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    Clinical Trial Results:
    A Multicentre, Randomized, Double-Blind, Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Tezepelumab in Reducing Oral Corticosteroid Use in Adults with Oral Corticosteroid Dependent Asthma (SOURCE)

    Summary
    EudraCT number
    		 2017-003079-69
    Trial protocol
    		 DE   PL  
    Global end of trial date
    25 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Oct 2021
    First version publication date
    08 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5180C00009
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03406078
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    151 85, Sodertalje, Sweden,
    Public contact
    Global Clinical Head, AstraZeneca, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Head, AstraZeneca Clinical Study Information, AstraZeneca, information.center@astrazeneca.com, +1 302 885 1180, 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
    25 Sep 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of tezepelumab compared with placebo in reducing the prescribed OCS maintenance dose in patients with asthma requiring chronic treatment with maintenance OCS in addition to high dose ICS plus LABA.
    Protection of trial subjects
    The protocol, protocol amendments, informed consent form (ICF), Investigator Brochure (IB), and other relevant documents (eg, advertisements) were submitted to an Institutional Review Board/Independent Ethics Committee (IRB/IEC) by the Investigator and reviewed and approved by the IRB/IEC before the study was initiated. The Investigator or his/her representative explained the nature of the study to the subject or his/her legally authorised representative and answered all questions regarding the study. Subjects were informed that their participation was voluntary. Subjects were required to sign a statement of informed consent that met the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study centre. The medical record must have included a statement that written informed consent was obtained before the subject was enrolled in the study and the date the written consent was obtained. The authorised person obtaining the informed consent must have also signed the ICF. Subjects must have been re-consented to the most current version of the ICF(s) during their participation in the study. A copy of the ICF(s) was provided to the subject.
    Background therapy
    		 Subjects must have received a physician-prescribed medium- or high-dose ICS as per GINA guideline (GINA 2017) for at least 12 months prior to visit 1. Documented treatment with prescribed LABA and high dose ICS (total daily dose >500μg fluticasone propionate dry powder formulation equivalent) for at least 3 months prior to visit 1. The ICS could be contained within an ICS/LABA combination product. Additional maintenance asthma controller medications were allowed according to standard practice of care. The use of additional asthma controller medications must have been documented for at least 3 months prior to visit 1. Subjects must have received OCS for the treatment of asthma for at least 6 months prior to visit 1 and on a stable dose of between ≥ 7.5 to ≤ 30mg (prednisone or prednisolone) daily or daily equivalent for at least 1 month prior to visit 1.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Mar 2018
    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
    Poland: 30
    Country: Number of subjects enrolled
    Turkey: 17
    Country: Number of subjects enrolled
    Ukraine: 15
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    United States: 17
    Country: Number of subjects enrolled
    Argentina: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 21
    Worldwide total number of subjects
    150
    EEA total number of subjects
    59
    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)
    120
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 60 centres in 7 countries. A total of 243 subjects were screened between 5MAR2018 and 27SEP2019, of which 150 were randomized and treated. 93 subjects were screen failures mainly due to exclusion criteria met and/or inclusion criteria not met. Assignment was done by Interactive Voice/Web Response System(IVRS/IWRS).

    Pre-assignment
    Screening details
    		 The screening period included a Run-in (2 weeks) and an OCS optimization phase (up to 8 weeks). At the end of period, subjects were randomized in 1:1 ratio for tezepelumab or placebo. Randomization was stratified by region (Central/Eastern Europe, Western Europe and North America, Rest of the World).

    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
    		 Tezepelumab
    Arm description
    		 Tezepelumab 210 mg administered every 4 weeks subcutaneously
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tezepelumab 210 mg administered every 4 weeks subcutaneously
    Investigational medicinal product code
    Other name
    Tezepelumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    210 mg Q4W

    Arm title
    		 Placebo
    Arm description
    		 Placebo administered every 4 weeks subcutaneously
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo administered every 4 weeks subcutaneously
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Q4W

    Number of subjects in period 1
    		Tezepelumab Placebo
    Started
    74
    76
    Completed
    68
    73
    Not completed
    6
    3
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    5
    2
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tezepelumab
    Reporting group description
    		 Tezepelumab 210 mg administered every 4 weeks subcutaneously

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered every 4 weeks subcutaneously

