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    Clinical Trial Results:
    A phase IIa, randomized, double-blind, placebo controlled, parallel group study to assess the safety and efficacy of subcutaneously administered BI 655066/ABBV-066 (risankizumab) as add-on therapy over 24 weeks in patients with severe persistent asthma.

    Summary
    EudraCT number
    		 2014-004932-20
    Trial protocol
    		 BE   GB   HU   NL   DE   PL   IT  
    Global end of trial date
    02 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Feb 2019
    First version publication date
    17 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1311.14
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02443298
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of the study were as follows: 1. Evaluate the safety, efficacy, and pharmacokinetics (PK) of risankizumab as compared to placebo in patients with severe persistent asthma, and 2. Evaluate treatment response as a function of the known clinical phenotypes and exploratory endotypes to inform a companion diagnostic stratification biomarker able to predict treatment response in further clinical studies.
    Protection of trial subjects
    Only patients that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All patients were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all patients was adhered to throughout the trial conduct.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Aug 2015
    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
    Belgium: 18
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    France: 21
    Country: Number of subjects enrolled
    Germany: 81
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Poland: 64
    Country: Number of subjects enrolled
    Korea, Republic of: 23
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    United Kingdom: 32
    Country: Number of subjects enrolled
    United States: 113
    Worldwide total number of subjects
    369
    EEA total number of subjects
    222
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    300
    From 65 to 84 years
    69
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a randomized, double-blind, placebo-controlled, parallel-group multicenter study to assess the efficacy and safety of risankizumab, an IL-23p19 monoclonal antibody, compared to placebo in patients with severe persistent asthma.

    Pre-assignment
    Screening details
    		 All patients were screened for eligibility to participate in the trial. Patients attended a specialist sites which ensured that they (the patients) met all strictly implemented inclusion/exclusion criteria. Patients were not to be randomized to trial treatment if any one of the specific entry criteria was violated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Assessor
    Blinding implementation details
    This was a randomized, double-blind, placebo-controlled, parallel-group multi-center study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Risankizumab
    Arm description
    		 Patients received subcutaneous injection of 1 milliliter (mL) prefilled syringe with 90 milligram/ milliliter (mg/mL) risankizumab once every 4 weeks (weeks 0, 4, 8, 12, 16, 20)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Risankizumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients received subcutaneous injection of 1 milliliter (mL) prefilled syringe with 90 milligram/ milliliter (mg/mL) risankizumab once every 4 weeks (weeks 0, 4, 8, 12, 16, 20)

    Arm title
    		 Placebo
    Arm description
    		 Patients received subcutaneous injection of 1 milliliter (mL) prefilled syringe consisting of matching placebo to risankizumab once every 4 weeks (weeks 0, 4, 8, 12, 16, 20)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients received subcutaneous injection of 1 milliliter (mL) prefilled syringe consisting of matching placebo to risankizumab once every 4 weeks (weeks 0, 4, 8, 12, 16, 20)

    Number of subjects in period 1 [1]
    		Risankizumab Placebo
    Started
    105
    109
    Completed
    101
    104
    Not completed
    4
    5
         Consent withdrawn by subject
    1
    2
         Adverse event, non-fatal
    3
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on the patients who had successfully completed the screening and received at least one of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Risankizumab
    Reporting group description
    		 Patients received subcutaneous injection of 1 milliliter (mL) prefilled syringe with 90 milligram/ milliliter (mg/mL) risankizumab once every 4 weeks (weeks 0, 4, 8, 12, 16, 20)

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received subcutaneous injection of 1 milliliter (mL) prefilled syringe consisting of matching placebo to risankizumab once every 4 weeks (weeks 0, 4, 8, 12, 16, 20)

