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    Clinical Trial Results:
    A Phase 2, Randomised, Double-blind, Placebo-controlled Study to Assess the Efficacy and Safety of MEDI3506 in Adult Participants with Uncontrolled Moderate-to-severe Asthma

    Summary
    EudraCT number
    		 2020-000789-40
    Trial protocol
    		 HU   DE  
    Global end of trial date
    06 Feb 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Dec 2023
    First version publication date
    28 Dec 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    D9181C00001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04570657
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    151 85, Södertälje, Sweden,
    Public contact
    Global Clinical Lead, AstraZeneca, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, 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
    06 Feb 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Feb 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to assess the effect of tozorakimab (MEDI3506) compared with placebo on lung function, in adult participants with uncontrolled moderate-to-severe asthma.
    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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Sep 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 87
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Hungary: 21
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    South Africa: 16
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 49
    Worldwide total number of subjects
    235
    EEA total number of subjects
    81
    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)
    235
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled and randomised in 52 study centres in 7 countries including Argentina, Germany, Hungary, Poland, South Africa, the United Kingdom, and the United States from 17 September 2020. The last participant completed their last study visit on 06 February 2023.

    Pre-assignment
    Screening details
    		 Adult participants with uncontrolled moderate to severe asthma were randomised in a 1:1:1 ratio to receive tozorakimab Dose A (lower dose), tozorakimab Dose B (higher dose), or placebo. Of the 478 participants screened, 250 were enrolled, and of these 15 were excluded from analysis due to invalidity of data.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tozorakimab Dose A
    Arm description
    		 Participants were randomised to receive tozorakimab Dose A by SC injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tozorakimab
    Investigational medicinal product code
    MEDI3506
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Tozorakimab Dose A by subcutaneous (SC) injection.

    Arm title
    		 Tozorakimab Dose B
    Arm description
    		 Participants were randomised to receive tozorakimab Dose B by SC injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tozorakimab
    Investigational medicinal product code
    MEDI3506
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Tozorakimab Dose B by SC injection.

    Arm title
    		 Placebo
    Arm description
    		 Participants were randomised to receive placebo by SC injection.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo by SC injection.

    Number of subjects in period 1
    		Tozorakimab Dose A Tozorakimab Dose B Placebo
    Started
    77
    77
    81
    Intent to Treat (ITT) Population
    77
    77
    81
    As-treated Population
    77
    77
    81
    Pharmacokinetic (PK) Population
    75 [1]
    77
    0 [2]
    Completed
    76
    74
    77
    Not completed
    1
    3
    4
         Consent withdrawn by subject
    1
    2
    2
         Physician decision
    -
    1
    -
         Adverse event, non-fatal
    -
    -
    1
         Lost to follow-up
    -
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Two participants in the tozorakimab Dose A arm were not included in the PK population due to no post-baseline PK results.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants in the placebo arm were not included in the PK population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tozorakimab Dose A
    Reporting group description
    		 Participants were randomised to receive tozorakimab Dose A by SC injection.

    Reporting group title
    Tozorakimab Dose B
    Reporting group description
    		 Participants were randomised to receive tozorakimab Dose B by SC injection.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomised to receive placebo by SC injection.

    Reporting group values
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo Total
    Number of subjects
    		 77 77 81 235
    Age Categorical
    Units: participants
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 77 77 81 235
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.1 ( 11.97 ) 43.1 ( 12.37 ) 48.3 ( 10.41 ) -
    Gender Categorical
    Units: participants
        Female
    		 53 54 43 150
        Male
    		 24 23 38 85
    Race
    Units: Subjects
        Asian
    		 0 0 1 1
        Black or African American
    		 4 8 7 19
        White
    		 71 67 72 210
        Other
    		 2 2 1 5
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 26 24 33 83
        Not Hispanic or Latino
    		 51 53 48 152

    End points

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    End points reporting groups
    Reporting group title
    Tozorakimab Dose A
    Reporting group description
    		 Participants were randomised to receive tozorakimab Dose A by SC injection.

    Reporting group title
    Tozorakimab Dose B
    Reporting group description
    		 Participants were randomised to receive tozorakimab Dose B by SC injection.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomised to receive placebo by SC injection.

