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    Clinical Trial Results:
    A Phase II, Randomized, Double-blind, Placebo-controlled Bronchoscopy Study to Evaluate the Effects of Lebrikizumab on Airway Eosinophilic Inflammation in Patients with Uncontrolled Asthma on Inhaled Corticosteroids and a Second Controller Medication

    Summary
    EudraCT number
    		 2014-000275-14
    Trial protocol
    		 SE   IE   GB  
    Global end of trial date
    13 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Oct 2017
    First version publication date
    21 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GB29260
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02099656
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.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
    13 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to evaluate the effect of lebrikizumab in reducing airway eosinophilic inflammation in subjects with uncontrolled asthma, who are using inhaled corticosteroid (ICS) treatment and a second controller medication, as measured by a relative change in the number of airway submucosal eosinophils per surface area of basal lamina (cells per square millimetre [cells/mm^2]) obtained via endobronchial biopsy at Week 12 compared to baseline.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 Subjects continued their ICS controller therapy, as they were receiving prior to screening, throughout the study. ICS therapy included 500–2000 micrograms per day (mcg/day) of fluticasone propionate dry powder inhaler (DPI) or equivalent. Subjects also continued their second asthma controller therapy, as they were receiving prior to screening, throughout the study. The following second controller medications were included in the study: long-acting beta-agonist (LABA), leukotriene receptor antagonist (LTRA), long-acting muscarinic antagonist (LAMA), or theophylline.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Nov 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    United States: 34
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Sweden: 7
    Worldwide total number of subjects
    64
    EEA total number of subjects
    17
    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)
    63
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects 18-75 years of age (inclusive) with uncontrolled asthma on inhaled corticosteroid (ICS) therapy and on an eligible second controller medication were recruited. The screening period was three weeks and included four visits (Visits 1, 2, 3, and 4a) and a final assessment of eligibility prior to randomisation at Visit 4b.

    Pre-assignment
    Screening details
    		 Asthma had to be diagnosed >/= 12 months before first screening visit. Bronchodilator response, which was defined as >/= 12% relative improvement in forced expiratory volume in 1 second (FEV1) after bronchodilator administration, had to be demonstrated within the 12 months before Visit 1 or at Visit 1, 2, or 3 of screening.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects with uncontrolled asthma on ICS therapy and a second controller medication received subcutaneous (SC) injection of lebrikizumab matching placebo on Days 1 and 8, and on Weeks 4 and 8.
    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
    Matching placebo was administered by SC injection on Day 1, Day 8, Week 4, and Week 8.

    Arm title
    		 Lebrikizumab
    Arm description
    		 Subjects with uncontrolled asthma on inhaled corticosteroids (ICS) therapy and a second controller medication received SC injection of lebrikizumab on Days 1 and 8, and on Weeks 4 and 8.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lebrikizumab
    Investigational medicinal product code
    Other name
    RO5490255
    Pharmaceutical forms
    Solution for injection in pre-filled pen
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lebrikizumab 125 milligrams (mg) was administered by SC injection on Day 1, Day 8, Week 4, and Week 8.

    Number of subjects in period 1
    		Placebo Lebrikizumab
    Started
    33
    31
    Completed
    33
    30
    Not completed
    0
    1
         Refusal to do follow up 2 due to Sponsor info
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with uncontrolled asthma on ICS therapy and a second controller medication received subcutaneous (SC) injection of lebrikizumab matching placebo on Days 1 and 8, and on Weeks 4 and 8.

    Reporting group title
    Lebrikizumab
    Reporting group description
    		 Subjects with uncontrolled asthma on inhaled corticosteroids (ICS) therapy and a second controller medication received SC injection of lebrikizumab on Days 1 and 8, and on Weeks 4 and 8.

