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    Clinical Trial Results:
    A 52-Week, Multicentre, Randomized, Double-Blind, Parallel Group, Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Tralokinumab in Adults and Adolescents with Asthma Inadequately Controlled on Inhaled Corticosteroid Plus Long-Acting β2-Agonist (STRATOS 1)

    Summary
    EudraCT number
    2013-005614-35
    Trial protocol
    DE   HU   PL   SK   BG   BE  
    Global end of trial date
    18 Jul 2017

    Results information
    Results version number
    v2(current)
    This version publication date
    21 Jun 2018
    First version publication date
    27 Jan 2018
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    D2210C00007
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02161757
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AstraZeneca
    Sponsor organisation address
    200 Orchard Ridge Drive, Gaithersburg, United States, MD 20878
    Public contact
    Global Clinical Lead, AstraZeneca, 1 3013980582, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca, 1 3013980582, ClinicalTrialTransparency@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000782-PIP01-09
    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
    18 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Feb 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of tralokinumab 300 milligrams (mg) administered every 2 weeks compared with placebo on the annualised asthma exacerbation rate (AAER) in adult and adolescent patients with asthma that is inadequately controlled with inhaled corticosteroid (ICS) plus long-acting β2-agonists (LABA).
    Protection of trial subjects
    This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council for Harmonisation/Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics.
    Background therapy
    Patients were maintained on their currently prescribed ICS-LABA therapy and any additional maintenance asthma controller medications throughout the study period.
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Jun 2014
    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
    United States: 281
    Country: Number of subjects enrolled
    Bulgaria: 170
    Country: Number of subjects enrolled
    Poland: 166
    Country: Number of subjects enrolled
    Argentina: 119
    Country: Number of subjects enrolled
    Peru: 101
    Country: Number of subjects enrolled
    Ukraine: 80
    Country: Number of subjects enrolled
    Vietnam: 80
    Country: Number of subjects enrolled
    Korea, Republic of: 75
    Country: Number of subjects enrolled
    Hungary: 59
    Country: Number of subjects enrolled
    Germany: 32
    Country: Number of subjects enrolled
    Colombia: 15
    Country: Number of subjects enrolled
    Slovakia: 12
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Spain: 3
    Worldwide total number of subjects
    1202
    EEA total number of subjects
    451
    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)
    43
    Adults (18-64 years)
    963
    From 65 to 84 years
    196
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    First patient enrolled: 13 Jun 2014; Week 52 cut-off: 28 Feb 2017; Last Patient Last Visit Week 72: 18 Jul 2017. Study performed at 254 sites in 14 countries. Patients were maintained on currently prescribed inhaled corticosteroid long-acting β2-agonist therapy + any additional maintenance asthma controller medications throughout the study period.

    Pre-assignment
    Screening details
    2248 patients signed informed consent, 1669 entered screening/run-in period, 1207 patients were randomised to receive treatment with tralokinumab 300 mg, or placebo, every 2 weeks (Q2W) or every 4 weeks (Q4W). Of the 1207 patients randomised, 1202 received investigational product (IP).

    Period 1
    Period 1 title
    Randomised Through Start Treatment
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Data analyst, Assessor, Subject
    Blinding implementation details
    Neither the patient nor any of the investigator or sponsor staff who are involved in the treatment or clinical evaluation and monitoring of the patients will be aware of the study treatment received. Since tralokinumab and placebo are visually distinct, investigational product (IP) will be handled by an unblinded IP manager at the site and will be administered by an unblinded investigational site study team member who will not be involved in the management of study patients.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Tralo 300 mg Q2W
    Arm description
    Tralokinumab 300 mg administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses). Follow-up visits were conducted at Weeks 56 and 72.
    Arm type
    Experimental

    Investigational medicinal product name
    Tralokinumab
    Investigational medicinal product code
    CAT-354
    Other name
    Tralo
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    150 milligram/millilitre (mg/mL) solution for injection in an accessorised pre-filled syringe, 1.0 mL fill volume. Each patient received 2 injections of 150 mg tralokinumab at each dosing interval to receive a total dose of 300 mg.

    Arm title
    Tralo 300 mg Q4W
    Arm description
    Tralokinumab 300 mg administered subcutaneously Q4W over a 52-week treatment period (up to 13 doses). Follow-up visits were conducted at Weeks 56 and 72.
    Arm type
    Experimental

    Investigational medicinal product name
    Tralokinumab
    Investigational medicinal product code
    CAT-354
    Other name
    Tralo
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    150 mg/mL solution for injection in an accessorised pre-filled syringe, 1.0 mL fill volume. Each patient received 2 injections of 150 mg tralokinumab at each dosing interval to receive a total dose of 300 mg.

    Arm title
    Placebo
    Arm description
    Placebo was administered subcutaneously over a 52-week treatment period. The placebo treatment group is a pooled treatment group (placebo Q2W + placebo Q4W) where the 2 placebo cohorts were given weights proportional to the number of patients in each cohort. Follow-up visits were conducted at Weeks 56 and 72.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo solution for injection in an accessorised pre-filled syringe, 1.0 mL fill volume. Each patient received 2 injections of placebo at each dosing interval.

    Number of subjects in period 1
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Started
    401
    406
    400
    Completed
    398
    404
    400
    Not completed
    3
    2
    0
         Did not receive treatment
    3
    2
    -
    Period 2
    Period 2 title
    Treatment Through Study Completion
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    Neither the patient nor any of the investigator or sponsor staff who are involved in the treatment or clinical evaluation and monitoring of the patients will be aware of the study treatment received. Since tralokinumab and placebo are visually distinct, investigational product (IP) will be handled by an unblinded IP manager at the site and will be administered by an unblinded investigational site study team member who will not be involved in the management of study patients.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Tralo 300 mg Q2W
    Arm description
    Tralokinumab 300 mg administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses).
    Arm type
    Experimental

    Investigational medicinal product name
    Tralokinumab
    Investigational medicinal product code
    CAT-354
    Other name
    Tralo
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    150 mg/mL solution for injection in an accessorised pre-filled syringe, 1.0 mL fill volume. Each patient received 2 injections of 150 mg tralokinumab at each dosing interval to receive a total dose of 300 mg.