    Primary: Change from Baseline to Week 16 in Pre-bronchodilator (Pre-BD) Forced Expiratory Volume in the First Second (FEV1) as Measured in the Study Clinic

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    End point title
    		 Change from Baseline to Week 16 in Pre-bronchodilator (Pre-BD) Forced Expiratory Volume in the First Second (FEV1) as Measured in the Study Clinic
    End point description
    In-clinic spirometry measurements were taken prior to the administration of bronchodilators. Baseline was the last measurement prior to first injection of investigational product (IP). The least squares (LS) means, LS mean differences and 80% confidence intervals (CIs), and one-sided p-value results were based on a mixed model repeated measures (MMRM). The model included fixed effects for baseline, background medication, geographic region, baseline inhaled corticosteroids (ICS) total daily dose, visit, treatment, and the baseline by visit and treatment by visit interactions. Visits within participant were considered as repeated measurements. The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
    End point type
    Primary
    End point timeframe
    Baseline and week 16
    End point values
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo
    Number of subjects analysed
    76
    77
    81
    Units: litres
        least squares mean (standard error)
    0.148 ( 0.047 )
    0.116 ( 0.048 )
    0.112 ( 0.046 )
    Statistical analysis title
    		 LS Mean Difference: Tozorakimab Dose B - Placebo
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.473 [1]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.004
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.071
         upper limit
    		 0.079
    Notes
    [1] - One-sided p-value
    Statistical analysis title
    		 LS Mean Difference: Tozorakimab Dose A - Placebo
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.267 [2]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.036
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.038
         upper limit
    		 0.111
    Notes
    [2] - One-sided p-value

    Secondary: Change from Baseline to Weeks 8 and 16 in Post-bronchodilator (Post-BD) FEV1 as Measured in the Study Clinic

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    End point title
    		 Change from Baseline to Weeks 8 and 16 in Post-bronchodilator (Post-BD) FEV1 as Measured in the Study Clinic
    End point description
    In-clinic spirometry measurements were taken following the use of bronchodilators. Bronchodilatation was induced using albuterol (90 µg metered dose), salbutamol (100 µg metered dose), or levalbuterol (45 µg metered dose), and measurements were taken after up to a maximum of 4 inhalations. Baseline was the last measurement prior to first injection of IP. The LS means, LS mean differences and 80% CIs, and one-sided p-value results were based on MMRM. The model included fixed effects for baseline, background medication, geographic region, baseline ICS total daily dose, visit, treatment, and the baseline by visit and treatment by visit interactions. Visits within participant were considered as repeated measurements. The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
    End point type
    Secondary
    End point timeframe
    Baseline and weeks 8 and 16
    End point values
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo
    Number of subjects analysed
    24
    25
    35
    Units: litres
    least squares mean (standard error)
        Week 8
    -0.062 ( 0.067 )
    0.008 ( 0.068 )
    -0.050 ( 0.060 )
        Week 16
    -0.064 ( 0.067 )
    -0.050 ( 0.068 )
    -0.026 ( 0.060 )
    Statistical analysis title
    		 Week 8 Difference: Tozorakimab Dose A - Placebo
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.437 [3]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.012
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.086
    Notes
    [3] - One-sided p-value
    Statistical analysis title
    		 Week 8 Difference: Tozorakimab Dose B - Placebo
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.221 [4]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.059
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.039
         upper limit
    		 0.157
    Notes
    [4] - One-sided p-value
    Statistical analysis title
    		 Week 16 Difference: Tozorakimab Dose A - Placebo
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.308 [5]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.038
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.136
         upper limit
    		 0.06
    Notes
    [5] - One-sided p-value
    Statistical analysis title
    		 Week 16 Difference: Tozorakimab Dose B - Placebo
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.372 [6]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.025
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.122
         upper limit
    		 0.072
    Notes
    [6] - One-sided p-value