    Reporting group values
    		 Placebo Lebrikizumab Total
    Number of subjects
    		 33 31 64
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 33 30 63
        From 65-84 years
    		 0 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.9 ( 12.8 ) 45.9 ( 12.5 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 14 15 29
        Male
    		 19 16 35

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with uncontrolled asthma on ICS therapy and a second controller medication received subcutaneous (SC) injection of lebrikizumab matching placebo on Days 1 and 8, and on Weeks 4 and 8.

    Reporting group title
    Lebrikizumab
    Reporting group description
    		 Subjects with uncontrolled asthma on inhaled corticosteroids (ICS) therapy and a second controller medication received SC injection of lebrikizumab on Days 1 and 8, and on Weeks 4 and 8.

    Primary: Relative Change From Baseline in the Number of Airway Submucosal Eosinophils per Surface Area of Basal Lamina

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    End point title
    		 Relative Change From Baseline in the Number of Airway Submucosal Eosinophils per Surface Area of Basal Lamina
    End point description
    To evaluate the effect of lebrikizumab in reducing airway eosinophilic inflammation the relative change from baseline in the number of airway submucosal eosinophils per surface area of basal lamina (cells per square millimetre [cells/mm^2]) was measured after an endobronchial biopsy was performed. Baseline results are presented as 10^9 cells per square metre (10^9 cells/m^2). Relative change was defined as the absolute change from baseline to Week 12, divided by the value at baseline and presented as percentage. The Primary analysis Patients (PP) population was defined as a subset of subjects from the intent-to-treat (ITT) population who received at least one dose of the study drug, and who had evaluable biopsies available for both baseline (Visit 4a) and Week 12 visits. Subjects were grouped according to actual treatment received.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    25
    26
    Units: percentage change from baseline
    arithmetic mean (standard deviation)
        Baseline, Value at Visit (10^9 cells/m^2)
    0.439 ( 0.418 )
    0.224 ( 0.228 )
        Week 12, Percentage Change from Baseline
    73.9 ( 169.4 )
    75.6 ( 167.8 )
    Statistical analysis title
    		 Placebo versus Lebrikizumab
    Comparison groups
    Placebo v Lebrikizumab
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    7.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -82.5
         upper limit
    		 97.6

    Secondary: Absolute Change From Baseline in Number of Airway Submucosal Eosinophils per Surface Area of Basal Lamina

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    End point title
    		 Absolute Change From Baseline in Number of Airway Submucosal Eosinophils per Surface Area of Basal Lamina
    End point description
    To evaluate the effect of lebrikizumab on airway eosinophilic inflammation the absolute change in the number of airway submucosal eosinophils per surface area of basal lamina (cells/mm^2) was measured after an endobronchial biopsy was performed. Results are presented as 10^9 cells/m^2. The PP population was defined as a subset of subjects from the ITT population who received at least one dose of the study drug, and who had evaluable biopsies available for both baseline (Visit 4a) and Week 12 visits. Subjects were grouped according to actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    25
    26
    Units: 10^9 cells/m^2
    arithmetic mean (standard deviation)
        Baseline, Value at Visit
    0.439 ( 0.418 )
    0.224 ( 0.228 )
        Week 12, Change from Baseline
    -0.017 ( 0.457 )
    0.055 ( 0.212 )
    No statistical analyses for this end point

    Secondary: Relative Change From Baseline in the Number of Airway Epithelial Eosinophils per Surface Area of Basal Lamina

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    End point title
    		 Relative Change From Baseline in the Number of Airway Epithelial Eosinophils per Surface Area of Basal Lamina
    End point description
    To evaluate the effect of lebrikizumab on airway eosinophilic inflammation the relative change in the number of airway epithelial eosinophils per surface area of basal lamina (cells/mm^2) was measured after an endobronchial biopsy was performed. Baseline results are presented as 10^9 cells/m^2. Relative change was defined as the absolute change from baseline to Week 12, divided by the value at baseline and presented as percentage. The PP population was defined as a subset of subjects from the ITT population who received at least one dose of the study drug, and who had evaluable biopsies available for both baseline (Visit 4a) and Week 12 visits. Subjects were grouped according to actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    12
    14
    Units: percentage change from baseline
    arithmetic mean (standard deviation)
        Baseline, Value at Visit (10^9/m^2)
    0.054 ( 0.103 )
    0.045 ( 0.11 )
        Week 12, Percentage Change from Baseline
    -14.5 ( 61.5 )
    45.5 ( 171.1 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Number of Airway Epithelial Eosinophils per Surface Area of Basal Lamina

