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    Clinical Trial Results:
    A Randomized, Double-Blind, Parallel Group, Multicenter 24 Week Study to Assess the Efficacy and Safety of Budesonide and Formoterol Fumarate Metered Dose Inhaler Relative to Budesonide Metered Dose Inhaler and Open-Label Symbicort® Turbuhaler® in Participants with Inadequately Controlled Asthma (VATHOS)

    Summary
    EudraCT number
    		 2021-002026-24
    Trial protocol
    		 IT   DE   ES  
    Global end of trial date
    26 Feb 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Jul 2025
    First version publication date
    16 Jul 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D5982C00006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05202262
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    Forskargatan 18, Södertälje, Sweden,
    Public contact
    Global Clinical Lead, AstraZeneca, +1 18772409479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, +1 18772409479, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Apr 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Feb 2025
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Feb 2025
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of Budesonide and Formoterol Fumarate Metered Dose Inhaler (BFF MDI) 320/9.6 μg BID compared with Budesonide MDI 320 μg and open-label Symbicort TBH 320/9 μg over 24 weeks. BFF MDI 160/9.6 μg BID is included to evaluate dose response by comparing to BFF MDI 320/9.6 μg BID.
    Protection of trial subjects
    The conduct of this study met all the local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and was consistent with the ICH guidelines on GCP. Participating participants signed the informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Jan 2022
    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
    Canada: 37
    Country: Number of subjects enrolled
    Germany: 129
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Japan: 33
    Country: Number of subjects enrolled
    Spain: 22
    Country: Number of subjects enrolled
    United States: 323
    Country: Number of subjects enrolled
    Viet Nam: 22
    Worldwide total number of subjects
    581
    EEA total number of subjects
    166
    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)
    21
    Adults (18-64 years)
    448
    From 65 to 84 years
    112
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects with inadequately controlled asthma (ACQ-7 total score ≥ 1.5) despite treatment with medium dose ICS or ICS/LABA were recruited at 147 sites across 7 countries. Participants were randomized in a 1:2:2:2 scheme to BFF MDI 160/9.6 μg, BFF MDI 320/9.6 μg, BD MDI 320 μg, or open-label Symbicort.

    Pre-assignment
    Screening details
    		 All participants had to be taking a stable daily medium dose ICS or ICS/LABA for at least 8 weeks prior to Visit 1. Of the 645 randomized participants, all populations exclude 60 participants from 11 sites due GCP violation and 4 participants due to not receiving therapy.

    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
    		 BFF MDI 160/9.6 μg
    Arm description
    		 Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 160/9.6 μg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide/formoterol fumarate pressurized inhalation suspension, desiccated flow path device
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Two inhalations BID of 80/4.8 μg per actuation. Total daily dose: 320/19.2 μg.

    Arm title
    		 BFF MDI 320/9.6 μg
    Arm description
    		 Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 320/9.6 μg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Budesonide/formoterol fumarate pressurized inhalation suspension, desiccated flow path device
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Two inhalations BID of 160/4.8 μg per actuation. Total daily dose: 640/19.2 μg.

    Arm title
    		 BD MDI 320 μg
    Arm description
    		 Budesonide MDI (BD MDI), 320 μg
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Budesonide pressurized inhalation suspension, desiccated flow path device
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Two inhalations BID of 160 μg per actuation. Total daily dose: 640 μg.

    Arm title
    		 Symbicort TBH 320/9 μg
    Arm description
    		 Open-Label Comparator Symbicort Turbuhaler 320/9 μg
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Symbicort®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Pressurised inhalation
    Routes of administration
    Inhalation use
    Dosage and administration details
    Two inhalations BID of 160/4.5 μg per actuation. Total daily dose: 640/18 μg.

    Number of subjects in period 1
    		BFF MDI 160/9.6 μg BFF MDI 320/9.6 μg BD MDI 320 μg Symbicort TBH 320/9 μg
    Started
    88
    163
    168
    162
    Completed
    81
    150
    155
    151
    Not completed
    7
    13
    13
    11
         Physician decision
    3
    3
    -
    -
         Failure to meet randomization criteria
    -
    1
    -
    1
         Adverse event, non-fatal
    -
    1
    -
    -
         Pregnancy
    -
    -
    -
    1
         Various Reasons
    2
    5
    3
    4
         Lost to follow-up
    -
    -
    4
    -
         Withdrawal by subject
    2
    3
    5
    4
         Development of withdrawal Criteria
    -
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BFF MDI 160/9.6 μg
    Reporting group description
    		 Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 160/9.6 μg