    Secondary: Serum Concentrations of Tozorakimab

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    End point title
    		 Serum Concentrations of Tozorakimab [7]
    End point description
    Tozorakimab serum concentrations were measured using a validated assay method. The PK population included participants who received at least one dose of tozorakimab and had at least one detectable serum concentration measurement post-first dose of study intervention. Participants with data available at each time point are presented. 99999 = Geometric mean (CV%) could not be calculated due to too many samples with tozorakimab concentrations below the limit of quantification.
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic (PK) samples were taken pre-dose (day 1) and at weeks 1, 4, 8, 12, 16, 20, and 24
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: It was pre-specified for serum concentrations of tozorakimab to be assessed in participants included in the tozorakimab Dose A and tozorakimab Dose B reporting arms only.
    End point values
    		 Tozorakimab Dose A Tozorakimab Dose B
    Number of subjects analysed
    75
    77
    Units: µg/L
    geometric mean (geometric coefficient of variation)
        Pre-dose (n=74, 77)
    99999 ( 99999 )
    99999 ( 99999 )
        Week 1 (n=74, 76)
    8939.24 ( 367.31 )
    18374.15 ( 239.89 )
        Week 4 (n=72, 72)
    2165.82 ( 180.17 )
    4102.04 ( 168.60 )
        Week 8 (n=74, 70)
    2680.07 ( 113.59 )
    4476.11 ( 109.27 )
        Week 12 (n=74, 75)
    2673.94 ( 121.08 )
    4646.57 ( 153.62 )
        Week 16 (n=71, 72)
    2742.93 ( 128.83 )
    5007.93 ( 117.76 )
        Week 20 (n=75, 72)
    356.56 ( 177.25 )
    761.75 ( 152.78 )
        Week 24 (n=74, 72)
    80.36 ( 170.34 )
    146.67 ( 214.16 )
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-drug Antibodies (ADAs)

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    End point title
    		 Number of Participants with Anti-drug Antibodies (ADAs)
    End point description
    ADA prevalence is the number of participants ADA positive (ADA+) at baseline (BL) and/or post-BL. Treatment-emergent ADA+ (TE-ADA +) positive is defined as being either of treatment-induced ADA+ (ADA negative [ADA-] at BL and at least one post-BL ADA+) and treatment-boosted ADA+ (ADA+ at BL and BL titre is boosted by ≥ 4-fold increase at ≥ 1 post-BL time point). Treatment-emergent ADA- (TE-ADA-) is defined as ADA+ but not fulfilling the definition of TE-ADA+. ADA persistently positive is defined as ADA- at BL and ADA+ at ≥ 2 post-BL assessment with ≥ 16 weeks between first and last positive assessments, or ADA+ at the last post-BL assessment. ADA transiently positive is defined as ADA- at BL, having at least one post-BL ADA+ assessment and not fulfilling the conditions of ADA persistently positive. BL is defined as the last ADA assessment prior to first injection of IP. The as-treated population included participants who were randomised and received any study intervention.
    End point type
    Secondary
    End point timeframe
    Blood samples were taken pre-dose (day 1) and at weeks 1, 4, 8, 12, 16, and 24
    End point values
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo
    Number of subjects analysed
    77
    77
    81
    Units: participants
        ADA prevalence (n=77, 77, 81)
    3
    3
    1
        TE-ADA+ (n=75, 77, 81)
    3
    2
    1
        Treatment-induced ADA+ (n=75, 77, 81)
    3
    2
    1
        TE-ADA- (n=75, 77, 81)
    0
    1
    0
        Baseline and post-baseline + (n=74, 77, 81)
    0
    1
    0
        ADA persistently positive (n=74, 77, 81)
    3
    1
    0
        ADA transiently positive (n=74, 77, 81)
    0
    1
    1
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 16 in the Asthma Control Questionnaire-6 (ACQ-6) Score

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    End point title
    		 Change from Baseline to Week 16 in the Asthma Control Questionnaire-6 (ACQ-6) Score
    End point description
    In the ACQ-6, participants were asked to recall how their asthma has been during the previous week by responding to one BD-use question and 5 symptom questions. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between >0.75 and <1.5 indicate partly controlled asthma, and scores ≥1.5 indicate not well-controlled asthma. Results were based on an MMRM which included fixed effects for baseline, background medication, geographic region, baseline ICS total daily dose, visit, treatment and the baseline by visit and treatment by visit interactions. Visits within participant were considered as repeated measurements. A negative change from baseline indicates an improvement in asthma control. The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
    End point type
    Secondary
    End point timeframe
    Baseline and week 16
    End point values
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo
    Number of subjects analysed
    76
    77
    81
    Units: score on a scale
        least squares mean (standard error)
    -0.925 ( 0.117 )
    -0.942 ( 0.117 )
    -0.895 ( 0.112 )
    Statistical analysis title
    		 LS Mean Difference: Tozorakimab Dose B - Placebo
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.371 [8]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.047
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.231
         upper limit
    		 0.137
    Notes
    [8] - One-sided p-value
    Statistical analysis title
    		 LS Mean Difference: Tozorakimab Dose A - Placebo
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.416 [9]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.03
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.215
         upper limit
    		 0.154
    Notes
    [9] - One-sided p-value