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    End point title
    		 Absolute Change From Baseline in Number of Airway Epithelial Eosinophils per Surface Area of Basal Lamina
    End point description
    To evaluate the effect of lebrikizumab on airway eosinophilic inflammation the absolute change in the number of airway epithelial eosinophils per surface area of basal lamina (cells/mm^2) was measured after an endobronchial biopsy was performed. Results are presented as 10^9 cells/m^2. The PP population was defined as a subset of subjects from the ITT population who received at least one dose of the study drug, and who had evaluable biopsies available for both baseline (Visit 4a) and Week 12 visits. Subjects were grouped according to actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    12
    14
    Units: 10^9 cells/m^2
    arithmetic mean (standard deviation)
        Baseline, Value at Visit
    0.054 ( 0.103 )
    0.045 ( 0.11 )
        Week 12, Change from Baseline
    -0.031 ( 0.087 )
    -0.01 ( 0.089 )
    No statistical analyses for this end point

    Secondary: Relative Change From Baseline in Number of Airway Submucosal Eosinophils per Volume of Submucosa

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    End point title
    		 Relative Change From Baseline in Number of Airway Submucosal Eosinophils per Volume of Submucosa
    End point description
    To evaluate the effect of lebrikizumab on airway eosinophilic inflammation the relative change in the number of airway submucosal eosinophils per volume of submucosa (cells per cubic millimetre [cells/mm^3]) was measured after an endobronchial biopsy was performed. Baseline results are presented as 10^9 cells/litre (L). Relative change was defined as the absolute change from baseline to Week 12, divided by the value at baseline and presented as percentage. The PP population was defined as a subset of subjects from the ITT population who received at least one dose of the study drug, and who had evaluable biopsies available for both baseline (Visit 4a) and Week 12 visits. Subjects were grouped according to actual treatment received.The number of subjects analysed is indicated by n for each arm at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    25
    26
    Units: percentage change from baseline
    arithmetic mean (standard deviation)
        Baseline, Value at Visit (10^9 cells/L)
    1.567 ( 1.386 )
    1.094 ( 1.056 )
        Week 12, Percentage Change from Baseline
    61.5 ( 157.2 )
    51.2 ( 134 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Number of Airway Submucosal Eosinophils per Volume of Submucosa

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    End point title
    		 Absolute Change From Baseline in Number of Airway Submucosal Eosinophils per Volume of Submucosa
    End point description
    To evaluate the effect of lebrikizumab on airway eosinophilic inflammation the absolute change in the number of airway submucosal eosinophils per volume of submucosa (cells/mm^3) was measured after an endobronchial biopsy was performed. Results are presented as 10^9 cells/L. The PP population was defined as a subset of subjects from the ITT population who received at least one dose of the study drug, and who had evaluable biopsies available for both baseline (Visit 4a) and Week 12 visits. Subjects were grouped according to actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    25
    26
    Units: 10^9 cells/L
    arithmetic mean (standard deviation)
        Baseline, Value at Visit
    1.567 ( 1.386 )
    1.094 ( 1.056 )
        Week 12, Change from Baseline
    0.259 ( 1.313 )
    0.198 ( 0.971 )
    No statistical analyses for this end point

    Secondary: Relative Change From Baseline in Number of Airway Epithelial Eosinophils per Volume of Epithelium