    Reporting group title
    BFF MDI 320/9.6 μg
    Reporting group description
    		 Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 320/9.6 μg

    Reporting group title
    BD MDI 320 μg
    Reporting group description
    		 Budesonide MDI (BD MDI), 320 μg

    Reporting group title
    Symbicort TBH 320/9 μg
    Reporting group description
    		 Open-Label Comparator Symbicort Turbuhaler 320/9 μg

    Reporting group values
    		 BFF MDI 160/9.6 μg BFF MDI 320/9.6 μg BD MDI 320 μg Symbicort TBH 320/9 μg Total
    Number of subjects
    		 88 163 168 162 581
    Age Categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 3 6 7 5 21
        Adults (18-64 years)
    		 68 124 132 124 448
        From 65-84 years
    		 17 33 29 33 112
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 49.5 ( 17.1 ) 49.6 ( 15.9 ) 49.0 ( 15.1 ) 51.2 ( 15.4 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 48 102 109 103 362
        Male
    		 40 61 59 59 219
    Race
    Units: Subjects
        Black or African American
    		 10 16 18 24 68
        Asian
    		 9 22 18 19 68
        White
    		 64 120 123 114 421
        Other
    		 5 5 9 5 24
    Prior asthma medication
    Units: Subjects
        ICS
    		 12 17 20 19 68
        ICS/LABA
    		 76 146 147 143 512
        ICS/LAMA/LABA
    		 0 0 1 0 1
    Region of enrollment
    Units: Subjects
        Canada
    		 6 13 10 8 37
        Germany
    		 27 33 39 30 129
        Italy
    		 4 4 1 6 15
        Japan
    		 4 12 8 9 33
        Spain
    		 3 6 7 6 22
        United States
    		 41 89 99 94 323
        Vietnam
    		 3 6 4 9 22
    Baseline reversibility (%)
    Reversibility (%) is calculated as (Post-Albuterol FEV1 - Pre-Albuterol FEV1)/Pre-Albuterol FEV1 x100
    Units: Percentage
        arithmetic mean (standard deviation)
    		 18.3 ( 11.4 ) 17.7 ( 13.0 ) 19.9 ( 10.9 ) 20.0 ( 15.8 ) -
    Baseline pre-bronchodilator FEV1 (L)
    Units: Litre
        arithmetic mean (standard deviation)
    		 2.313 ( 0.663 ) 2.160 ( 0.664 ) 2.130 ( 0.558 ) 2.099 ( 0.586 ) -

    End points

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    End points reporting groups
    Reporting group title
    BFF MDI 160/9.6 μg
    Reporting group description
    		 Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 160/9.6 μg

    Reporting group title
    BFF MDI 320/9.6 μg
    Reporting group description
    		 Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 320/9.6 μg

    Reporting group title
    BD MDI 320 μg
    Reporting group description
    		 Budesonide MDI (BD MDI), 320 μg

    Reporting group title
    Symbicort TBH 320/9 μg
    Reporting group description
    		 Open-Label Comparator Symbicort Turbuhaler 320/9 μg

    Primary: Change from baseline in morning pre-dose trough FEV1 over 24 Weeks

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    End point title
    		 Change from baseline in morning pre-dose trough FEV1 over 24 Weeks
    End point description
    Change from baseline in morning pre-dose trough FEV1 over 24 Weeks. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.
    End point type
    Primary
    End point timeframe
    Over 24 Weeks
    End point values
    		 BFF MDI 160/9.6 μg BFF MDI 320/9.6 μg BD MDI 320 μg Symbicort TBH 320/9 μg
    Number of subjects analysed
    86
    161
    166
    158
    Units: Litre
        least squares mean (standard error)
    0.140 ( 0.0222 )
    0.106 ( 0.0162 )
    0.025 ( 0.0159 )
    0.123 ( 0.0163 )
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The ANCOVA model includes treatment, visit, prior maintenance medication, treatment-by-visit interaction, baseline trough FEV1, and percent Albuterol reversibility.
    Comparison groups
    BFF MDI 320/9.6 μg v BD MDI 320 μg
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0004
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.036
         upper limit
    		 0.125
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0227
    Notes
    [1] - An increase in estimate favors study drug. The number of subjects analyzed is based on the Efficacy Set, which excludes 6 participants who were randomized multiple times at sites or studies within the program. Additionally, only subjects with non-missing baseline covariates used in the analysis model are included in the analysis.