    Secondary: Number of Participants with a Decrease in ACQ-6 Score ≥ 0.5 from Baseline to Week 16

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    End point title
    		 Number of Participants with a Decrease in ACQ-6 Score ≥ 0.5 from Baseline to Week 16
    End point description
    In the ACQ-6, participants were asked to recall how their asthma has been during the previous week by responding to one BD-use question and 5 symptom questions. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between >0.75 and <1.5 indicate partly controlled asthma, and scores ≥1.5 indicate not well-controlled asthma. A decrease in ACQ-6 score baseline indicates an improvement in asthma control, and individual changes of at least 0.5 are considered clinically meaningful. The ITT population included participants who were randomised and received any study intervention. Participants with missing ACQ-6 scores were not included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and week 16
    End point values
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo
    Number of subjects analysed
    73
    74
    77
    Units: participants
    53
    56
    53
    Statistical analysis title
    		 Odds Ratio: Tozorakimab Dose B versus Placebo
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.348
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.41
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 2.25
    Statistical analysis title
    		 Odds Ratio: Tozorakimab Dose A versus Placebo
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.612
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.2
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.9

    Secondary: Change from Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores

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    End point title
    		 Change from Baseline to Week 16 in St George's Respiratory Questionnaire (SGRQ) Domain and Total Scores
    End point description
    The SGRQ is a 50-item patient-reported outcome instrument to measure the health status of participants with airway obstruction diseases, giving a total score and 3 domain scores (symptoms, activity, and impacts). The total score is expressed as a percentage of overall impairment, with 100 representing the worst possible health status and 0 the best possible health status. Each domain score ranges from 0 to 100, with higher scores indicating greater impairment. A negative change from baseline indicates an improvement in impairments. Results were based on an MMRM which included fixed effects for baseline, background medication, geographic region, baseline ICS total daily dose, visit, treatment and the baseline by visit and treatment by visit interactions. Visits within participant were considered as repeated measurements. The ITT population included participants who were randomised and received any study intervention. Participants with data available are included.
    End point type
    Secondary
    End point timeframe
    Baseline and week 16
    End point values
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo
    Number of subjects analysed
    76
    77
    80
    Units: score on a scale
    least squares mean (standard error)
        SGRQ Activity Total Score
    -10.340 ( 2.477 )
    -11.706 ( 2.507 )
    -10.342 ( 2.390 )
        SGRQ Impacts Total Score
    -8.237 ( 1.750 )
    -8.509 ( 1.774 )
    -6.816 ( 1.689 )
        SGRQ Symptoms Total Score
    -15.290 ( 2.828 )
    -19.130 ( 2.873 )
    -15.981 ( 2.726 )
        SGRQ Total Score
    -10.133 ( 1.815 )
    -11.366 ( 1.838 )
    -9.470 ( 1.750 )
    Statistical analysis title
    		 SGRQ Activity Score: Tozorakimab Dose A - Placebo
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5 [10]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.002
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -3.825
         upper limit
    		 3.828
    Notes
    [10] - One-sided p-value
    Statistical analysis title
    		 SGRQ Activity Score: Tozorakimab Dose B - Placebo
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.324 [11]
    Method
    		 MMRM
    Parameter type
    		 Ls mean difference
    Point estimate
    -1.364
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -5.198
         upper limit
    		 2.47
    Notes
    [11] - One-sided p-value
    Statistical analysis title
    		 SGRQ Impacts Score: Tozorakimab Dose A - Placebo
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.248 [12]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -1.421
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -4.103
         upper limit
    		 1.26
    Notes
    [12] - One-sided p-value
    Statistical analysis title
    		 SGRQ Impacts Score: Tozorakimab Dose B - Placebo
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21 [13]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -1.694
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -4.383
         upper limit
    		 0.996
    Notes
    [13] - One-sided p-value
    Statistical analysis title
    		 SGRQ Symptoms Score: Tozorakimab Dose A - Placebo
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42 [14]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.691
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -3.715
         upper limit
    		 5.096
    Notes
    [14] - One-sided p-value
    Statistical analysis title
    		 SGRQ Symptoms Score: Tozorakimab Dose B - Placebo
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.181 [15]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -3.15
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -7.579
         upper limit
    		 1.28
    Notes
    [15] - One-sided p-value
    Statistical analysis title
    		 SGRQ Total Score: Tozorakimab Dose A - Placebo
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.38 [16]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.663
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -3.454
         upper limit
    		 2.129
    Notes
    [16] - One-sided p-value
    Statistical analysis title
    		 SGRQ Total Score: Tozorakimab Dose B - Placebo
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.192 [17]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -1.896
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -4.694
         upper limit
    		 0.903
    Notes
    [17] - One-sided p-value