    Arm title
    Tralo 300 mg Q4W
    Arm description
    Tralokinumab 300 mg administered subcutaneously Q4W over a 52-week treatment period (up to 13 doses).
    Arm type
    Experimental

    Investigational medicinal product name
    Tralokinumab
    Investigational medicinal product code
    CAT-354
    Other name
    Tralo
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    150 mg/mL solution for injection in an accessorised pre-filled syringe, 1.0 mL fill volume. Each patient received 2 injections of 150 mg tralokinumab at each dosing interval to receive a total dose of 300 mg.

    Arm title
    Placebo
    Arm description
    Placebo was administered subcutaneously over a 52-week treatment period. The placebo treatment group is a pooled treatment group (placebo Q2W + placebo Q4W) where the 2 placebo cohorts were given weights proportional to the number of patients in each cohort.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo solution for injection in an accessorised pre-filled syringe, 1.0 mL fill volume. Each patient received 2 injections of placebo at each dosing interval.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 presents data for all patients randomised until the start of treatment and Period 2 presents data for all patients who received study treatment (tralokinumab or placebo). The analysis population for baseline characteristics was the full analysis set, defined as all patients who received at least one dose of IP. Period 2 is therefore the baseline period.
    Number of subjects in period 2
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Started
    398
    404
    400
    Completed treatment for Week 52 cut-off
    332 [2]
    355 [3]
    360 [4]
    Completed
    341
    361
    361
    Not completed
    57
    43
    39
         Protocol deviation
    -
    1
    2
         Adverse event, serious fatal
    2
    1
    1
         Adverse event, non-fatal
    1
    1
    -
         Unspecified
    20
    19
    12
         Consent withdrawn by subject
    27
    19
    20
         Lost to follow-up
    7
    2
    4
    Notes
    [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: The Milestone field reports the number of patients who completed treatment up to the Week 52 data cut-off, whereas the Completed field reports the number of patients who completed the study up to Week 72. The results are correctly stated for the Placebo arm that more patients completed the study overall compared to those completing treatment up to Week 52 since the latter also included patients who discontinued treatment but who completed study assessments.
    [3] - 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: The Milestone field reports the number of patients who completed treatment up to the Week 52 data cut-off, whereas the Completed field reports the number of patients who completed the study up to Week 72. The results are correctly stated for the Tralo 300 mg Q2W arm that more patients completed the study overall compared to those completing treatment up to Week 52 since the latter also included patients who discontinued treatment but who completed study assessments.
    [4] - 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: The Milestone field reports the number of patients who completed treatment up to the Week 52 data cut-off, whereas the Completed field reports the number of patients who completed the study up to Week 72. The results are correctly stated for the Tralo 300 mg Q4W arm that more patients completed the study overall compared to those completing treatment up to Week 52 since the latter also included patients who discontinued treatment but who completed study assessments.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tralo 300 mg Q2W
    Reporting group description
    Tralokinumab 300 mg administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses).

    Reporting group title
    Tralo 300 mg Q4W
    Reporting group description
    Tralokinumab 300 mg administered subcutaneously Q4W over a 52-week treatment period (up to 13 doses).

    Reporting group title
    Placebo
    Reporting group description
    Placebo was administered subcutaneously over a 52-week treatment period. The placebo treatment group is a pooled treatment group (placebo Q2W + placebo Q4W) where the 2 placebo cohorts were given weights proportional to the number of patients in each cohort.

    Reporting group values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo Total
    Number of subjects
    398 404 400 1202
    Age categorical
    Units: Subjects
        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)
    14 15 14 43
        Adults (18-64 years)
    332 322 309 963
        From 65-84 years
    52 67 77 196
        85 years and over
    0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    49.4 ± 14.3 51.1 ± 13.9 51.4 ± 14.3 -
    Sex: Female, Male
    Units: Subjects
        Female
    252 281 265 798
        Male
    146 123 135 404
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    21 22 25 68
        Asian
    53 55 55 163
        Native Hawaiian or Other Pacific Islander
    1 0 0 1
        Black or African American
    21 16 14 51
        White
    285 297 288 870
        More than one race
    0 0 0 0
        Unknown or Not Reported
    17 14 18 49

    End points

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    End points reporting groups
    Reporting group title
    Tralo 300 mg Q2W
    Reporting group description
    Tralokinumab 300 mg administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses). Follow-up visits were conducted at Weeks 56 and 72.

    Reporting group title
    Tralo 300 mg Q4W
    Reporting group description
    Tralokinumab 300 mg administered subcutaneously Q4W over a 52-week treatment period (up to 13 doses). Follow-up visits were conducted at Weeks 56 and 72.

    Reporting group title
    Placebo
    Reporting group description
    Placebo was administered subcutaneously over a 52-week treatment period. The placebo treatment group is a pooled treatment group (placebo Q2W + placebo Q4W) where the 2 placebo cohorts were given weights proportional to the number of patients in each cohort. Follow-up visits were conducted at Weeks 56 and 72.
    Reporting group title
    Tralo 300 mg Q2W
    Reporting group description
    Tralokinumab 300 mg administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses).

    Reporting group title
    Tralo 300 mg Q4W
    Reporting group description
    Tralokinumab 300 mg administered subcutaneously Q4W over a 52-week treatment period (up to 13 doses).

    Reporting group title
    Placebo
    Reporting group description
    Placebo was administered subcutaneously over a 52-week treatment period. The placebo treatment group is a pooled treatment group (placebo Q2W + placebo Q4W) where the 2 placebo cohorts were given weights proportional to the number of patients in each cohort.