    Secondary: Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 0 to 3 hours (AUC0-3) over 24 Weeks

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    End point title
    		 Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 0 to 3 hours (AUC0-3) over 24 Weeks
    End point description
    Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 0 to 3 hours (AUC0-3) over 24 Weeks. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.
    End point type
    Secondary
    End point timeframe
    Over 24 Weeks
    End point values
    		 BFF MDI 160/9.6 μg BFF MDI 320/9.6 μg BD MDI 320 μg Symbicort TBH 320/9 μg
    Number of subjects analysed
    87
    161
    166
    159
    Units: Litre
        least squares mean (standard error)
    0.294 ( 0.0221 )
    0.267 ( 0.0162 )
    0.078 ( 0.0159 )
    0.245 ( 0.0163 )
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The ANCOVA model includes treatment, visit, prior maintenance medication, treatment-by-visit interaction, baseline trough FEV1, and percent Albuterol reversibility.
    Comparison groups
    BFF MDI 320/9.6 μg v BD MDI 320 μg
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.145
         upper limit
    		 0.234
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0227
    Notes
    [2] - An increase in estimate favors study drug. The number of subjects analyzed is based on the Efficacy Set, which excludes 6 participants who were randomized multiple times at sites or studies within the program. Additionally, only subjects with non-missing baseline covariates used in the analysis model are included in the analysis.

    Secondary: Onset of action on Day 1: Absolute change in FEV1 at 5 minutes on Day 1

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    End point title
    		 Onset of action on Day 1: Absolute change in FEV1 at 5 minutes on Day 1
    End point description
    Onset of action on Day 1: Absolute change in FEV1 at 5 minutes on Day 1. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.
    End point type
    Secondary
    End point timeframe
    On Day 1
    End point values
    		 BFF MDI 160/9.6 μg BFF MDI 320/9.6 μg BD MDI 320 μg Symbicort TBH 320/9 μg
    Number of subjects analysed
    84
    159
    158
    156
    Units: Litre
        least squares mean (standard error)
    0.236 ( 0.0167 )
    0.184 ( 0.0122 )
    0.041 ( 0.0121 )
    0.161 ( 0.0123 )
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The ANCOVA model includes treatment, timepoint, prior maintenance medication, treatment-by-timepoints interaction, baseline tFEV1, and % Albuterol reversibility.
    Comparison groups
    BFF MDI 320/9.6 μg v BD MDI 320 μg
    Number of subjects included in analysis
    317
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.144
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.11
         upper limit
    		 0.177
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0172
    Notes
    [3] - An increase in estimate favors study drug. The number of subjects analyzed is based on the Efficacy Set, which excludes 6 participants who were randomized multiple times at sites or studies within the program. Additionally, only subjects with non-missing baseline covariates used in the analysis model are included in the analysis.

    Secondary: Change from baseline in the mean number of puffs of rescue medication use (puffs/day) over 24 Weeks

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    End point title
    		 Change from baseline in the mean number of puffs of rescue medication use (puffs/day) over 24 Weeks
    End point description
    Change from baseline in the mean number of puffs of rescue medication use (puffs/day) over 24 Weeks. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.
    End point type
    Secondary
    End point timeframe
    Over 24 Weeks
    End point values
    		 BFF MDI 160/9.6 μg BFF MDI 320/9.6 μg BD MDI 320 μg Symbicort TBH 320/9 μg
    Number of subjects analysed
    85
    157
    163
    153
    Units: Puffs
        least squares mean (standard error)
    -0.350 ( 0.1061 )
    -0.481 ( 0.0781 )
    -0.213 ( 0.0764 )
    -0.443 ( 0.0791 )
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The ANCOVA model includes treatment, 4-week interval, their interaction, prior maintenance medication, severe asthma exacerbation history, baseline daily rescue use, baseline tFEV1, and % Albuterol reversibility.
    Comparison groups
    BFF MDI 320/9.6 μg v BD MDI 320 μg
    Number of subjects included in analysis
    320
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.0146
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.268
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.482
         upper limit
    		 -0.053
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1092
    Notes
    [4] - A decrease in estimate favors study drug. The number of subjects analyzed is based on the Efficacy Set, which excludes 6 participants who were randomized multiple times at sites or studies within the program. Additionally, only subjects with non-missing baseline covariates used in the analysis model are included in the analysis.