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    End point title
    		 Relative Change From Baseline in Number of Airway Epithelial Eosinophils per Volume of Epithelium
    End point description
    To evaluate the effect of lebrikizumab on airway eosinophilic inflammation the relative change in the number of airway epithelial eosinophils per volume of epithelium (cells/mm^3) was measured after an endobronchial biopsy was performed. Baseline results are presented as 10^9 cells/L. Relative change was defined as the absolute change from baseline to Week 12, divided by the value at baseline and presented as percentage. The PP population was defined as a subset of subjects from the ITT population who received at least one dose of the study drug, and who had evaluable biopsies available for both baseline (Visit 4a) and Week 12 visits. Subjects were grouped according to actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    12
    14
    Units: percentage change from baseline
    arithmetic mean (standard deviation)
        Baseline, Value at Visit (10^9 cells/L)
    1.051 ( 1.234 )
    1.283 ( 2.736 )
        Week 12, Percentage Change from Baseline
    136.1 ( 527.4 )
    958.4 ( 2349.1 )
    No statistical analyses for this end point

    Secondary: Absolute Change From Baseline in Number of Airway Epithelial Eosinophils per Volume of Epithelium

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    End point title
    		 Absolute Change From Baseline in Number of Airway Epithelial Eosinophils per Volume of Epithelium
    End point description
    To evaluate the effect of lebrikizumab on airway eosinophilic inflammation the absolute change in the number of airway epithelial eosinophils per volume of epithelium (cells/mm^3) was measured after an endobronchial biopsy was performed. Results are presented as 10^9 cells/L. The PP population was defined as a subset of subjects from the ITT population who received at least one dose of the study drug, and who had evaluable biopsies available for both baseline (Visit 4a) and Week 12 visits. Subjects were grouped according to actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    12
    14
    Units: 10^9 cells/L
    arithmetic mean (standard deviation)
        Baseline, Value at Visit
    1.051 ( 1.234 )
    1.283 ( 2.736 )
        Week 12, Change from Baseline
    -0.168 ( 1.118 )
    0.274 ( 3.389 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Blood Eosinophil Count

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    End point title
    		 Change From Baseline in Blood Eosinophil Count
    End point description
    Blood eosinophil counts were performed at multiple time points from baseline (BL) to Week 20. The safety evaluable population was defined as all subjects who received at least one dose of study drug, with subjects grouped according to the actual treatment received. The number of subjects analysed is indicated by n for each arm at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 4, Week 8, Week 12, Week 16, Week 20
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    33
    31
    Units: 10^9 cells/L
    arithmetic mean (standard deviation)
        Baseline, Value at Visit (n=33, 31)
    0.33 ( 0.235 )
    0.248 ( 0.142 )
        Week 1, Change from BL (n=33, 30)
    0.014 ( 0.148 )
    0.024 ( 0.103 )
        Week 4, Change from BL (n=31, 31)
    -0.01 ( 0.175 )
    0.066 ( 0.168 )
        Week 8, Change from BL (n=30, 30)
    0 ( 0.212 )
    0.066 ( 0.202 )
        Week 12, Change from BL (n=31, 31)
    -0.039 ( 0.202 )
    0.062 ( 0.248 )
        Week 16, Change from BL (n=33, 30)
    -0.015 ( 0.207 )
    0.114 ( 0.279 )
        Week 20, Change from BL (n=32, 27)
    0.022 ( 0.139 )
    0.07 ( 0.229 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Immunoglobulin E (IgE) Levels

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    End point title
    		 Change From Baseline in Immunoglobulin E (IgE) Levels
    End point description
    IgE levels were measured at multiple time points from baseline (BL) to Week 20.The safety evaluable population was defined as all subjects who received at least one dose of study drug, with subjects grouped according to the actual treatment received. The number of subjects analysed is indicated by n for each arm at each time point. Results are presented in International Units per millilitre (IU/mL).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 12, Week 20
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    33
    31
    Units: IU/mL
    arithmetic mean (standard deviation)
        Baseline, Value at Visit (n=33, 29)
    269 ( 289.7 )
    265.2 ( 296.5 )
        Week 1, Change from BL (n=32, 29)
    8.9 ( 22 )
    -9.1 ( 33.3 )
        Week 12, Change from BL, (n=31, 29)
    21.1 ( 93.7 )
    -37.2 ( 63.7 )
        Week 20, Change from BL, (n=33, 25)
    11.2 ( 73.9 )
    -44.2 ( 83.9 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Serum Periostin Levels