    Primary: Annualised asthma exacerbation rate (AAER) up to Week 52

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    End point title
    Annualised asthma exacerbation rate (AAER) up to Week 52
    End point description
    Asthma exacerbation was defined as a worsening of asthma that led to any of the following: • Use of systemic corticosteroids for at least 3 days; a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids. • An emergency room (ER) or urgent care (UC) visit (defined as evaluation and treatment for <24 hours in an ER or UC centre) due to asthma that required systemic corticosteroids (see above). • An inpatient hospitalisation (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥24 hours) due to asthma. AAER = number of exacerbations*365.25 / (follow-up date – date of randomisation + 1) (where maximum follow-up time for a patient was approximately 52 weeks). AAER in the tralokinumab group was compared to that seen in the placebo group up to Week 52 using a negative binomial model; rate ratios and rate reductions are both presented for comparative statistical analyses.
    End point type
    Primary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    398
    404
    400
    Units: Events/year
        number (confidence interval 95%)
    0.56 (0.46 to 0.67)
    0.54 (0.45 to 0.65)
    0.60 (0.50 to 0.72)
    Statistical analysis title
    AAER: rate ratio
    Statistical analysis description
    Tralo 300 mg Q2W vs placebo. The null hypothesis was that the exacerbation rate during the 52-week double-blind treatment period on tralokinumab was equal to the corresponding exacerbation rate on placebo.
    Comparison groups
    Tralo 300 mg Q2W v Placebo
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.5859
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    1.21
    Notes
    [1] - Covariates in the model included treatment group, geographical region, age group, periostin group at baseline and number of exacerbations in the year before the study.
    Statistical analysis title
    AAER: rate ratio
    Statistical analysis description
    Tralo 300 mg Q4W vs placebo. The null hypothesis was that the exacerbation rate during the 52-week double-blind treatment period on tralokinumab was equal to the corresponding exacerbation rate on placebo.
    Comparison groups
    Tralo 300 mg Q4W v Placebo
    Number of subjects included in analysis
    804
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.4406
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.17
    Notes
    [2] - Covariates in the model included treatment group, geographical region, age group, periostin group at baseline and number of exacerbations in the year before the study.
    Statistical analysis title
    AAER: rate reduction
    Statistical analysis description
    Tralo 300 mg Q2W vs placebo. The null hypothesis was that the exacerbation rate during the 52-week double-blind treatment period on tralokinumab was equal to the corresponding exacerbation rate on placebo.
    Comparison groups
    Tralo 300 mg Q2W v Placebo
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.5859
    Method
    Negative binominal
    Parameter type
    Rate reduction
    Point estimate
    7.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.76
         upper limit
    28.39
    Notes
    [3] - Covariates in the model included treatment group, geographical region, age group, periostin group at baseline and number of exacerbations in the year before the study.
    Statistical analysis title
    AAER: rate reduction
    Statistical analysis description
    Tralo 300 mg Q4W vs placebo. The null hypothesis was that the exacerbation rate during the 52-week double-blind treatment period on tralokinumab was equal to the corresponding exacerbation rate on placebo.
    Comparison groups
    Tralo 300 mg Q4W v Placebo
    Number of subjects included in analysis
    804
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.4406
    Method
    Negative binominal
    Parameter type
    Rate reduction
    Point estimate
    9.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.16
         upper limit
    30.5
    Notes
    [4] - Covariates in the model included treatment group, geographical region, age group, periostin group at baseline and number of exacerbations in the year before the study.

    Secondary: Percent change from baseline to Week 52 in pre-dose/pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1)

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    End point title
    Percent change from baseline to Week 52 in pre-dose/pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1)
    End point description
    Lung function was assessed by FEV1 which was measured by spirometry. Spirometry was performed by the Investigator or authorised delegate according to American Thoracic Society/European Respiratory Society guidelines. The mean percent change from baseline in pre-BD FEV1 at Week 52 is presented. Only patients with data available at the timepoints of testing were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    357
    373
    363
    Units: Percent change from baseline
        arithmetic mean (standard deviation)
    16.366 ± 27.349
    12.099 ± 26.253
    10.136 ± 24.206
    Statistical analysis title
    Percent change from baseline in pre-BD FEV1
    Statistical analysis description
    Tralo 300 mg Q2W vs placebo. Restricted maximum likelihood (REML) based repeated measures analysis performed on patients with a baseline pre-dose/pre-BD FEV1 assessment.
    Comparison groups
    Tralo 300 mg Q2W v Placebo
    Number of subjects included in analysis
    720
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    Method
    Parameter type
    Least square (LS) Mean difference
    Point estimate
    6.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.34
         upper limit
    9.73
    Notes
    [5] - Fixed categorical effects of treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.
    Statistical analysis title
    Percent change from baseline in pre-BD FEV1
    Statistical analysis description
    Tralo 300 mg Q4W vs placebo. REML based repeated measures analysis performed on patients with a baseline pre-dose/pre-BD FEV1 assessment.
    Comparison groups
    Tralo 300 mg Q4W v Placebo
    Number of subjects included in analysis
    736
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    2.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.58
         upper limit
    5.77
    Notes
    [6] - Fixed categorical effects of treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

    Secondary: Change from baseline to Week 52 in total asthma symptom score (bi-weekly means)

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    End point title
    Change from baseline to Week 52 in total asthma symptom score (bi-weekly means)
    End point description
    Asthma symptoms during night-time and daytime were recorded by the patient each morning and evening in the Asthma Daily Diary. Symptoms were recorded using a 4-point response scale, which ranged from 0 to 3, where 0 indicated no asthma symptoms. Asthma symptom daytime score (recorded in the evening), night-time score (recorded in the morning), and total score were calculated separately. The daily asthma symptom total score was calculated by taking the sum of the night-time and daytime asthma symptom scores recorded each day, ranging from 0 to 6. A lower symptom score indicated a better outcome. The change from baseline in bi-weekly mean daily asthma symptom total score is presented. Only patients with data available at the timepoints of testing were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    313
    313
    312
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.09 ± 1.22
    -1.00 ± 1.11
    -1.03 ± 1.13
    Statistical analysis title
    Change from baseline in total asthma symptom score
    Statistical analysis description
    Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis.
    Comparison groups
    Tralo 300 mg Q2W v Placebo
    Number of subjects included in analysis
    625
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    -0.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.23
         upper limit
    0.04
    Notes
    [7] - Fixed categorical effects of baseline asthma symptom score, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.
    Statistical analysis title
    Change from baseline in total asthma symptom score
    Statistical analysis description
    Tralo 300 mg Q4W vs placebo. REML based repeated measures analysis.
    Comparison groups
    Tralo 300 mg Q4W v Placebo
    Number of subjects included in analysis
    625
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.15
         upper limit
    0.12
    Notes
    [8] - Fixed categorical effects of baseline asthma symptom score, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