    Reporting group values
    		 Risankizumab Placebo Total
    Number of subjects
    		 105 109 214
    Age categorical
    Units: Subjects
    Age Continuous
    Randomized Set (RS): This patient set included all randomized patients, whether treated or not.
    Units: years
        arithmetic mean (standard deviation)
    		 54.1 ± 11.3 52.3 ± 12.5 -
    Sex: Female, Male
    Randomized Set (RS): This patient set included all randomized patients, whether treated or not.
    Units: Subjects
        Female
    		 69 64 133
        Male
    		 36 45 81
    Race (NIH/OMB)
    Randomized Set (RS): This patient set included all randomized patients, whether treated or not.
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 11 11 22
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 9 8 17
        White
    		 84 88 172
        More than one race
    		 1 1 2
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Randomized Set (RS): This patient set included all randomized patients, whether treated or not.
    Units: Subjects
        Hispanic or Latino
    		 3 3 6
        Not Hispanic or Latino
    		 102 106 208
        Unknown or Not Reported
    		 0 0 0
    Oral corticosteroid (OCS) use at baseline
    Randomized Set (RS): This patient set included all randomized patients, whether treated or not.
    Units: Subjects
        Use of OCS at baseline - Yes
    		 15 17 32
        Use of OCS at baseline - No
    		 90 92 182
    Baseline Morning peak expiratory flow (PEF)
    Randomized Set (RS): This patient set included all randomized patients, whether treated or not.
    Units: Liter/Minute (L/min)
        arithmetic mean (standard deviation)
    		 299.34 ± 110.50 309.56 ± 115.34 -
    Baseline 24 Hour Rescue Medication Use
    Baseline 24 Hour Rescue Medication Use: Average over the 14 days prior to randomization. Randomized Set (RS): This patient set included all randomized patients, whether treated or not.
    Units: Puff
        arithmetic mean (standard deviation)
    		 3.17 ± 3.81 3.89 ± 4.78 -
    Baseline First 5 questions of the Asthma Control Questionnaire (ACQ5) Score
    Randomized Set (RS): This patient set included all randomized patients, whether treated or not.
    Units: Unit on scale
        arithmetic mean (standard deviation)
    		 2.15 ± 1.15 2.39 ± 1.17 -

    End points

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    End points reporting groups
    Reporting group title
    Risankizumab
    Reporting group description
    		 Patients received subcutaneous injection of 1 milliliter (mL) prefilled syringe with 90 milligram/ milliliter (mg/mL) risankizumab once every 4 weeks (weeks 0, 4, 8, 12, 16, 20)

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received subcutaneous injection of 1 milliliter (mL) prefilled syringe consisting of matching placebo to risankizumab once every 4 weeks (weeks 0, 4, 8, 12, 16, 20)

    Primary: Time to first asthma worsening during the planned 24 week treatment period

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    End point title
    		 Time to first asthma worsening during the planned 24 week treatment period
    End point description
    Time to first asthma worsening during the planned 24 week treatment period: Asthma worsening was defined as the occurrence of any one of the following four criteria: a) Decrease from baseline of ≥30% in morning peak expiratory flow (PEF) on at least 2 consecutive days. b) Increase from baseline of ≥50% and an increase of least 4 puffs in daily use of rescue medication for at least 2 consecutive days. c) Increase from baseline of ≥0.75 units in ACQ5. d) Severe asthma exacerbations defined as initiation of systemic corticosteroids (prednisone or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a total daily dose of ≥ 20 mg for three or more consecutive days was considered a severe asthma exacerbation. Full Analysis Set (FAS): All randomized patients who received at least one dose of treatment.
    End point type
    Primary
    End point timeframe
    24 weeks
    End point values
    		 Risankizumab Placebo
    Number of subjects analysed
    105 [1]
    109 [2]
    Units: Days
        median (confidence interval 80%)
    40.00 (30.00 to 52.00)
    85.50 (63.00 to 131.00)
    Notes
    [1] - FAS
    [2] - FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This was analyzed by using a Cox proportional hazards model that included treatment and the stratification factor of OCS use at baseline as fixed effects. Comparison of Risankizumab to Placebo
    Comparison groups
    Risankizumab v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0255
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.46
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 1.18
         upper limit
    		 1.81

    Secondary: Time to first asthma worsening during the planned 24 week treatment period according to alternative definition

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    End point title
    		 Time to first asthma worsening during the planned 24 week treatment period according to alternative definition
    End point description
    Time to first asthma worsening during the planned 24 week treatment period according to alternative definition: Asthma worsening was defined as the occurrence of any one of the following four criteria: a) Decrease from baseline of ≥30% in morning peak expiratory flow (PEF) on at least 2 consecutive days. b) Increase from baseline of ≥50% and an increase of least 4 puffs in daily use of rescue medication for at least 2 consecutive days. c) Increase from baseline of ≥0.5 units in ACQ5. d) Severe asthma exacerbations defined as initiation of systemic corticosteroids (prednisone or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a total daily dose of ≥ 20 mg for three or more consecutive days was considered a severe asthma exacerbation. Full Analysis Set (FAS): All randomized patients who received at least one dose of treatment.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Risankizumab Placebo
    Number of subjects analysed
    105 [3]
    109 [4]
    Units: Days
        median (confidence interval 80%)
    20.00 (16.00 to 25.00)
    37.00 (31.00 to 45.00)
    Notes
    [3] - FAS
    [4] - FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    This was analyzed by using a Cox proportional hazards model that included treatment and the stratification factor of OCS use at baseline as fixed effects. Comparison of Risankizumab to Placebo.
    Comparison groups
    Risankizumab v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0131
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.47
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 1.79