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    End point title
    		 Change From Baseline in Serum Periostin Levels
    End point description
    Serum periostin levels were measured at multiple time points from baseline (BL) to Week 20.The safety evaluable population was defined as all subjects who received at least one dose of study drug, with subjects grouped according to the actual treatment received. The number of subjects analysed is indicated by n for each arm at each time point. Results are presented in nanograms per millilitre (ng/mL).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 12, Week 20
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    33
    31
    Units: ng/mL
    arithmetic mean (standard deviation)
        Baseline, Value at Visit (n=33, 31)
    51.67 ( 16.01 )
    52.77 ( 18.93 )
        Week 1, Change from BL (n=32, 31)
    -2.23 ( 5.11 )
    -4.33 ( 6.26 )
        Week 12, Change from BL (n=31, 31)
    0.99 ( 11.37 )
    -5.08 ( 6.94 )
        Week 20, Change from BL (n=33, 28)
    0.4 ( 10.8 )
    -4.53 ( 6.73 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Chemokine Ligand (CCL)-17 Levels

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    End point title
    		 Change From Baseline in Chemokine Ligand (CCL)-17 Levels
    End point description
    CCL-17 levels were planned to be measured at multiple time points from baseline (BL) to Week 20.The safety evaluable population was defined as all subjects who received at least one dose of study drug, with subjects grouped according to the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 12, Week 20
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    0 [1]
    0 [2]
    Units: pg/mL
        arithmetic mean (standard deviation)
    ( )
    ( )
    Notes
    [1] - CCL-17 data were not available for analysis.
    [2] - CCL-17 data were not available for analysis.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Lung Epithelial Cell Chloride Channel Accessory 1 (CLCA1) Gene Expression

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    End point title
    		 Change From Baseline in Lung Epithelial Cell Chloride Channel Accessory 1 (CLCA1) Gene Expression
    End point description
    CLCA1 gene expression at the messenger ribonucleic acid (mRNA) transcript levels in lung epithelial cells was measured by RNA-sequencing at baseline (BL) and Week 12. Change in gene expression levels is reported as reads per kilobase million (RPKM) at Week 12 relative to BL.The PP population was defined as a subset of subjects from the ITT population who received at least one dose of the study drug, and who had evaluable biopsies available for both baseline (Visit 4a) and Week 12 visits. Subjects were grouped according to actual treatment received. The number of subjects analysed is indicated by n for each arm at each time point.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 12
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    25
    26
    Units: RPKM
    arithmetic mean (standard deviation)
        Baseline, Value at Visit (n=21, 20)
    2.36 ( 3.72 )
    7.88 ( 23.83 )
        Week 12, Change from BL (n=17, 13)
    -0.11 ( 5.76 )
    -9.66 ( 25.35 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Lung Epithelial Cell SerpinB2 Gene Expression

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    End point title
    		 Change From Baseline in Lung Epithelial Cell SerpinB2 Gene Expression
    End point description
    SerpinB2 gene expression at the mRNA transcript levels in lung epithelial cells was measured by RNA-sequencing at baseline (BL) and Week 12. Change in gene expression levels is reported as RPKM at Week 12 relative to BL.The PP population was defined as a subset of subjects from the ITT population who received at least one dose of the study drug, and who had evaluable biopsies available for both baseline (Visit 4a) and Week 12 visits. Subjects were grouped according to actual treatment received. The number of subjects analysed is indicated by n for each arm at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    25
    26
    Units: RPKM
    arithmetic mean (standard deviation)
        Baseline, Value at Visit (n=21, 20)
    3.58 ( 3.09 )
    3.75 ( 3.61 )
        Week 12, Change from BL (n=17, 13)
    0.37 ( 5.43 )
    -0.88 ( 6.08 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Lung Epithelial Cell CCL-26 Gene Expression