    Reporting group values
    		 Tezepelumab Placebo Total
    Number of subjects
    		 74 76 150
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 58 62 120
        From 65-84 years
    		 16 14 30
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.5 ( 12.1 ) 53.4 ( 11.9 ) -
    Sex: Female, Male
    Units: Participants
        Male
    		 25 31 56
        Female
    		 49 45 94

    End points

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    End points reporting groups
    Reporting group title
    Tezepelumab
    Reporting group description
    		 Tezepelumab 210 mg administered every 4 weeks subcutaneously

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered every 4 weeks subcutaneously

    Primary: Categorized percent reduction from baseline in the daily OCS dose while not losing asthma control

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    End point title
    		 Categorized percent reduction from baseline in the daily OCS dose while not losing asthma control
    End point description
    Categorized percent reduction from baseline at Week 48. Percent change from baseline is defined as {final dose-baseline dose)/baseline dose}*100, and the categories of percent change from baseline in daily OCS dose are defined as: ≥90% to ≤100% reduction, ≥75% to <90% reduction, ≥50% to <75% reduction, >0% to <50% reduction, and, no change or any increase.
    End point type
    Primary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    74
    76
    Units: Participants
        >=90% to <=100% reduction
    40
    35
        >=75% to <90% reduction
    5
    4
        >=50% to <75% reduction
    10
    14
        >0% to <50% reduction
    5
    9
        no change or any increase
    14
    14
    Statistical analysis title
    		 Proportional odds model
    Statistical analysis description
    Response variable: categorised % reduction from baseline in final OCS dose. Covariates in the model: treatment, region and daily OCS dose at baseline.
    Comparison groups
    Placebo v Tezepelumab
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.434
    Method
    		 Proportional odds model
    Parameter type
    		 Cumulative Odds Ratio
    Point estimate
    1.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 2.35

    Secondary: Annualised asthma exacerbation rate (AAER)

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    End point title
    		 Annualised asthma exacerbation rate (AAER)
    End point description
    The annualized exacerbation rate is based on exacerbations reported by the investigator in the eCRF over 48 weeks.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    74
    76
    Units: Annual rate of event over time at risk
        least squares mean (confidence interval 95%)
    1.38 (0.98 to 1.95)
    2.00 (1.46 to 2.74)
    No statistical analyses for this end point

    Secondary: Proportion of subjects with 100% reduction from baseline in daily OCS dose at Week 48

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    End point title
    		 Proportion of subjects with 100% reduction from baseline in daily OCS dose at Week 48
    End point description
    Proportion of subjects with 100% reduction from baseline in daily OCS dose at Week 48. Percent change from baseline is defined as {(final dose-baseline dose)/baseline dose}*100.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    74
    76
    Units: Participants
    40
    35
    No statistical analyses for this end point

    Secondary: Proportion of subjects with daily OCS dose ≤5 mg at Week 48

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    End point title
    		 Proportion of subjects with daily OCS dose ≤5 mg at Week 48
    End point description
    Proportion of subjects with daily OCS dose ≤5 mg at Week 48.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    74
    76
    Units: Participants
    53
    55
    No statistical analyses for this end point

    Secondary: Proportion of subjects with ≥50% reduction from baseline in daily OCS dose at Week 48

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    End point title
    		 Proportion of subjects with ≥50% reduction from baseline in daily OCS dose at Week 48
    End point description
    Proportion of subjects with ≥50% reduction from baseline in daily OCS dose at Week 48. Percent change from baseline is defined as {(final dose-baseline dose)/baseline dose}*100.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    74
    76
    Units: Participants
    55
    53
    No statistical analyses for this end point

    Secondary: Change from baseline in pre-bronchodilator (pre-BD) forced expiratory volume in 1 second (FEV1)

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    End point title
    		 Change from baseline in pre-bronchodilator (pre-BD) forced expiratory volume in 1 second (FEV1)
    End point description
    Change from baseline in pre-BD FEV1 at Week 48. FEV1 is defined as the volume of air exhaled from the lungs in the first second of a forced expiration.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    65
    64
    Units: Litre
        least squares mean (standard error)
    0.21 ( 0.046 )
    -0.04 ( 0.046 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Weekly mean daily Asthma Symptom Score via the daily Asthma Symptom Diary