    Secondary: Change from baseline to Week 52 in 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 to Week 52 in Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) total score
    End point description
    The AQLQ(S)+12 is a questionnaire that measures health-related quality of life for patients with asthma aged 12 and older. The questionnaire comprises 32 questions and has 4 separate domains (asthma symptoms, activity limitations, emotional function and environmental stimuli). Patients were asked to recall their experiences during the previous 2 weeks and to score each of the questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). The total score was calculated as the mean response to all questions, ranging from 1 (severe impairment) to 7 (no impairment). Individual AQLQ(S)+12 total score changes of ≥0.5 were considered to be clinically meaningful. The mean change from baseline in AQLQ(S)+12 score at Week 52 is presented. Only patients with data available at the timepoints of testing were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    304
    321
    315
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    1.18 ± 1.17
    1.16 ± 1.14
    1.03 ± 1.24
    Statistical analysis title
    Change in mean score from baseline for AQLQ(S)+12
    Statistical analysis description
    Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis.
    Comparison groups
    Tralo 300 mg Q2W v Placebo
    Number of subjects included in analysis
    619
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.01
         upper limit
    0.31
    Notes
    [9] - Fixed categorical effects of baseline AQLQ(S)+12 score, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.
    Statistical analysis title
    Change in mean score from baseline for AQLQ(S)+12
    Statistical analysis description
    Tralo 300 mg Q4W vs placebo. REML based repeated measures analysis.
    Comparison groups
    Tralo 300 mg Q4W v Placebo
    Number of subjects included in analysis
    636
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    0.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.03
         upper limit
    0.28
    Notes
    [10] - Fixed categorical effects of baseline AQLQ(S)+12 score, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

    Secondary: Change from baseline to Week 52 in Asthma Control Questionnaire-6 (ACQ-6) score

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    End point title
    Change from baseline to Week 52 in Asthma Control Questionnaire-6 (ACQ-6) score
    End point description
    The ACQ-6 questionnaire is a shortened version of the ACQ (omitting FEV1 measurement) that assesses asthma symptoms (night-time awakenings, symptoms on waking, activity limitation, dyspnoea, wheezing) and rescue short-acting β2-agonists medication use during the past week. Questions were weighted equally and scored on a 7-point scale from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ-6 score was the mean of the responses, ranging 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 a score >1.5 indicates not well-controlled asthma. Individual changes of at least 0.5 were considered to be clinically meaningful. The mean change from baseline in ACQ-6 score at Week 52 is presented. Only patients with data available at the timepoints of testing were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    324
    344
    329
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.19 ± 1.06
    -1.12 ± 1.03
    -1.02 ± 1.14
    Statistical analysis title
    Change in mean score from baseline for ACQ-6
    Statistical analysis description
    Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis.
    Comparison groups
    Tralo 300 mg Q2W v Placebo
    Number of subjects included in analysis
    653
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    -0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.29
         upper limit
    -0.02
    Notes
    [11] - Fixed categorical effects of baseline ACQ-6 score, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.
    Statistical analysis title
    Change in mean score from baseline for ACQ-6
    Statistical analysis description
    Tralo 300 mg Q4W vs placebo. REML based repeated measures analysis.
    Comparison groups
    Tralo 300 mg Q4W v Placebo
    Number of subjects included in analysis
    673
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    -0.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.26
         upper limit
    0.01
    Notes
    [12] - Fixed categorical effects of baseline ACQ-6 score, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

    Secondary: AAER associated with an ER/UC visit, or a hospitalisation up to Week 52

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    End point title
    AAER associated with an ER/UC visit, or a hospitalisation up to Week 52
    End point description
    The annual rate of exacerbations associated with an ER/UC visit or hospitalisation up to Week 52 are presented for non-adjudicated data (i.e. events assessed by the Investigator and recorded in the electronic case report form). AAER = Number of Exacerbations*365.25 / (Follow-up date – Date of randomisation + 1) (where maximum follow-up time for a patient was approximately 52 weeks).
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    398
    404
    400
    Units: Events/year
        number (confidence interval 95%)
    0.04 (0.02 to 0.06)
    0.06 (0.04 to 0.09)
    0.07 (0.05 to 0.11)
    Statistical analysis title
    AAER associated with ER/UC visit / hospitalisation
    Statistical analysis description
    Tralo 300 mg Q2W vs placebo.
    Comparison groups
    Tralo 300 mg Q2W v Placebo
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority [13]
    P-value
    = 0.0369
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    0.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.3
         upper limit
    0.96
    Notes
    [13] - Covariates in the model included treatment group, geographical region, age group, periostin group at baseline and number of exacerbations resulting in hospitalisation or ER treatment (yes/no) in the year before the study.
    Statistical analysis title
    AAER associated with ER/UC visit / hospitalisation
    Statistical analysis description
    Tralo 300 mg Q4W vs placebo.
    Comparison groups
    Tralo 300 mg Q4W v Placebo
    Number of subjects included in analysis
    804
    Analysis specification
    Pre-specified
    Analysis type
    superiority [14]
    P-value
    = 0.3603
    Method
    Negative binomial
    Parameter type
    Rate ratio
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    1.33
    Notes
    [14] - Covariates in the model included treatment group, geographical region, age group, periostin group at baseline and number of exacerbations resulting in hospitalisation or ER treatment (yes/no) in the year before the study.