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    End point title
    		 Change From Baseline in Lung Epithelial Cell CCL-26 Gene Expression
    End point description
    CCL-26 gene expression at the mRNA transcript levels in lung epithelial cells was measured by RNA-sequencing at baseline (BL) and Week 12. Change in gene expression levels is reported as RPKM at Week 12 relative to BL. The PP population was defined as a subset of subjects from the ITT population who received at least one dose of the study drug, and who had evaluable biopsies available for both baseline (Visit 4a) and Week 12 visits. Subjects were grouped according to actual treatment received. The number of subjects analysed is indicated by n for each arm at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    25
    26
    Units: RPKM
    arithmetic mean (standard deviation)
        Baseline, Value at Visit (n=21, 20)
    0.15 ( 0.23 )
    0.25 ( 0.44 )
        Week 12, Change from BL (n=17, 13)
    0.09 ( 0.54 )
    0.01 ( 0.42 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Lung Epithelial Cell Nitric Oxide Synthase 2 (NOS2) Gene Expression

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    End point title
    		 Change From Baseline in Lung Epithelial Cell Nitric Oxide Synthase 2 (NOS2) Gene Expression
    End point description
    NOS2 gene expression at the mRNA transcript levels in lung epithelial cells was measured by RNA-sequencing at baseline (BL) and Week 12. Change in gene expression levels is reported as RPKM at Week 12 relative to BL. The PP population was defined as a subset of subjects from the ITT population who received at least one dose of the study drug, and who had evaluable biopsies available for both baseline (Visit 4a) and Week 12 visits. Subjects were grouped according to actual treatment received. The number of subjects analysed is indicated by n for each arm at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    25
    26
    Units: RPKM
    arithmetic mean (standard deviation)
        Baseline, Value at Visit (n=21, 20)
    5.09 ( 8.92 )
    5.28 ( 7.1 )
        Week 12, Change from BL (n=17, 13)
    -0.68 ( 5.16 )
    -3.26 ( 5.91 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Lung Epithelial Cell Periostin (POSTN) Gene Expression

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    End point title
    		 Change From Baseline in Lung Epithelial Cell Periostin (POSTN) Gene Expression
    End point description
    POSTN gene expression at the mRNA transcript levels in lung epithelial cells was measured by RNA-sequencing at baseline (BL) and Week 12. Change in gene expression levels is reported as RPKM at Week 12 relative to BL. The PP population was defined as a subset of subjects from the ITT population who received at least one dose of the study drug, and who had evaluable biopsies available for both baseline (Visit 4a) and Week 12 visits. Subjects were grouped according to actual treatment received. The number of subjects analysed is indicated by n for each arm at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    25
    26
    Units: RPKM
    arithmetic mean (standard deviation)
        Baseline, Value at Visit (n=21, 20)
    6.65 ( 6.5 )
    7.14 ( 6.65 )
        Week 12, Change from BL (n=17, 13)
    -0.08 ( 7.53 )
    -3.54 ( 4.91 )
    No statistical analyses for this end point

    Secondary: Relative Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO)