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    End point title
    		 Change from baseline in Weekly mean daily Asthma Symptom Score via the daily Asthma Symptom Diary
    End point description
    Change from baseline in Asthma Symptom Diary score at Week 48. The Asthma Symptom Diary comprises of 10 items (5 items in the morning; 5 items in the evening). Asthma symptoms during night time and daytime are recorded by the patient each morning and evening in the daily diary. A daily ASD score is the mean of the 10 items. Responses for all 10 items are required to calculate the daily ASD score; otherwise, it is treated as missing. For the 7-day average asthma symptom score, scoring is done with no imputation using the mean of at least 4 of the 7 daily ASD scores as a mean weekly item score. The 7-day average ASD score ranges from 0 to 4, where 0 indicates no asthma symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    58
    68
    Units: Score on a scale
        least squares mean (standard error)
    -0.36 ( 0.071 )
    -0.26 ( 0.068 )
    No statistical analyses for this end point

    Secondary: Change from baseline in weekly mean rescue medication use

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    End point title
    		 Change from baseline in weekly mean rescue medication use
    End point description
    Change from baseline in weekly mean rescue medication use at Week 48. Daily rescue medication use is defined as: Number of night inhaler puffs + 2 x [number of night nebulizer times] + number of daytime inhaler puffs + 2 x [number of day nebulizer times]. Each timepoint is calculated as weekly means based on daily diary data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    60
    70
    Units: weekly mean use
        least squares mean (standard error)
    -0.85 ( 0.280 )
    -0.37 ( 0.268 )
    No statistical analyses for this end point

    Secondary: Change from baseline in weekly mean home peak expiratory flow (PEF) (morning and evening)

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    End point title
    		 Change from baseline in weekly mean home peak expiratory flow (PEF) (morning and evening)
    End point description
    Change from baseline in weekly mean morning and evening peak expiratory flow (PEF) at Week 48. Home PEF testing will be performed by the subject in the morning upon awakening and in the evening at bedtime using an electronic, hand-held spirometer. Each timepoint is calculated as weekly means.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    74
    76
    Units: L/min
    least squares mean (standard error)
        morning PEF (n teze = 59, n pbo = 70)
    13.29 ( 5.653 )
    -9.71 ( 5.435 )
        evening PEF (n teze = 59, n pbo = 69)
    10.05 ( 5.980 )
    -11.37 ( 5.749 )
    No statistical analyses for this end point

    Secondary: Change from baseline in weekly mean number of night-time awakening due to asthma

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    End point title
    		 Change from baseline in weekly mean number of night-time awakening due to asthma
    End point description
    Change from baseline in weekly mean number of night time awakenings at Week 48. Each timepoint is calculated as weekly mean number of awakenings due to asthma based on daily diary data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    59
    70
    Units: Percentage of nights with awakenings
        least squares mean (standard error)
    -15.71 ( 3.482 )
    -12.79 ( 3.317 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Asthma Control Questionnaire 6 (ACQ-6) score

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    End point title
    		 Change from baseline in Asthma Control Questionnaire 6 (ACQ-6) score
    End point description
    Change from baseline in ACQ-6 at Week 48. The ACQ-6 captures asthma symptoms and short-acting β2-agonist use via subject-report. Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely uncontrolled). The ACQ-6 score is the mean of the responses.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    66
    68
    Units: Score on a scale
        least squares mean (standard error)
    -0.87 ( 0.125 )
    -0.51 ( 0.123 )
    No statistical analyses for this end point

    Secondary: Change from baseline in Standardized Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(s)+12) total score

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    End point title
    		 Change from baseline in Standardized Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(s)+12) total score
    End point description
    Change from baseline in AQLQ(S)+12 as compared to placebo at Week 48. The AQLQ(S)+12 is a questionnaire that measures the health-related quality of life experienced by asthma subjects. The total score is defined as the average of all 32 questions in the AQLQ(S)+12 questionnaire. AQLQ(S)+12 is a 7-point scale questionnaire, ranging from 7 (no impairment) to 1 (severe impairment).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    66
    67
    Units: Score on a scale
        least squares mean (standard error)
    0.94 ( 0.124 )
    0.58 ( 0.123 )
    No statistical analyses for this end point