    Secondary: Number of Participants Achieving ACQ-6 Well Controlled Status at Week 16

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    End point title
    		 Number of Participants Achieving ACQ-6 Well Controlled Status at Week 16
    End point description
    In the ACQ-6, participants were asked to recall how their asthma has been during the previous week by responding to one BD-use question and 5 symptom questions. Questions were weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). Mean scores of ≤ 0.75 indicate well-controlled asthma, scores between >0.75 and <1.5 indicate partly controlled asthma, and scores ≥1.5 indicate not well-controlled asthma. The ITT population included participants who were randomised and received any study intervention. Participants with missing ACQ-6 scores were not included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and week 16
    End point values
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo
    Number of subjects analysed
    73
    74
    77
    Units: participants
    17
    18
    21
    Statistical analysis title
    		 Odds Ratio: Tozorakimab Dose B versus Placebo
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.679
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.86
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.38
    Statistical analysis title
    		 Odds Ratio: Tozorakimab Dose A versus Placebo
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.575
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.81
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.31

    Secondary: Number of Participants with a Decrease in SGRQ Total Score of ≥ 4 Points from Baseline to Week 16

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    End point title
    		 Number of Participants with a Decrease in SGRQ Total Score of ≥ 4 Points from Baseline to Week 16
    End point description
    The SGRQ is a 50-item patient-reported outcome instrument to measure the health status of participants with airway obstruction diseases, giving a total score and 3 domain scores (symptoms, activity, and impacts). The total score is expressed as a percentage of overall impairment, with 100 representing the worst possible health status and 0 the best possible health status. A decrease in the SGRQ total score indicates an improvement in overall impairment. The ITT population included participants who were randomised and received any study intervention. Participants with missing SGRQ scores were not included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and week 16
    End point values
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo
    Number of subjects analysed
    73
    74
    77
    Units: participants
    50
    53
    54
    Statistical analysis title
    		 Odds Ratio: Tozorakimab Dose B versus Placebo
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.84
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.07
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.7
    Statistical analysis title
    		 Odds Ratio: Tozorakimab Dose A versus Placebo
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.828
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.93
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.46

    Secondary: Asthma CompEx Annualised Event Rate

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    End point title
    		 Asthma CompEx Annualised Event Rate
    End point description
    The annualised rate of asthma CompEx events was calculated as the total number of asthma CompEx events / (date of last dose of IP + 28 - date of first dose of IP - recovery time + 1) / 365.25. The rates, rate ratios, and one-sided p-values were estimated from a negative binomial regression, with the log(follow up time) included as an offset term. The dependent variable will be the number of CompEx events during the on-treatment period (i.e., from baseline to last dose date +28 days), and the model will include treatment group, background medication, geographic region and baseline ICS total daily dose as covariates. The ITT population included participants who were randomised and received any study intervention.
    End point type
    Secondary
    End point timeframe
    Baseline to week 16
    End point values
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo
    Number of subjects analysed
    77
    77
    81
    Units: events per participant-treatment year
        number (confidence interval 80%)
    0.86 (0.58 to 1.28)
    0.69 (0.44 to 1.07)
    0.99 (0.68 to 1.44)
    Statistical analysis title
    		 Rate Ratio: Tozorakimab Dose B versus Placebo
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.166 [18]
    Method
    		 Negative binomial regression
    Parameter type
    		 Rate ratio
    Point estimate
    0.7
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 1.12
    Notes
    [18] - One-sided p-value
    Statistical analysis title
    		 Rate Ratio: Tozorakimab Dose A versus Placebo
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.346 [19]
    Method
    		 Negative binomial regression
    Parameter type
    		 Rate ratio
    Point estimate
    0.87
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.36
    Notes
    [19] - One-sided p-value