    Secondary: Annualized rate of asthma worsening during the planned 24 week treatment period

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    End point title
    		 Annualized rate of asthma worsening during the planned 24 week treatment period
    End point description
    Annualized rate of asthma worsening during the planned 24 week treatment period. Asthma worsening was defined as the occurrence of any one of the following four criteria: a) Decrease from baseline of ≥30% in morning peak expiratory flow (PEF) on at least 2 consecutive days. b) Increase from baseline of ≥50% and an increase of least 4 puffs in daily use of rescue medication for at least 2 consecutive days. c) Increase from baseline of ≥0.75 units in ACQ5. d) Severe asthma exacerbations defined as initiation of systemic corticosteroids (prednisone or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a total daily dose of ≥ 20 mg for three or more consecutive days was considered a severe asthma exacerbation. Mean is Annualized rate. Full Analysis Set (FAS): All randomized patients who received at least one dose of treatment.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Risankizumab Placebo
    Number of subjects analysed
    105 [5]
    109 [6]
    Units: Days
        arithmetic mean (standard error)
    4.8412 ± 0.577
    3.2410 ± 0.401
    Notes
    [5] - FAS
    [6] - FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Annualized rate is obtained from fitting a negative binomial regression including logarithm of the exposure as an offset, treatment, and OCS use at baseline as covariate. Comparison of Risankizumab to Placebo
    Comparison groups
    Risankizumab v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0065
    Method
    		 Negative binomial regression
    Parameter type
    		 Rate Ratio
    Point estimate
    1.4937
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 1.2366
         upper limit
    		 1.8044
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.22

    Secondary: Time to first severe asthma exacerbation during the planned 24 week treatment period

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    End point title
    		 Time to first severe asthma exacerbation during the planned 24 week treatment period
    End point description
    Time to first severe asthma exacerbation during the planned 24 week treatment period. Severe asthma exacerbation was defined as initiation of systemic corticosteroids (prednisone or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a total daily dose of ≥ 20 mg for three or more consecutive days was considered a severe asthma exacerbation. Full Analysis Set (FAS): All randomized patients who received at least one dose of treatment. 99999 = not estimable due to an insufficient numbers of patient with an event
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Risankizumab Placebo
    Number of subjects analysed
    105 [7]
    109 [8]
    Units: Days
        median (confidence interval 80%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [7] - FAS
    [8] - FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Time to first event is obtained from fitting a Cox proportional−hazards model including treatment, and OCS use at baseline as covariate. Comparison of Risankizumab to Placebo.
    Comparison groups
    Risankizumab v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4619
    Method
    		 Cox proportional hazards model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.18
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.57

    Secondary: Annualized rate of severe asthma exacerbation during the planned 24-week treatment period

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    End point title
    		 Annualized rate of severe asthma exacerbation during the planned 24-week treatment period
    End point description
    Annualized rate of severe asthma exacerbation during the planned 24-week treatment period. Severe asthma exacerbation was defined as initiation of systemic corticosteroids (prednisone or equivalent) for 3 or more consecutive days for asthma. Additionally, for subjects on maintenance systemic corticosteroids, at least doubling of the maintenance dose resulting in a total daily dose of ≥ 20 mg for three or more consecutive days was considered a severe asthma exacerbation. Mean is Annualized rate. Full Analysis Set (FAS): All randomized patients who received at least one dose of treatment.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Risankizumab Placebo
    Number of subjects analysed
    105 [9]
    109 [10]
    Units: Days
        arithmetic mean (standard error)
    1.5901 ± 0.257
    1.4051 ± 0.228
    Notes
    [9] - FAS
    [10] - FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Annualized rate is obtained from fitting a negative binomial regression including logarithm of the exposure as an offset, treatment, and OCS use at baseline as covariate. Comparison of Risankizumab to Placebo.
    Comparison groups
    Risankizumab v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.555
    Method
    		 Negative binomial regression
    Parameter type
    		 Rate Ratio
    Point estimate
    1.1317
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.8652
         upper limit
    		 1.4803
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.237