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    End point title
    		 Relative Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO)
    End point description
    Description: FeNO was measured at multiple time points from baseline (BL) to Week 12. At BL FeNO is reported as parts per billion (ppb). Relative change was defined as the absolute change from baseline to each time point, divided by the value at baseline and presented as percentage. The PP population was defined as a subset of subjects from the ITT population who received at least one dose of the study drug, and who had evaluable biopsies available for both baseline (Visit 4a) and Week 12 visits. Subjects were grouped according to actual treatment received. The number of subjects analysed is indicated by n for each arm at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 4, Week 8, Week 12
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    25
    26
    Units: percentage change from baseline
    arithmetic mean (standard deviation)
        Baseline, Value at Visit (n=25, 26)
    32.3 ( 35.8 )
    34.5 ( 28 )
        Week 1, Change from BL (n=25, 26)
    2.5 ( 43.8 )
    -16.9 ( 37.8 )
        Week 4, Change from BL (n=25, 26)
    21.2 ( 71.1 )
    -25.9 ( 45.4 )
        Week 8, Change from BL (n=24, 25)
    12.1 ( 45.3 )
    -23.4 ( 37.7 )
        Week 12, Change from BL (n=24, 26)
    8.8 ( 53.2 )
    -24.8 ( 40.4 )
    No statistical analyses for this end point

    Secondary: Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)

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    End point title
    		 Relative Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1)
    End point description
    FEV1 was measured at multiple time points from baseline (BL) to Week 12. At BL FEV1 is reported as volume in litres (L). Relative change was defined as the absolute change from baseline to each time point, divided by the value at baseline and presented as percentage. The PP population was defined as a subset of subjects from the ITT population who received at least one dose of the study drug, and who had evaluable biopsies available for both baseline (Visit 4a) and Week 12 visits. Subjects were grouped according to actual treatment received. The number of subjects analysed is indicated by n for each arm at each time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 4, Week 8, Week 12
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    25
    26
    Units: percentage change from baseline
    arithmetic mean (standard deviation)
        Baseline, Value at Visit (n=25, 26)
    2.352 ( 0.79 )
    2.15 ( 0.611 )
        Week 1, Change from BL (n=25, 26)
    2.327 ( 13.949 )
    5.385 ( 13.584 )
        Week 4, Change from BL (n=25, 26)
    -0.27 ( 13.39 )
    0.716 ( 13.956 )
        Week 8, Change from BL (n=24, 24)
    1.006 ( 12.925 )
    9.838 ( 22.463 )
        Week 12, Change from BL (n=24, 26)
    -1.649 ( 16.453 )
    6.278 ( 19.035 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Treatment-Emergent Adverse Events

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    End point title
    		 Percentage of Subjects With Treatment-Emergent Adverse Events
    End point description
    An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. The safety evaluable population was defined as all subjects who received at least one dose of study drug, with subjects grouped according to the actual treatment received.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 20
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    33
    31
    Units: percentage of subjects
        number (not applicable)
    69.7
    67.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Anti-Therapeutic Antibodies (ATAs) to Lebrikizumab

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    End point title
    		 Percentage of Subjects With Anti-Therapeutic Antibodies (ATAs) to Lebrikizumab
    End point description
    Presence of ATAs to lebrikizumab was measured at baseline and up to Week 20. Reported is the percentage of subjects with ATAs to lebrikizumab at baseline and post-baseline. The safety evaluable population was defined as all subjects who received at least one dose of study drug, with subjects grouped according to the actual treatment received. The number of subjects analysed is indicated by n for each arm at each time point.
    End point type
    Secondary
    End point timeframe
    From Baseline up to Week 20
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    33
    31
    Units: percentage of subjects
    number (not applicable)
        Baseline (n=31, 31)
    0
    3.2
        Post-baseline (n=33, 29)
    3
    6.9
    No statistical analyses for this end point

    Secondary: Serum Lebrikizumab Concentration at Week 12

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    End point title
    		 Serum Lebrikizumab Concentration at Week 12 [3]
    End point description
    To measure serum lebrikizumab concentration blood samples were taken from subjects in the lebrikizumab arm before dosing at Week 12. The safety evaluable population was defined as all subjects who received at least one dose of study drug, with subjects grouped according to the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Pre-dose (Hour 0) at Week 12
    Notes
    [3] - 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: Serum lebrikizumab concentration was only measured in the arm that received lebrikizumab treatment. Therefore, data are only reported for the lebrikizumab arm.
    End point values
    		 Lebrikizumab
    Number of subjects analysed
    31
    Units: micrograms per millilitre (mcg/mL)
        arithmetic mean (standard deviation)
    13.5 ( 6.59 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in CCL-13 Levels