    Secondary: Number of Participants for Time to First Asthma CompEx Event

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    End point title
    		 Number of Participants for Time to First Asthma CompEx Event
    End point description
    Asthma CompEx is a combination of exacerbations of asthma and diary events (i.e., a combination of electronic diary [eDiary] variables). eDiary events are defined by criteria using morning/evening diary variables of PEF, symptoms, and use of rescue medication. A participant was considered to have a CompEx event if they had one or both of an asthma exacerbation or diary event. For participants who did not experience an on-treatment CompEx event, date of censoring was the minimum between the date of last dose + 28 days, and the last day of eDiary recording during the on-treatment period. Time to first Asthma CompEx event was calculated as [start date of first event or censoring - date of first dose] + 1. The ITT population included participant who were randomised and received any study intervention.
    End point type
    Secondary
    End point timeframe
    Baseline to week 16
    End point values
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo
    Number of subjects analysed
    77
    77
    81
    Units: participants
    19
    15
    15
    Statistical analysis title
    		 Hazard Ratio: Tozorakimab Dose B versus Placebo
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.461 [20]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.7
    Notes
    [20] - One-sided p-value estimated using a Cox regression model with treatment group, background medication, geographic region, and ICS total daily dose as covariates.
    Statistical analysis title
    		 Hazard Ratio: Tozorakimab Dose A versus Placebo
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.239 [21]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.3
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 2
    Notes
    [21] - One-sided p-value estimated using a Cox regression model with treatment group, background medication, geographic region, and ICS total daily dose as covariates.

    Secondary: Percent Change from Baseline to Week 16 in Concentration of Fractional Exhaled Nitric Oxide (FeNO) in Exhaled Breath

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    End point title
    		 Percent Change from Baseline to Week 16 in Concentration of Fractional Exhaled Nitric Oxide (FeNO) in Exhaled Breath
    End point description
    A standardised single-breath FeNO test was performed to evaluate airway inflammation. Results were based on MMRM on log-transformed change from baseline. Log-transformed change from baseline is calculated as the visit value in log minus the baseline value in log. The results from the model were then back transformed. The model included fixed effects for baseline (in log), background medication, geographic region, baseline ICS total daily dose, visit, treatment and the baseline by visit and treatment by visit interactions. Visits within subject were considered as repeated measurements.
    End point type
    Secondary
    End point timeframe
    Baseline and week 16
    End point values
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo
    Number of subjects analysed
    74
    77
    81
    Units: percent change
        least squares mean (confidence interval 80%)
    -17.429 (-23.423 to -10.965)
    -16.500 (-22.548 to -9.981)
    -5.007 (-11.612 to 2.091)
    Statistical analysis title
    		 Geometric LS Mean Ratio
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.04 [22]
    Method
    		 MMRM
    Parameter type
    		 Geometric LS mean ratio
    Point estimate
    0.879
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 0.966
    Notes
    [22] - One-sided p-value
    Statistical analysis title
    		 Geometric LS Mean Ratio
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.029 [23]
    Method
    		 MMRM
    Parameter type
    		 Geometric LS Mean Ratio
    Point estimate
    0.869
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.791
         upper limit
    		 0.956
    Notes
    [23] - One-sided p-value

    Secondary: Eosinophil Count

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    End point title
    		 Eosinophil Count
    End point description
    The eosinophil count at baseline and week 16 are presented. Baseline was defined as the last measurement prior to first injection of IP.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 16
    End point values
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo
    Number of subjects analysed
    77
    77
    81
    Units: 10^9 cells/L
    geometric mean (geometric coefficient of variation)
        Baseline (N=77, 77, 81)
    0.187 ( 80.4 )
    0.200 ( 88.4 )
    0.178 ( 83.3 )
        Week 16 (N=65, 70, 73)
    0.122 ( 82.9 )
    0.136 ( 77.6 )
    0.185 ( 93.2 )
    Statistical analysis title
    		 Week 16 Geometric LS Mean Ratio
    Statistical analysis description
    Tozorakimab Dose B versus Placebo
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [24]
    Method
    		 MMRM
    Parameter type
    		 Geometric LS Mean Ratio
    Point estimate
    0.675
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.599
         upper limit
    		 0.76
    Notes
    [24] - One-sided p-value
    Statistical analysis title
    		 Week 16 Geometric LS Mean Ratio
    Statistical analysis description
    Tozorakimab Dose A versus Placebo
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 < 0.001 [26]
    Method
    		 MMRM
    Parameter type
    		 Geometric LS Mean Ratio
    Point estimate
    0.63
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.559
         upper limit
    		 0.71
    Notes
    [25] - A total of 156 participants were included in this analysis.
    [26] - One-sided p-value