    Secondary: Trough forced expiratory volume in 1 second (FEV1) in-clinic change from baseline at week 24

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    End point title
    		 Trough forced expiratory volume in 1 second (FEV1) in-clinic change from baseline at week 24
    End point description
    Trough forced expiratory volume in 1 second (FEV1) in-clinic change from baseline at week 24. Full Analysis Set (FAS): All randomized patients who received at least one dose of treatment. One patient not included in the analysis due to missing baseline value. Number of patients with either baseline or on-treatment data at the respective week and does not require having both.
    End point type
    Secondary
    End point timeframe
    Baseline and 24 weeks
    End point values
    		 Risankizumab Placebo
    Number of subjects analysed
    105 [11]
    109 [12]
    Units: Liter (L)
        least squares mean (standard error)
    -0.052 ± 0.036
    -0.013 ± 0.035
    Notes
    [11] - FAS
    [12] - FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect repeated measures (MMRM) model including treatment, OCS use at baseline, test day, treatment−by−test day interaction, baseline, and baseline−by−test day interaction as covariates patient as a random effect. Unstructured covariance structure for within−patient variation. Comparison of Risankizumab to Placebo.
    Comparison groups
    Risankizumab v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4423
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.039
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.104
         upper limit
    		 0.026
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.051

    Secondary: Post-bronchodilator forced expiratory volume in 1 second (FEV1) in-clinic change from baseline at week 24

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    End point title
    		 Post-bronchodilator forced expiratory volume in 1 second (FEV1) in-clinic change from baseline at week 24
    End point description
    Post-bronchodilator forced expiratory volume in 1 second (FEV1) in-clinic change from baseline at week 24. FAS: All randomized patients who received at least one dose of treatment. One patient not included in the analysis due to missing baseline value and one patient not included in the analysis due to missing on-treatment data. Number of patients with either baseline or on-treatment data at the respective week and does not require having both.
    End point type
    Secondary
    End point timeframe
    Baseline and 24 weeks
    End point values
    		 Risankizumab Placebo
    Number of subjects analysed
    105 [13]
    109 [14]
    Units: Liter (L)
        least squares mean (standard error)
    -0.097 ± 0.032
    -0.030 ± 0.032
    Notes
    [13] - FAS
    [14] - FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting a mixed effect repeated measures (MMRM) model including treatment, OCS use at baseline, test day, treatment−by−test day interaction, baseline, and baseline−by−test day interaction as covariates patient as a random effect. Unstructured covariance structure for within−patient variation. Comparison of Risankizumab to Placebo.
    Comparison groups
    Risankizumab v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1377
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.068
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -0.126
         upper limit
    		 -0.009
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.045

    Secondary: Weekly Asthma Control Questionaire score at week 24

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    End point title
    		 Weekly Asthma Control Questionaire score at week 24
    End point description
    Weekly Asthma Control Questionaire score at week 24. Full Analysis Set (FAS): All randomized patients who received at least one dose of treatment. Ten patients excluded from the analysis due to missing data at week 24.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Risankizumab Placebo
    Number of subjects analysed
    105 [15]
    109 [16]
    Units: Unit on Scale
        least squares mean (standard error)
    1.857 ± 0.099
    1.708 ± 0.099
    Notes
    [15] - FAS
    [16] - FAS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The adjusted mean (SE) are obtained from fitting an analysis of covariance (ANCOVA) model separately for each week including treatment, OCS use at baseline, and baseline as covariates. The weekly averages of daily measurements are calculated before fitting the model. Comparison of Risankizumab to Placebo.
    Comparison groups
    Risankizumab v Placebo
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1985
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.149
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.297
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.115

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the administration of first dose of study medication until 16 weeks after last dose of study medication, up to 40 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Risankizumab
    Reporting group description
    		 Patients received subcutaneous injection of 1 milliliter (mL) prefilled syringe with 90 milligram/ milliliter (mg/mL) risankizumab once every 4 weeks (weeks 0, 4, 8, 12, 16, 20)