    Secondary: Change from baseline in European Quality of Life - 5 Dimension 5 Levels (EQ-5D-5L) visual analogue scale (VAS) scores at Week 52

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    End point title
    Change from baseline in European Quality of Life - 5 Dimension 5 Levels (EQ-5D-5L) visual analogue scale (VAS) scores at Week 52
    End point description
    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 problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty. The patient was asked to indicate his/her current health state by selecting the most appropriate level in each of the 5 dimensions. The questionnaire also included a VAS, where the patient was asked to rate current health status on a scale of 0 to 100, with 0 being the worst imaginable health state. The mean change from baseline in EQ-5D-5L VAS scores at Week 52 is presented. Only patients with data available at the timepoints of testing were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    306
    319
    324
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    10.68 ± 20.33
    9.00 ± 18.99
    10.06 ± 18.92
    No statistical analyses for this end point

    Secondary: Change from baseline in total asthma rescue medication use at Week 52 (bi-weekly means)

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    End point title
    Change from baseline in total asthma rescue medication use at Week 52 (bi-weekly means)
    End point description
    Salbutamol, albuterol or levalbuterol were used as rescue medication during the study in the event of a worsening of asthma symptoms. Rescue medication use was measured by the bi-weekly mean number of inhalations (puffs) per day, calculated as: total morning puffs + total evening puffs + 2*(total morning nebuliser use + total evening nebuliser use)/ total number of days with data in bi-weekly period. The change from baseline in bi-weekly mean total asthma rescue medication use at Week 52 is presented. Only patients with data available at the timepoints of testing were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    313
    313
    312
    Units: Puffs/day
        arithmetic mean (standard deviation)
    -2.18 ± 3.46
    -2.15 ± 3.69
    -2.04 ± 3.84
    Statistical analysis title
    Mean change from baseline in rescue medication use
    Statistical analysis description
    Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis.
    Comparison groups
    Tralo 300 mg Q2W v Placebo
    Number of subjects included in analysis
    625
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    -0.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.51
         upper limit
    0.29
    Notes
    [15] - Fixed categorical effects of baseline rescue medication use, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.
    Statistical analysis title
    Mean change from baseline in rescue medication use
    Statistical analysis description
    Tralo 300 mg Q4W vs placebo. REML based repeated measures analysis.
    Comparison groups
    Tralo 300 mg Q4W v Placebo
    Number of subjects included in analysis
    625
    Analysis specification
    Pre-specified
    Analysis type
    superiority [16]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    -0.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.56
         upper limit
    0.24
    Notes
    [16] - Fixed categorical effects of baseline rescue medication use, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

    Secondary: Change from baseline in home peak expiratory flow (PEF) (morning and evening) at Week 52

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    End point title
    Change from baseline in home peak expiratory flow (PEF) (morning and evening) at Week 52
    End point description
    Home PEF testing was performed by the patient using an electronic, hand-held spirometer (peak flow meter) and was performed in the morning upon awakening (prior to taking their morning asthma controller) and in the evening at bedtime (prior to taking their evening asthma controller). The mean change from baseline in home PEF values at Week 52 are presented separately for morning and evening. Only patients with data available at the timepoints of testing were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    321
    326
    329
    Units: L/min
    arithmetic mean (standard deviation)
        Morning PEF (n=320,326,329)
    12.95 ± 85.66
    7.55 ± 74.97
    5.23 ± 74.10
        Evening PEF (n=321,319,326)
    8.89 ± 83.02
    0.68 ± 73.19
    -0.28 ± 76.05
    Statistical analysis title
    Mean change from baseline in morning PEF
    Statistical analysis description
    Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis.
    Comparison groups
    Tralo 300 mg Q2W v Placebo
    Number of subjects included in analysis
    650
    Analysis specification
    Pre-specified
    Analysis type
    superiority [17]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    6.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.53
         upper limit
    16.03
    Notes
    [17] - Fixed categorical effects of baseline PEF (morning), treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.
    Statistical analysis title
    Mean change from baseline in morning PEF
    Statistical analysis description
    Tralo 300 mg Q4W vs placebo. REML based repeated measures analysis.
    Comparison groups
    Tralo 300 mg Q4W v Placebo
    Number of subjects included in analysis
    655
    Analysis specification
    Pre-specified
    Analysis type
    superiority [18]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    1.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.99
         upper limit
    11.53
    Notes
    [18] - Fixed categorical effects of baseline PEF (morning), treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.
    Statistical analysis title
    Mean change from baseline in evening PEF
    Statistical analysis description
    Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis.
    Comparison groups
    Tralo 300 mg Q2W v Placebo
    Number of subjects included in analysis
    650
    Analysis specification
    Pre-specified
    Analysis type
    superiority [19]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    7.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.6
         upper limit
    16.87
    Notes
    [19] - Fixed categorical effects of baseline PEF (evening), treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.
    Statistical analysis title
    Mean change from baseline in evening PEF
    Statistical analysis description
    Traco 300 mg Q4W vs placebo. REML based repeated measures analysis.
    Comparison groups
    Tralo 300 mg Q4W v Placebo
    Number of subjects included in analysis
    655
    Analysis specification
    Pre-specified
    Analysis type
    superiority [20]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    0.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.13
         upper limit
    10.35
    Notes
    [20] - Fixed categorical effects of baseline PEF (evening), treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

    Secondary: Change from baseline in night-time awakenings due to asthma requiring rescue medication use at Week 52 (bi-weekly means [percentage])