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    End point title
    		 Change From Baseline in CCL-13 Levels
    End point description
    CCL-13 levels were measured at multiple time points from baseline (BL) to Week 20. The safety evaluable population was defined as all subjects who received at least one dose of study drug, with subjects grouped according to the actual treatment received. The number of subjects analysed is indicated by n for each arm at each time point. Results are presented in picograms per millilitre (pg/mL).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 12, Week 20
    End point values
    		 Placebo Lebrikizumab
    Number of subjects analysed
    33
    31
    Units: pg/mL
    arithmetic mean (standard deviation)
        Baseline, Value at Visit (n=33, 31)
    209.2 ( 90.3 )
    1949.5 ( 9459.5 )
        Week 1, Change from BL (n=32, 31)
    -3 ( 31.9 )
    -502.7 ( 2656.9 )
        Week 12, Change from BL (n=31, 31)
    9.9 ( 33.8 )
    -1014.6 ( 5419.2 )
        Week 20, Change from BL (n=32, 27)
    4.1 ( 38 )
    -1017.3 ( 5116 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to Week 20
    Adverse event reporting additional description
    The safety evaluable population was defined as all subjects who received at least one dose of study drug, with subjects grouped according to the actual treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Lebrikizumab
    Reporting group description
    		 Subjects with uncontrolled asthma on inhaled corticosteroids (ICS) therapy and a second controller medication received SC injection of lebrikizumab on Days 1 and 8, and on Weeks 4 and 8.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects with uncontrolled asthma on ICS therapy and a second controller medication received subcutaneous (SC) injection of lebrikizumab matching placebo on Days 1 and 8, and on Weeks 4 and 8.

    Serious adverse events
    		 Lebrikizumab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 31 (19.35%)
    1 / 33 (3.03%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 33 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 33 (3.03%)
         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
    		 Lebrikizumab Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 31 (38.71%)
    17 / 33 (51.52%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 33 (6.06%)
         occurrences all number
    5
    5
    Pyrexia
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 33 (9.09%)
         occurrences all number
    1
    4
    Vomiting
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    3 / 31 (9.68%)
    7 / 33 (21.21%)
         occurrences all number
    4
    9
    Dyspnoea
         subjects affected / exposed
    1 / 31 (3.23%)
    4 / 33 (12.12%)
         occurrences all number
    1
    4
    Cough
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 33 (9.09%)
         occurrences all number
    2
    3
    Sinus congestion
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 31 (6.45%)
    2 / 33 (6.06%)
         occurrences all number
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 33 (6.06%)
         occurrences all number
    1
    2
    Urinary tract infection
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Sinusitis
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jun 2014
    Required abstinence or highly effective contraception starting on Visit 1 (Day − 21). Removed a duplicate exclusion criterion. Updated Medical Monitor contact information. Clarified who within the Sponsor will be unblinded to eosinophil counts.
    29 Sep 2015
    Updated the screening period inhaled corticosteroid (ICS)-compliance requirement from 80% to 70%. Updated the time to re-screening after a subject was deemed non-compliant with ICS during screening from 4 to 6 weeks to at least 1 week. Clarified that the criteria for demonstrating uncontrolled asthma is an Asthma Control Questionnaire-5 score of >/= 1.5 and the presence of asthma symptoms. Corrected an error in the previous Protocol for Appendix 1 visit assessment time windows. Updated Internal Monitoring Committee membership and functioning. Updated the total planned enrollment from 120 to 80 subjects. Updated the analysis plan to include an optional unblinded interim analysis of efficacy and safety. Updated Medical Monitor contact information.

    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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