    Secondary: Percentage of responders in ACQ-7 (≥ 0.5 decrease equals response) over 24 Weeks

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    End point title
    		 Percentage of responders in ACQ-7 (≥ 0.5 decrease equals response) over 24 Weeks
    End point description
    Percentage of responders in ACQ-7 (≥ 0.5 decrease equals response) over 24 Weeks. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.
    End point type
    Secondary
    End point timeframe
    Over 24 Weeks
    End point values
    		 BFF MDI 160/9.6 μg BFF MDI 320/9.6 μg BD MDI 320 μg Symbicort TBH 320/9 μg
    Number of subjects analysed
    86
    162
    166
    158
    Units: Responders
    66
    111
    99
    116
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The logistic regression model includes treatment, prior maintenance medication, baseline instrument score, baseline tFEV1, and % Albuterol reversibility.
    Comparison groups
    BFF MDI 320/9.6 μg v BD MDI 320 μg
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.0634
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.549
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.976
         upper limit
    		 2.46
    Notes
    [5] - An odds ratio greater than 1 favors study drug. The number of subjects analyzed is based on the Efficacy Set, which excludes 6 participants who were randomized multiple times at sites or studies within the program. Additionally, only subjects with non-missing baseline covariates used in the analysis model are included in the analysis.

    Secondary: Percentage of responders in ACQ-5 (≥ 0.5 decrease equals response) over 24 Weeks

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    End point title
    		 Percentage of responders in ACQ-5 (≥ 0.5 decrease equals response) over 24 Weeks
    End point description
    Percentage of responders in ACQ-5 (≥ 0.5 decrease equals response) over 24 Weeks. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.
    End point type
    Secondary
    End point timeframe
    Over 24 Weeks
    End point values
    		 BFF MDI 160/9.6 μg BFF MDI 320/9.6 μg BD MDI 320 μg Symbicort TBH 320/9 μg
    Number of subjects analysed
    86
    162
    166
    158
    Units: Responders
    67
    120
    109
    116
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The logistic regression model includes treatment, prior maintenance medication, baseline instrument score, baseline tFEV1, and % Albuterol reversibility.
    Comparison groups
    BFF MDI 320/9.6 μg v BD MDI 320 μg
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.0731
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.557
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.959
         upper limit
    		 2.526
    Notes
    [6] - An odds ratio greater than 1 favors study drug. The number of subjects analyzed is based on the Efficacy Set, which excludes 6 participants who were randomized multiple times at sites or studies within the program. Additionally, only subjects with non-missing baseline covariates used in the analysis model are included in the analysis.

    Secondary: Percentage of responders in the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(s) +12) (≥ 0.5 increase equals response) over 24 Weeks

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    End point title
    		 Percentage of responders in the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(s) +12) (≥ 0.5 increase equals response) over 24 Weeks
    End point description
    Percentage of responders in the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(s) +12) (≥ 0.5 increase equals response) over 24 Weeks. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.
    End point type
    Secondary
    End point timeframe
    Over 24 Weeks
    End point values
    		 BFF MDI 160/9.6 μg BFF MDI 320/9.6 μg BD MDI 320 μg Symbicort TBH 320/9 μg
    Number of subjects analysed
    83
    153
    162
    150
    Units: Responders
    44
    91
    81
    77
    Statistical analysis title
    		 Primary analysis
    Statistical analysis description
    The logistic regression model includes treatment, prior maintenance medication, baseline instrument score, baseline tFEV1, and % Albuterol reversibility.
    Comparison groups
    BFF MDI 320/9.6 μg v BD MDI 320 μg
    Number of subjects included in analysis
    315
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.0233
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.732
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.077
         upper limit
    		 2.784
    Notes
    [7] - An odds ratio greater than 1 favors study drug. The number of subjects analyzed is based on the Efficacy Set, which excludes 6 participants who were randomized multiple times at sites or studies within the program. Additionally, only subjects with non-missing baseline covariates used in the analysis model are included in the analysis.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of first dose of IP up to and including 1 day following the date of last IP dose.
    Adverse event reporting additional description
    Adverse events were reported by the participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). The Investigator and any designees were responsible for detecting, documenting, and recording events that meet the definition of an AE.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    BD MDI 320 µg
    Reporting group description
    		 Budesonide MDI (BD MDI), 320 μg