    Other pre-specified: Change from Baseline to Week 16 in Pre-BD FEV1 as Measured in the Study Clinic: Analysis per Number of Exacerbations in Last 12 Months

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    End point title
    		 Change from Baseline to Week 16 in Pre-BD FEV1 as Measured in the Study Clinic: Analysis per Number of Exacerbations in Last 12 Months
    End point description
    In-clinic spirometry measurements were taken prior to the administration of bronchodilators. Baseline was the last measurement prior to first injection of IP. The LS means, LS mean differences and 80% CIs, and one-sided p-value results were based on MMRM. The model included fixed effects for baseline, visit, treatment, and the baseline by visit and treatment by visit interactions. Visits within participant were considered as repeated measurements. Analysis is presented by the number of exacerbations experienced within the 12 months prior to baseline (1 or ≥ 2 exacerbations in the previous 12 months). The ITT population included participants who were randomised and received any study intervention.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and week 16
    End point values
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo
    Number of subjects analysed
    45
    47
    52
    Units: litres
    least squares mean (standard error)
        1 Exacerbation in Last 12 Months (N=45, 47, 52)
    0.188 ( 0.065 )
    0.042 ( 0.070 )
    0.165 ( 0.062 )
        ≥ 2 Exacerbations in Last 12 Months (N=31, 30, 29)
    0.059 ( 0.067 )
    0.194 ( 0.065 )
    -0.018 ( 0.069 )
    Statistical analysis title
    		 LS Mean Difference: Tozorakimab Dose A - Placebo
    Statistical analysis description
    Analysis of treatment difference in participants with 1 exacerbation in the last 12 months.
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.385 [27]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.023
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.078
         upper limit
    		 0.124
    Notes
    [27] - One-sided p-value; alpha = 0.1
    Statistical analysis title
    		 LS Mean Difference: Tozorakimab Dose A - Placebo
    Statistical analysis description
    Analysis of treatment difference in participants with ≥ 2 exacerbations in the last 12 months.
    Comparison groups
    Tozorakimab Dose A v Placebo
    Number of subjects included in analysis
    97
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 = 0.186 [29]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.077
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.034
         upper limit
    		 0.187
    Notes
    [28] - A total of 90 participants were included in this analysis.
    [29] - One-sided p-value; alpha = 0.1
    Statistical analysis title
    		 LS Mean Difference: Tozorakimab Dose B - Placebo
    Statistical analysis description
    Analysis of treatment difference in participants with ≥ 2 exacerbations in the last 12 months.
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 = 0.007 [31]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    0.212
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.102
         upper limit
    		 0.322
    Notes
    [30] - A total of 90 participants were included in this analysis.
    [31] - One-sided p-value; alpha = 0.1
    Statistical analysis title
    		 LS Mean Difference: Tozorakimab Dose B - Placebo
    Statistical analysis description
    Analysis of treatment difference in participants with 1 exacerbation in the last 12 months.
    Comparison groups
    Tozorakimab Dose B v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06 [32]
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.123
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.224
         upper limit
    		 -0.022
    Notes
    [32] - One-sided p-value; alpha = 0.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to Week 24 (up to 24 weeks)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Tozorakimab Dose A
    Reporting group description
    		 Participants were randomised to receive tozorakimab Dose A by SC injection.

    Reporting group title
    Tozorakimab Dose B
    Reporting group description
    		 Participants were randomised to receive tozorakimab Dose B by SC injection.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants were randomised to receive placebo by SC injection.