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    End point title
    Change from baseline in night-time awakenings due to asthma requiring rescue medication use at Week 52 (bi-weekly means [percentage])
    End point description
    The patient captured night-time awakenings (yes/no) and the use of rescue medication during these awakenings (yes/no) each morning in the Asthma Daily Diary. Night-time awakenings (percentage) was defined as the number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data. The change from baseline in bi-weekly means (percentage) night-time awakenings due to asthma requiring rescue medication use at Week 52 is presented. Only patients with data available at the timepoints of testing were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) and Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    346
    357
    357
    Units: Percentage of nights with awakenings
        arithmetic mean (standard deviation)
    -37.63 ± 37.27
    -35.17 ± 37.49
    -36.00 ± 36.69
    Statistical analysis title
    Mean change from baseline in % of awakenings
    Statistical analysis description
    Tralo 300 mg Q2W vs placebo. REML based repeated measures analysis.
    Comparison groups
    Tralo 300 mg Q2W v Placebo
    Number of subjects included in analysis
    703
    Analysis specification
    Pre-specified
    Analysis type
    superiority [21]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    -1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.29
         upper limit
    1.69
    Notes
    [21] - Fixed categorical effects of baseline number (%) of awakenings, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.
    Statistical analysis title
    Mean change from baseline in % of awakenings
    Statistical analysis description
    Tralo 300 mg Q4W vs placebo. REML based repeated measures analysis.
    Comparison groups
    Tralo 300 mg Q4W v Placebo
    Number of subjects included in analysis
    714
    Analysis specification
    Pre-specified
    Analysis type
    superiority [22]
    Method
    Parameter type
    LS Mean difference
    Point estimate
    -2.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.84
         upper limit
    1.12
    Notes
    [22] - Fixed categorical effects of baseline number (%) of awakenings, treatment group, geographical region, age group, periostin group, visit and treatment-by-visit interaction and number of asthma exacerbations in year before study as a fixed covariate.

    Secondary: Number of patients with ≥1 asthma exacerbation up to Week 52

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    End point title
    Number of patients with ≥1 asthma exacerbation up to Week 52
    End point description
    The number of patients with ≥1 asthma exacerbation up to Week 52 is presented.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    398
    404
    400
    Units: Participants
    128
    124
    133
    Statistical analysis title
    Proportion of patients ≥ 1 asthma exacerbations
    Statistical analysis description
    Tralo 300 mg Q2W vs placebo.
    Comparison groups
    Tralo 300 mg Q2W v Placebo
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    = 0.732
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.95
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.71
         upper limit
    1.28
    Notes
    [23] - The estimate of each odds ratio was obtained from two separate models, from a Cochran-Mantel-Haenszel test controlling for geographical region, age group and periostin group at baseline.
    Statistical analysis title
    Proportion of patients ≥ 1 asthma exacerbations
    Statistical analysis description
    Tralo 300 mg Q4W vs placebo.
    Comparison groups
    Tralo 300 mg Q4W v Placebo
    Number of subjects included in analysis
    804
    Analysis specification
    Pre-specified
    Analysis type
    superiority [24]
    P-value
    = 0.421
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.65
         upper limit
    1.19
    Notes
    [24] - The estimate of each odds ratio was obtained from two separate models, from a Cochran-Mantel-Haenszel test controlling for geographical region, age group and periostin group at baseline.

    Secondary: Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questions (WPAI+CIQ): Productivity Loss at Week 52

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    End point title
    Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questions (WPAI+CIQ): Productivity Loss at Week 52
    End point description
    The WPAI+CIQ consists of questions about how asthma and asthma-related issues impact a patient’s ability to work, attend classes and perform regular daily activities. The questionnaire contains 10 questions relating to the patient’s experience over the previous 7 days. The WPAI+CIQ outcomes for productivity loss are presented separately for those currently employed and for those currently in school and are expressed as mean productivity loss (percentage) at Week 52, with higher numbers indicating less productivity. Work Productivity Loss = {Q2/(Q2+Q4)+[(1-Q2/(Q2+Q4))x(Q5/10)]}*100 (Absenteeism = Q2/(Q2+Q4)*100; Presenteeism = (Q5/10)*100). Class Productivity Loss = {Q7/(Q7+Q8) + [(1-Q7/(Q7+Q8))x(Q9/10)]}*100 (Absenteeism = Q7/ (Q7+Q8)*100; Presenteeism = (Q9/10)*100). Note: QX refers to response to question number X on WPAI+CIQ questionnaire. Only patients with data available at the timepoints of testing were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    123
    130
    137
    Units: Percent productivity loss
    arithmetic mean (standard deviation)
        Currently employed (n=112,116,118)
    27.71 ± 24.06
    28.48 ± 25.11
    31.25 ± 25.34
        Currently in school (n=11,14,19)
    33.13 ± 28.03
    31.79 ± 34.28
    32.31 ± 28.46
    No statistical analyses for this end point

    Secondary: WPAI+CIQ: Activity Impairment at Week 52

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    End point title
    WPAI+CIQ: Activity Impairment at Week 52
    End point description
    The WPAI+CIQ consists of questions about how asthma and asthma-related issues impact a patient’s ability to work, attend classes and perform regular daily activities. The questionnaire contains 10 questions relating to the patient’s experience over the previous 7 days. The WPAI+CIQ outcomes for activity impairment are presented separately for those currently employed and for those currently in school and are expressed as mean impairment percentages at Week 52, with higher numbers indicating greater impairment. Activity impairment = (Q10/10)*100. Note: QX refers to response to question number X on WPAI+CIQ questionnaire. Only patients with data available at the timepoints of testing were included in the analysis.
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    134
    135
    146
    Units: Percent Impairment
    arithmetic mean (standard deviation)
        Currently employed (n=120,119,127)
    23.25 ± 21.31
    23.53 ± 22.57
    27.01 ± 23.21
        Currently in school (n=14,16,19)
    29.29 ± 20.56
    27.50 ± 29.55
    28.95 ± 23.07
    No statistical analyses for this end point

    Secondary: Asthma-related healthcare encounters by type up to Week 52

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    End point title
    Asthma-related healthcare encounters by type up to Week 52
    End point description
    Broad-based healthcare utilisation asthma-related event information was collected by the Investigator/authorised delegate at each visit. At Visit 1, healthcare resource utilisation information was collected with a 1-year recall period; subsequent visits collected information with a recall period of ‘since the last scheduled visit’. Total number of times the healthcare encounter occurred was calculated across all patients for each of the following categories: • Ambulance transport, • Emergency room visits, • Unscheduled outpatient visits (visit to specialist and/or visit to primary healthcare physician and/or other healthcare visit), • Home visits (home visit, physician and/or other healthcare professional), • Telephone calls (telephone calls to physician and/or nurse), and • Advanced pulmonary function test.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    398
    404
    400
    Units: Encounters
        Ambulance transport
    5
    15
    16
        Emergency room visits
    59
    87
    64
        Unscheduled outpatient visits
    1750
    1786
    1705
        Home visits
    21
    5
    6
        Telephone calls
    515
    463
    198
        Advanced pulmonary function test
    84
    70
    67
    No statistical analyses for this end point