    Secondary: Change from baseline in European Quality of Life – 5 Dimensions 5 Levels Questionnaire (EQ-5D-5L) score

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    End point title
    		 Change from baseline in European Quality of Life – 5 Dimensions 5 Levels Questionnaire (EQ-5D-5L) score
    End point description
    Change from baseline in EQ-5D-5L at Week 48. The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no/slight/moderate/severe/extreme problems) that reflect increasing levels of difficulty. The EQ-5D-5L scores are converted into a single index-based value (Health State Valuation), using the UK population-based weights. The Helth State Valuation is scored between 0 to 1, where higher score indicates a better health state.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    62
    58
    Units: Score on a scale
        least squares mean (standard error)
    0.07 ( 0.026 )
    0.00 ( 0.027 )
    No statistical analyses for this end point

    Secondary: Number of asthma specific resource utilizations

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    End point title
    		 Number of asthma specific resource utilizations
    End point description
    Number of asthma specific resource utilizations (e.g. unscheduled physician visits, unscheduled phone calls to physicians, use of other asthma medications) over 48 weeks.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    74
    76
    Units: Participants
        Hospitalisation
    5
    10
        Emergency room visit
    4
    7
        Unscheduled visit to specialist
    29
    41
        Home visit
    1
    2
        Telephone call
    26
    43
        Ambulance transport
    0
    1
    No statistical analyses for this end point

    Secondary: Change from baseline in Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questionnaire (WPAI+CIQ) score

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    End point title
    		 Change from baseline in Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questionnaire (WPAI+CIQ) score
    End point description
    Change from baseline in WPAI+CIQ score at Week 48. The WPAI+CIQ consists of questions about how asthma and asthma related issues impact a subject’s ability to work, attend classes, and perform regular daily activities.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    74
    76 [1]
    Units: Percentage
    arithmetic mean (standard deviation)
        Work productivity loss (n teze = 22, n pbo = 21)
    -6.27 ( 25.30 )
    -9.66 ( 36.63 )
        Class productivity loss (n teze = 1, n pbo = 0)
    -10.00 ( 0 )
    0 ( 0 )
        Activity impairment (n teze = 59, n pbo = 59)
    -13.2 ( 29.3 )
    -7.8 ( 26.4 )
    Notes
    [1] - No subject in Placebo arm selected the option 'in school' on the WPAI+CIQ questionnaire at Week 48.
    No statistical analyses for this end point

    Secondary: Change from baseline in FENO

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    End point title
    		 Change from baseline in FENO
    End point description
    Change from baseline in fractional exhaled nitric oxide (FeNO) at week 48.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    58
    57
    Units: ppb
        least squares mean (standard error)
    -11.71 ( 2.757 )
    -1.40 ( 2.774 )
    No statistical analyses for this end point

    Secondary: Change from baseline in peripheral blood eosinophils

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    End point title
    		 Change from baseline in peripheral blood eosinophils
    End point description
    Change from baseline in blood eosinophil counts at week 48.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    63
    67
    Units: cells/μL
        least squares mean (standard error)
    -83.79 ( 17.078 )
    33.38 ( 16.605 )
    No statistical analyses for this end point

    Secondary: Change from baseline from total serum IgE

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    End point title
    		 Change from baseline from total serum IgE
    End point description
    Change from baseline in total serum IgE at week 48.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 48
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    65
    67
    Units: IU/mL
        least squares mean (standard error)
    -80.66 ( 36.253 )
    37.77 ( 35.621 )
    No statistical analyses for this end point

    Secondary: PK: Serum trough concentrations

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    End point title
    		 PK: Serum trough concentrations
    End point description
    Serum trough concentrations at each scheduled visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4, Week 12, Week 24, Week 40, Week 48, Week 60
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    74
    0 [2]
    Units: μg/mL
    geometric mean (geometric coefficient of variation)
        Baseline
    0 ( 0 )
    ( )
        Week 4
    10.3298 ( 42.31 )
    ( )
        Week 12
    17.9626 ( 57.85 )
    ( )
        Week 24
    18.9210 ( 55.83 )
    ( )
        Week 40
    16.7095 ( 181.44 )
    ( )
        Week 48
    13.9224 ( 352.35 )
    ( )
        Week 60
    3.5591 ( 177.36 )
    ( )
    Notes
    [2] - The placebo arm is not applicable since it is not the experimental product.
    No statistical analyses for this end point