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received subcutaneous injection of 1 milliliter (mL) prefilled syringe consisting of matching placebo to risankizumab once every 4 weeks (weeks 0, 4, 8, 12, 16, 20)

    Serious adverse events
    		 Risankizumab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 105 (13.33%)
    21 / 109 (19.27%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Electrocardiogram T wave abnormal
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dyskinesia
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Sudden hearing loss
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    6 / 105 (5.71%)
    5 / 109 (4.59%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthmatic crisis
         subjects affected / exposed
    1 / 105 (0.95%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 105 (0.95%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 105 (0.95%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 105 (0.95%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 105 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Risankizumab Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    84 / 105 (80.00%)
    80 / 109 (73.39%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    9 / 105 (8.57%)
    3 / 109 (2.75%)
         occurrences all number
    10
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 105 (6.67%)
    6 / 109 (5.50%)
         occurrences all number
    10
    13
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    65 / 105 (61.90%)
    58 / 109 (53.21%)
         occurrences all number
    153
    145
    Dyspnoea
         subjects affected / exposed
    6 / 105 (5.71%)
    7 / 109 (6.42%)
         occurrences all number
    9
    18
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 105 (0.00%)
    6 / 109 (5.50%)
         occurrences all number
    0
    6
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    11 / 105 (10.48%)
    9 / 109 (8.26%)
         occurrences all number
    11
    10
    Nasopharyngitis
         subjects affected / exposed
    11 / 105 (10.48%)
    22 / 109 (20.18%)
         occurrences all number
    12
    31
    Sinusitis
         subjects affected / exposed
    6 / 105 (5.71%)
    3 / 109 (2.75%)
         occurrences all number
    6
    5
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 105 (8.57%)
    10 / 109 (9.17%)
         occurrences all number
    10
    13
    Urinary tract infection
         subjects affected / exposed
    5 / 105 (4.76%)
    6 / 109 (5.50%)
         occurrences all number
    6
    7

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2015
    Total number of patients changed from 300 to 270; total number of patients in each arm changed from 150 to 135. Converted Visit 11 at week 36 to a phone visit. Removed Asthma Quality of Life Questionnaire (AQLQ) administration and endpoints related to AQLQ. Decreased frequency of blood collection for biomarkers and genotyping. Decreased number of patients to be enrolled in the Bronchoscopy Sub-study from approximately 25 patients in each group to 15 patients in each group. Added serum pregnancy test at Visit 1B. Inclusion Criterion 6 (severe asthma exacerbation) changed to be consistent with American Thoracic Society/European Respiratory Society (ATS/ERS) definitions. Exclusion Criterion 12 (description of birth control use) changed to align with local regulations. Added Exclusion Criterion 20 (exclusion of patients at high risk for allergy/hypersensitivity). Added criterion for investigator to discontinue patients from study for unexpected medical conditions that could compromise patient safety. Added that patients on anticoagulation therapy were not to undergo bronchoscopy procedures. Bronchial wash added to bronchoscopy procedure and storage/shipping conditions clarified. Clarifications on the planned assessments taken during the bronchoscopy procedure. Brief description of biomarker analyses added. Additional revisions included administrative updates and clarifications.
    04 Dec 2015
    Clarification in Exclusion Criterion 12 (description of birth control use)
    11 Jul 2016
    BI 655066 changed to risankizumab throughout document. Clarification of Screening Period. Total number of patients entered changed from 270 to 200; patients in each treatment group changed from 135 to 100. Modified reversibility criteria to align with current Global Initiative for Asthma guidelines and current practice for reversibility testing. Changed requirement for stable medication prior to screening from 6 weeks to 4 weeks. Changed Inclusion Criterion 6 to allow entry of patients with history of less than 2 asthma exacerbations in previous year but having asthma that was not adequately controlled. Additional instructions provided for reversibility testing. Additional revisions included administrative updates and clarifications.
    13 Oct 2016
    Product name changed to reflect change in license agreement with new US sponsor, AbbVie. Changes in reference to Sponsor from BI to AbbVie in US and BI for all other participating countries.
    17 Aug 2017
    Addition of alternative definitions 1 and 2 for asthma worsening. Addition of secondary and further endpoints. Asthma worsening criteria modified from increase of 0.5 units to 0.75 units. Statistical model for analysis of primary, secondary, and further endpoints was modified to only include one stratification factor: OCS use at baseline as a fixed effect. Revisions to reflect updates to the Investigator’s Brochure.

    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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