fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaccination complication
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 125 (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
    Seizure
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Eosinophilic granulomatosis with polyangiitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 125 (0.80%)
         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
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 125 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Periorbital abscess
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 125 (0.80%)
         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
    0 / 42 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Helicobacter infection
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Reference Treatment reduction
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 42 (47.62%)
    46 / 125 (36.80%)
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    4 / 42 (9.52%)
    17 / 125 (13.60%)
         occurrences all number
    4
    20
    Infections and infestations
    COVID-19
         subjects affected / exposed
    9 / 42 (21.43%)
    19 / 125 (15.20%)
         occurrences all number
    9
    19
    Bronchitis
         subjects affected / exposed
    1 / 42 (2.38%)
    7 / 125 (5.60%)
         occurrences all number
    1
    8
    Rhinitis
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 125 (0.80%)
         occurrences all number
    4
    1
    Nasopharyngitis
         subjects affected / exposed
    7 / 42 (16.67%)
    10 / 125 (8.00%)
         occurrences all number
    8
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jul 2020
    Amendment 1 Version 2.0: Removal of nasosorption sampling and addition of SARS-CoV-2 test and induced sputum sampling; study mitigation during study disruptions due to cases of civil crisis, natural disaster, or public health crisis which will provide sites with measures that may be implemented if a patient is not able to visit a study site to ensure that the clinical trial can continue whilst minimizing risk to the patient, maintaining compliance with Good Clinical Practice, and minimizing risks to the study integrity.
    17 Sep 2021
    Amendment 2 Version 3.0: Updated the estimated date of last patient completed; Added new criteria to include details about patients who received COVID-19 vaccination; New section was added to explain restrictions related to blood donation; Added new row to study treatment table to include conversion of 200/6 and 400/12 Symbicort into 'total' μg; Added wording about home completion of COVID- 19 related electronic patient reported outcome; Added new population for analysis-Safety Analysis. set
    15 Nov 2022
    Amendment 3 Version 4.0: Updated to add a secondary endpoint ie, clinical remission; Deleted reference to analysis after patients reach V6 (32 weeks).

    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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