    Serious adverse events
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 77 (1.30%)
    4 / 77 (5.19%)
    2 / 81 (2.47%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Acid peptic disease
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 77 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 77 (0.00%)
    2 / 77 (2.60%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 77 (0.00%)
    0 / 77 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Tozorakimab Dose A Tozorakimab Dose B Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 77 (32.47%)
    20 / 77 (25.97%)
    20 / 81 (24.69%)
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    4 / 77 (5.19%)
    7 / 77 (9.09%)
    2 / 81 (2.47%)
         occurrences all number
    5
    15
    5
    Injection site swelling
         subjects affected / exposed
    0 / 77 (0.00%)
    4 / 77 (5.19%)
    1 / 81 (1.23%)
         occurrences all number
    0
    5
    4
    Injection site urticaria
         subjects affected / exposed
    1 / 77 (1.30%)
    4 / 77 (5.19%)
    0 / 81 (0.00%)
         occurrences all number
    1
    7
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    4 / 77 (5.19%)
    2 / 77 (2.60%)
    3 / 81 (3.70%)
         occurrences all number
    4
    2
    3
    COVID-19
         subjects affected / exposed
    15 / 77 (19.48%)
    10 / 77 (12.99%)
    11 / 81 (13.58%)
         occurrences all number
    17
    12
    12
    Nasopharyngitis
         subjects affected / exposed
    6 / 77 (7.79%)
    5 / 77 (6.49%)
    4 / 81 (4.94%)
         occurrences all number
    6
    6
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Oct 2020
    - Removal of references to the interim analysis for the study. - Removal of airway volume and airway resistance computed tomography (CT) scan measures from airway remodelling endpoint. - Addition of study stopping criteria. - Removal of reference of relatedness of serious adverse events as a reason to discontinue participants from the study and 'any SAE of ≥ Grade 4 severity' added. - Addition of new discontinuation criterion - Severity rating scale for adverse events updated to a Grade 1 to 5 based on Common Terminology Criteria for Adverse Events (CTCAE).
    23 Feb 2021
    - Addition of provision for increased flexibility during the screening period, for clinical laboratory testing due to practical limitation in receiving test results. - Addition of provision for increased flexibility for COVID-19 PCR testing during the screening period due to practical limitation in receiving test results. - Clarification that all female participants should have had a pregnancy test. - Addition of provision for retesting of interferon gamma release assay (IGRA). - Provision of clarification to investigators of the sponsor's approach to COVID-19 vaccination in this study. - Addition of provision for retesting of N-terminal prohormone of B-type natriuretic peptide (NT-proBNP). - Adjustment to the periods to which the adherence criteria applied. - Addition of allowance that limited personnel that had responsibility for PK and ADA sample analysis could have access to the randomisation schedule. - Clarification that adenoviral vector vaccines were not considered live attenuated. - Addition of restriction on when vaccines against COVID-19 may have been administered, and clarification on the requirement to record COVID-19 vaccination.
    25 May 2021
    - To amend study endpoints as appropriate for the change to a 2-part study design. - To amend the study design to include 2 parts: Part A (main study) and Part B (airway hyperresponsiveness and remodelling study). - Specified that post-BD spirometry was to be performed if documented evidence of asthma was not already available. - Clarification that on days when IP was administered, all assessments should have been performed pre-dose unless otherwise specified. - Provision of clarity on pregnancy testing in female participants. - Clarification of provision for airwave oscillometry and in-clinic spirometry to be performed 4 hours post-administration of study intervention at randomisation. - Specified that the mean value of each parameter from the triplicate electrocardiogram was to be used as the baseline value. - Clarification of the doses of tozorakimab used in Part A. - Clarification of a positive IGRA test in the context of treated latent tuberculosis infection. - Clarification of eligibility criteria relating to history of asthma exacerbations and the use of systemic corticosteroids. - Clarified that assessment of injection site reactions after administration of study intervention was carried out by a blinded study team. - Updated list of medication withhold periods to be applied prior to scheduled spirometry, airway oscillometry, and FeNO measurement. - Updated information to be recorded if and when a participant received a COVID-19 vaccination. - Changed 'congenital abnormality' to 'congenital anomaly'. - Specified that ADA samples may have been tested for neutralising antibodies.
    08 Mar 2022
    - Removal of references to and text regarding Part B, and removal of occurrences of 'Part A' as Part B had been removed and Part A was the entirety of the study. - Addition of text to minimise any missing mandatory samples. - Updated rationale for risk of progression of heart failure. - Changes to the inclusion criteria to increase the permitted body mass index, and historic exacerbation requirement from one in 12 months to one in 24 months. - Changes to the exclusion criteria to remove the exclusion of all participants who tested positive for SARS-CoV-2 at the first screening visit, and all participants who tested positive at the second screening visit continued to be excluded; to remove the exclusion of participants with NT-proBNP above the upper limit of normal; and to remove reference to HbA1c in relation to the control of type 2 diabetes. - Removed dose from list of information to be recorded for COVID-19 vaccination. - Adjustment of requirements of acceptable documentation of historical asthma exacerbations. - Aligned with EU guidelines for data storage.

    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.
    15 participants at 1 study centre were excluded from the final analysis due to inability to confirm the validity of the data. This did not change the interpretation of the primary endpoint or for any other endpoint.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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