    Reporting group title
    BFF MDI 320/9.6 µg
    Reporting group description
    		 Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 320/9.6 μg

    Reporting group title
    BFF MDI 160/9.6 µg
    Reporting group description
    		 Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 160/9.6 μg

    Reporting group title
    Symbicort TBH 320/9 µg
    Reporting group description
    		 Open-Label Comparator Symbicort Turbuhaler 320/9 μg

    Serious adverse events
    		 BD MDI 320 µg BFF MDI 320/9.6 µg BFF MDI 160/9.6 µg Symbicort TBH 320/9 µg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 168 (0.60%)
    3 / 163 (1.84%)
    3 / 88 (3.41%)
    7 / 162 (4.32%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 163 (0.00%)
    1 / 88 (1.14%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial ischaemia
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 163 (0.00%)
    0 / 88 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 163 (0.00%)
    0 / 88 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastric ulcer
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 163 (0.00%)
    1 / 88 (1.14%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 163 (0.00%)
    0 / 88 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 163 (0.00%)
    1 / 88 (1.14%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 163 (0.00%)
    0 / 88 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 163 (0.61%)
    0 / 88 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 163 (0.00%)
    0 / 88 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 163 (0.61%)
    0 / 88 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 163 (0.61%)
    0 / 88 (0.00%)
    0 / 162 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 163 (0.00%)
    0 / 88 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 163 (0.00%)
    0 / 88 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 163 (0.00%)
    0 / 88 (0.00%)
    1 / 162 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 BD MDI 320 µg BFF MDI 320/9.6 µg BFF MDI 160/9.6 µg Symbicort TBH 320/9 µg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 168 (23.81%)
    45 / 163 (27.61%)
    31 / 88 (35.23%)
    39 / 162 (24.07%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 168 (1.79%)
    1 / 163 (0.61%)
    3 / 88 (3.41%)
    1 / 162 (0.62%)
         occurrences all number
    3
    1
    3
    1
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 163 (0.00%)
    2 / 88 (2.27%)
    0 / 162 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 163 (0.00%)
    2 / 88 (2.27%)
    0 / 162 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 168 (0.60%)
    3 / 163 (1.84%)
    2 / 88 (2.27%)
    0 / 162 (0.00%)
         occurrences all number
    1
    3
    2
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 168 (0.00%)
    4 / 163 (2.45%)
    1 / 88 (1.14%)
    1 / 162 (0.62%)
         occurrences all number
    0
    4
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 163 (0.61%)
    3 / 88 (3.41%)
    2 / 162 (1.23%)
         occurrences all number
    1
    1
    3
    2
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 168 (1.79%)
    3 / 163 (1.84%)
    1 / 88 (1.14%)
    5 / 162 (3.09%)
         occurrences all number
    3
    3
    1
    5
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 168 (7.14%)
    8 / 163 (4.91%)
    3 / 88 (3.41%)
    9 / 162 (5.56%)
         occurrences all number
    15
    12
    3
    10
    Nasopharyngitis
         subjects affected / exposed
    15 / 168 (8.93%)
    15 / 163 (9.20%)
    12 / 88 (13.64%)
    13 / 162 (8.02%)
         occurrences all number
    20
    17
    13
    19
    Bronchitis bacterial
         subjects affected / exposed
    2 / 168 (1.19%)
    2 / 163 (1.23%)
    2 / 88 (2.27%)
    2 / 162 (1.23%)
         occurrences all number
    2
    2
    2
    2
    COVID-19
         subjects affected / exposed
    8 / 168 (4.76%)
    15 / 163 (9.20%)
    3 / 88 (3.41%)
    11 / 162 (6.79%)
         occurrences all number
    8
    15
    3
    11
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 163 (0.61%)
    2 / 88 (2.27%)
    0 / 162 (0.00%)
         occurrences all number
    0
    2
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Oct 2021
    Clarity added for telemedicine visit conduct, order of assessments, and birth control methods. Additional details added for Treatment Policy estimand and sample size calculations.
    05 Dec 2023
    An amendment was required to update statistical methodology, including changes to estimands, the Type I error control procedure, covariates in the analysis models, and analysis sets and to add updated wording from the new AstraZeneca protocol standard template.
    07 Nov 2024
    An amendment was required due to Health Authority feedback to update statistical methodological approaches to handling intercurrent events and the Type I error control procedure for EU/RoW.

    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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