    Secondary: Asthma-related healthcare encounters by type up to Week 52: Hospitalisations

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    End point title
    Asthma-related healthcare encounters by type up to Week 52: Hospitalisations
    End point description
    Broad-based healthcare utilisation asthma-related event information was collected by the Investigator/authorised delegate at each visit. At Visit 1, healthcare resource utilisation information was collected with a 1-year recall period; subsequent visits collected information with a recall period of ‘since the last scheduled visit’. Total number of days spent in hospital was calculated across all patients for the following healthcare encounter category: • Hospitalisations (hospitalisations, intensive care and/or general care).
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    398
    404
    400
    Units: Days
    270
    345
    482
    No statistical analyses for this end point

    Secondary: Asthma-related healthcare encounters by type up to Week 52: Spirometry

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    End point title
    Asthma-related healthcare encounters by type up to Week 52: Spirometry
    End point description
    Broad-based healthcare utilisation asthma-related event information was collected by the Investigator/authorised delegate at each visit. At Visit 1, healthcare resource utilisation information was collected with a 1-year recall period; subsequent visits collected information with a recall period of ‘since the last scheduled visit’. Total number of assessments was calculated across all patients for the following healthcare encounter category: • Spirometry.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) up to Week 52
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    398
    404
    400
    Units: Assessments
    489
    520
    502
    No statistical analyses for this end point

    Secondary: Serum trough concentration (Ctrough) of tralokinumab during the study period up to Week 72

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    End point title
    Serum trough concentration (Ctrough) of tralokinumab during the study period up to Week 72 [25]
    End point description
    To evaluate the pharmacokinetics (PK), pre-dose blood samples were collected at each visit and tralokinumab concentrations in serum were determined. Mean Ctrough concentrations are presented at each indicated visit up to Week 72. All patients in the full analysis set who received tralokinumab and who had PK blood samples were included in the PK analysis set. Only patients with data available at the timepoints of testing were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Blood samples were collected pre-dose at Baseline (Week 0), and at Week 4, Week 8, Week 26, Week 52 and Week 72 (follow-up)
    Notes
    [25] - 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: The baseline period arms were ‘Tralo 300 mg Q2W’, ‘Tralo 300 mg Q4W’ and ‘Placebo’. Since this particular end point presents pharmacokinetic data of tralokinumab, it was not applicable to select the Placebo arm for the analysis.
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W
    Number of subjects analysed
    394 [26]
    401 [27]
    Units: micrograms/millilitre
    geometric mean (geometric coefficient of variation)
        Baseline (n=394,401)
    99999999 ± 99999999
    99999999 ± 99999999
        Week 4 (n=353,353)
    34.690 ± 199.269
    13.151 ± 188.026
        Week 8 (n=358,366)
    55.262 ± 159.824
    19.243 ± 112.830
        Week 26 (n=358,370)
    52.766 ± 257.341
    30.305 ± 255.039
        Week 52 (n=354,373)
    37.074 ± 675.764
    14.290 ± 437.472
        Week 72 (follow-up) (n=339,356)
    0.419 ± 238.749
    0.172 ± 171.973
    Notes
    [26] - 99999999 denotes that the value was not calculable.
    [27] - 99999999 denotes that the value was not calculable.
    No statistical analyses for this end point

    Secondary: Incidence rate of positive anti-drug antibodies (ADAs) including the characterisation of their neutralising potential

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    End point title
    Incidence rate of positive anti-drug antibodies (ADAs) including the characterisation of their neutralising potential
    End point description
    ADA assessments performed using a tiered approach (screening, confirmatory and titering assays). Confirmed ADA positive samples were also tested for neutralising antibodies (nAb). ADA prevalence defined as proportion of study population with drug-reactive antibodies at any point in time. ADA incidence (treatment-emergent ADA) defined as sum of treatment-induced (post-baseline ADA positive only) and treatment-boosted ADA. Persistently positive defined as positive at ≥2 post-baseline assessments (with ≥16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive defined as having ≥1 post-baseline ADA positive assessment and not fulfilling conditions of persistently positive. Treatment-boosted ADA defined as baseline positive ADA titer boosted to a 4-fold or higher level following drug administration. In some category titles 'positive' is denoted by 'pos'. Only patients with data available at timepoints of testing included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0), Week 26, Week 56 (follow-up) and Week 72 (follow-up)
    End point values
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Number of subjects analysed
    373
    382
    374
    Units: Participants
        ADA prevalence|
    7
    7
    9
        ADA incidence
    3
    2
    3
        ADA positive at baseline
    4
    5
    7
        ADA positive post-baseline
    3
    3
    8
        ADA pos post-baseline & pos at baseline
    0
    1
    6
        ADA pos post-baseline & not detected at baseline
    3
    2
    2
        ADA not detected post-baseline & pos at baseline
    4
    4
    1
        Persistent Positive
    2
    2
    7
        Transient Positive
    1
    1
    1
        Treatment-boosted ADA
    0
    0
    1
        nAB positive at any visit
    5
    5
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious and non-serious adverse event (AE) data reported for the treatment period, from baseline (Week 0) to end of treatment (Week 52). Deaths (all causes) is reported for the overall study period (including the extended follow-up period), up to Week 72.
    Adverse event reporting additional description
    Treatment-emergent AEs were defined with an onset date ≥ the first day of IP and ≤ (the last day of IP + dosing frequency). 'Dosing frequency’ was 2 or 4 weeks depending on whether patients were randomised to Q2W or Q4W dosing regimens. Patient population was safety analysis set which included all patients who received at least one dose of any IP.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Tralo 300 mg Q2W
    Reporting group description
    Tralokinumab 300 mg administered subcutaneously Q2W over a 52-week treatment period (up to 26 doses). Follow-up visits were conducted at Weeks 56 and 72.