    Secondary: Immunogenicity: Incidence of anti-drug antibodies (ADA)

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    End point title
    		 Immunogenicity: Incidence of anti-drug antibodies (ADA)
    End point description
    Anti-drug antibodies (ADA) responses at baseline and post baseline. Persistently positive is defined as positive at >=2 post baseline assessments (with >=16 weeks between the first and the last positive) or positive at last post baseline assessment. Transiently positive is defined as having at least one post baseline ADA positive assessment and not fulfilling the conditions of persistently positive. Treatment boosted ADA defined as baseline positive ADA that was boosted to a 4 fold or higher level following treatment. Treatment emergent ADA defined as sum of treatment induced ADA and treatment boosted ADA.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 60
    End point values
    		 Tezepelumab Placebo
    Number of subjects analysed
    74
    76
    Units: Participants
        ADA positive at baseline and/or post-baseline
    3
    2
        Any baseline ADA positive
    2
    2
        Only baseline ADA positive
    1
    1
        Any post-baseline ADA positive
    2
    1
        Both baseline and >=1 post-baseline ADA positive
    1
    1
        Treatment-induced ADA positive
    1
    0
        Treatment-boosted ADA positive
    0
    0
        TE-ADA positive (ADA incidence)
    1
    0
        ADA persistently positive
    1
    1
        ADA transiently positive
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until last study visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered subcutaneously

    Reporting group title
    Teze 210 mg Q4W
    Reporting group description
    		 Tezepelumab administered every 4 weeks subcutaneously

    Serious adverse events
    		 Placebo Teze 210 mg Q4W
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 76 (21.05%)
    12 / 74 (16.22%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Incisional hernia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    8 / 76 (10.53%)
    4 / 74 (5.41%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial secretion retention
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Intervertebral discitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Placebo Teze 210 mg Q4W
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 76 (63.16%)
    35 / 74 (47.30%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 76 (1.32%)
    3 / 74 (4.05%)
         occurrences all number
    1
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 76 (7.89%)
    2 / 74 (2.70%)
         occurrences all number
    6
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 76 (10.53%)
    3 / 74 (4.05%)
         occurrences all number
    9
    3
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    5 / 76 (6.58%)
    0 / 74 (0.00%)
         occurrences all number
    5
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 74 (1.35%)
         occurrences all number
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    8 / 76 (10.53%)
    6 / 74 (8.11%)
         occurrences all number
    15
    7
    Nasal polyps
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 74 (0.00%)
         occurrences all number
    6
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 76 (1.32%)
    4 / 74 (5.41%)
         occurrences all number
    2
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 76 (3.95%)
    4 / 74 (5.41%)
         occurrences all number
    3
    4
    Bronchitis bacterial
         subjects affected / exposed
    7 / 76 (9.21%)
    6 / 74 (8.11%)
         occurrences all number
    10
    14
    Nasopharyngitis
         subjects affected / exposed
    19 / 76 (25.00%)
    12 / 74 (16.22%)
         occurrences all number
    29
    14
    Oral candidiasis
         subjects affected / exposed
    4 / 76 (5.26%)
    4 / 74 (5.41%)
         occurrences all number
    5
    4
    Sinusitis
         subjects affected / exposed
    5 / 76 (6.58%)
    1 / 74 (1.35%)
         occurrences all number
    6
    1
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 76 (10.53%)
    9 / 74 (12.16%)
         occurrences all number
    8
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Apr 2018
    clarifications of eligibility criteria of enrolment in the extension study and acceptable OCS dose regimen, amendment of inclusion/exclusion criteria, changes to concomitant/prohibited medication
    12 Mar 2019
    Changes to the sample size, information about two database locks and unblinding rules after primary database lock added, amendment of measures to minimise bias and study assessments, amended inclusion/exclusion criteria, clarification on concomitant/prohibited medication
    14 May 2020
    changes to supportive outcome of key secondary objective, added appendix with guidance for changes related to the COVID-19 pandemic, new analyses specified related to COVID-19 pandemic, threshold of partially asthma control based on ACQ-6 score updated, clarification that safety analysis will be done based on 'on-study' period instead of 'post-treatment'

    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.
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
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