    Reporting group title
    Tralo 300 mg Q4W
    Reporting group description
    Tralokinumab 300 mg administered subcutaneously Q4W over a 52-week treatment period (up to 13 doses). Follow-up visits were conducted at Weeks 56 and 72.

    Reporting group title
    Placebo
    Reporting group description
    Placebo was administered subcutaneously over a 52-week treatment period. The placebo treatment group is a pooled treatment group (placebo Q2W + placebo Q4W) where the 2 placebo cohorts were given weights proportional to the number of patients in each cohort. Follow-up visits were conducted at Weeks 56 and 72.

    Serious adverse events
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 398 (10.05%)
    39 / 404 (9.65%)
    48 / 400 (12.00%)
         number of deaths (all causes)
    2
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 398 (0.25%)
    1 / 404 (0.25%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Uterine cancer
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Eosinophilic granulomatosis with polyangiitis
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    0 / 400 (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
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Hallucination
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    0 / 400 (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
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    0 / 400 (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
    Metrorrhagia
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Prostatitis
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Humerus fracture
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 404 (0.00%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Limb injury
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    0 / 400 (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
    Femur fracture
         subjects affected / exposed
    1 / 398 (0.25%)
    1 / 404 (0.25%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Post procedural complication
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    0 / 400 (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
    Post-traumatic pain
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    2 / 400 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Cardiac failure
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Cardiac failure acute
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Cardiac failure congestive
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Coronary artery disease
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Sinus node dysfunction
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    0 / 400 (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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    12 / 398 (3.02%)
    19 / 404 (4.70%)
    25 / 400 (6.25%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 23
    0 / 39
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Dyspnoea
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal oedema
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Radiculopathy
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 404 (0.00%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    0 / 400 (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
    Dizziness
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Vascular encephalopathy
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    0 / 400 (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
    Vertebrobasilar insufficiency
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 398 (0.00%)
    2 / 404 (0.50%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erosive duodenitis
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Swollen tongue
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 398 (0.50%)
    0 / 404 (0.00%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 398 (0.00%)
    2 / 404 (0.50%)
    0 / 400 (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
    Ankylosing spondylitis
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    0 / 400 (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
    Arthralgia
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteochondrosis
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    0 / 400 (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
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Synovitis
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    0 / 400 (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
    Trigger finger
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Hypokalaemia
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Hypovolaemia
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Chronic sinusitis
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    0 / 400 (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
    Peritonitis
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    0 / 400 (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
    Appendicitis
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Bronchitis
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 398 (0.00%)
    0 / 404 (0.00%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 398 (0.75%)
    3 / 404 (0.74%)
    4 / 400 (1.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    0 / 400 (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
    Pyelonephritis
         subjects affected / exposed
    1 / 398 (0.25%)
    0 / 404 (0.00%)
    0 / 400 (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
    Pyelonephritis acute
         subjects affected / exposed
    0 / 398 (0.00%)
    1 / 404 (0.25%)
    1 / 400 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    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
    Tralo 300 mg Q2W Tralo 300 mg Q4W Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    134 / 398 (33.67%)
    145 / 404 (35.89%)
    107 / 400 (26.75%)
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    35 / 398 (8.79%)
    33 / 404 (8.17%)
    28 / 400 (7.00%)
         occurrences all number
    55
    43
    45
    Nervous system disorders
    Headache
         subjects affected / exposed
    23 / 398 (5.78%)
    31 / 404 (7.67%)
    17 / 400 (4.25%)
         occurrences all number
    35
    42
    28
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    24 / 398 (6.03%)
    12 / 404 (2.97%)
    0 / 400 (0.00%)
         occurrences all number
    58
    29
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    20 / 398 (5.03%)
    23 / 404 (5.69%)
    18 / 400 (4.50%)
         occurrences all number
    29
    27
    24
    Upper respiratory tract infection
         subjects affected / exposed
    26 / 398 (6.53%)
    48 / 404 (11.88%)
    36 / 400 (9.00%)
         occurrences all number
    40
    61
    73
    Viral upper respiratory tract infection
         subjects affected / exposed
    44 / 398 (11.06%)
    48 / 404 (11.88%)
    37 / 400 (9.25%)
         occurrences all number
    62
    67
    55

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Sep 2014
    - Change in Forced Vital Capacity and Forced Expiratory Flow 25-75% were added as exploratory variables. - Death events were included in the adjudication process. - Additional samples were added for PK analysis to allow more extensive characterisation of the PK-pharmacodynamic relationship for tralokinumab. - Inclusion criteria were amended for the following reasons: to increase lower weight limit for adolescents to 40 kg; to clarify calculation of total daily ICS dose; to clarify what constitutes acceptable documentation to support patient eligibility; to make the protocol consistent with standard of care across included regions; to clarify the washout period for BD prior to the pre-BD FEV1 test and the reversibility test. - To allow use of selective β-adrenergic antagonists. - Exclusion criteria were amended to include 5-lipoxygenase inhibitors (eg, Zileuton) and roflumilast as restricted medications and to disallow bronchial thermoplasty before study entry or during the study. - Asthma medication restrictions were amended to allow background asthma therapy according to local standard of care; to clarify the use of once daily asthma medications and to clarify the restrictions on BDs. - Safety analysis set definition was revised. - Testing strategy for primary and key secondary objectives was revised.
    23 Feb 2015
    - Clinical - Global Impression of Change assessment was added to obtain an early indicator of subjects’ response to treatment. - Evaluation of cardiovascular, cerebrovascular and malignancy adverse events occurring after randomisation were added to the adjudication committee responsibilities as a result of sponsor decision to proactively implement independent adjudication of these across all Phase 3 studies conducted with human antibodies in patients with severe asthma.
    08 Oct 2015
    - Dosing requirements and restrictions were clarified.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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