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    Clinical Trial Results:
    A Phase II, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Lebrikizumab in Patients with Chronic Obstructive Pulmonary Disease and a History of Exacerbations

    Summary
    EudraCT number
    		 2015-001122-42
    Trial protocol
    		 HU   DK   PL  
    Global end of trial date
    25 Nov 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Nov 2017
    First version publication date
    19 Nov 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    WB29804
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02546700
    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
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 61 6878333, 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
    25 Nov 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of lebrikizumab compared with placebo in improving lung function, as measured by the absolute change in pre-bronchodilator forced expiratory volume in one second (FEV1) in participants with chronic obstructive pulmonary disease (COPD) and a history of exacerbations in the biomarker-high group (elevated serum periostin or blood eosinophils) and biomarker-low group.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP) according to the regulations and procedures described in the protocol. The sponsor and investigators strictly adhered to the stated provisions in the guidelines. This was documented by the investigator’s signature on the protocol agreeing to carry out all of its terms in accordance with the applicable regulations and law and to follow International Council for Harmonisation (ICH) GCP guidelines. Approval from the Institutional Review Board (IRB)/Ethics Committee (EC) was obtained before study start and was documented in a letter to the investigator specifying the date on which the committee met and granted the approval. Sponsor also obtained approval from the relevant Competent Authority prior to starting the study.
    Background therapy
    		 Participants continued on stable doses of their standard-of-care therapy for the duration of the 24-week placebo-controlled period that must have included inhaled corticosteroids (ICS) and at least one long-acting bronchodilator inhaler medication (long-acting beta agonist [LABA] and/or long-acting muscarinic antagonist [LAMA]).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Sep 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Hungary: 63
    Country: Number of subjects enrolled
    Poland: 45
    Country: Number of subjects enrolled
    Bulgaria: 41
    Country: Number of subjects enrolled
    Russian Federation: 47
    Country: Number of subjects enrolled
    Canada: 19
    Country: Number of subjects enrolled
    Mexico: 10
    Country: Number of subjects enrolled
    United States: 61
    Country: Number of subjects enrolled
    Argentina: 6
    Country: Number of subjects enrolled
    Denmark: 17
    Worldwide total number of subjects
    309
    EEA total number of subjects
    166
    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)
    144
    From 65 to 84 years
    165
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 391 participants were screened of which 309 participants were randomized.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo matched to lebrikizumab was administered subcutaneously once in every 4 weeks for a total of 6 doses.
    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 was administered as per the schedule mentioned in arm description.

    Arm title
    		 Lebrikizumab
    Arm description
    		 Lebrikizumab 125 milligrams (mg) was administered subcutaneously once in every 4 weeks for a total of 6 doses.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lebrikizumab
    Investigational medicinal product code
    RO5490255
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lebrikizumab was administered as per the schedule mentioned in arm description.

    Number of subjects in period 1
    		Placebo Lebrikizumab
    Started
    154
    155
    Completed
    144
    146
    Not completed
    10
    9
         Consent withdrawn by subject
    8
    2
         Adverse Event
    -
    2
         Death
    1
    1
         Lost to follow-up
    1
    -
         Lack of efficacy
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to lebrikizumab was administered subcutaneously once in every 4 weeks for a total of 6 doses.

    Reporting group title
    Lebrikizumab
    Reporting group description
    		 Lebrikizumab 125 milligrams (mg) was administered subcutaneously once in every 4 weeks for a total of 6 doses.

    Reporting group values
    		 Placebo Lebrikizumab Total
    Number of subjects
    		 154 155 309
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.6 ( 7.1 ) 64.5 ( 7.1 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 58 58 116
        Male
    		 96 97 193
    Subject analysis sets

    Subject analysis set title
    Placebo: Biomarker-High
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Placebo matched to lebrikizumab was administered subcutaneously once in every 4 weeks for a total of 6 doses to the participants considered as biomarker-high. Biomarker-high participants were defined as the participants with baseline (Day -14) periostin greater than or equal to (>=) 50 nanograms per milliliter (ng/mL) or blood eosinophils >=300 cells per microliter (cells/mcL).

    Subject analysis set title
    Lebrikizumab: Biomarker-High
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Lebrikizumab 125 mg was administered subcutaneously once in every 4 weeks for a total of 6 doses to the participants considered as biomarker-high. Biomarker-high participants were defined as the participants with baseline (Day -14) periostin >=50 ng/mL or blood eosinophils >=300 cells/mcL.

    Subject analysis set title
    Placebo: Biomarker-Low
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Placebo matched to lebrikizumab was administered subcutaneously once in every 4 weeks for a total of 6 doses to the participants considered as biomarker-low. Biomarker-low participants were defined as the participants with baseline (Day -14) periostin less than (<) 50 ng/mL and blood eosinophils <300 cells/mcL.

    Subject analysis set title
    Lebrikizumab: Biomarker-Low
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Lebrikizumab 125 mg was administered subcutaneously once in every 4 weeks for a total of 6 doses to the participants considered as biomarker-low. Biomarker-low participants were defined as the participants with baseline (Day -14) periostin <50 ng/mL and blood eosinophils <300 cells/mcL.

    Subject analysis sets values
    		 Placebo: Biomarker-High Lebrikizumab: Biomarker-High Placebo: Biomarker-Low Lebrikizumab: Biomarker-Low
    Number of subjects
    80
    86
    74
    69
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    65.8 ( 7.4 )
    65.2 ( 6.9 )
    63.2 ( 6.6 )
    63.6 ( 7.4 )
    Gender Categorical
    Units: Subjects
        Female
    33
    25
    25
    33
        Male
    47
    61
    49
    36

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to lebrikizumab was administered subcutaneously once in every 4 weeks for a total of 6 doses.

    Reporting group title
    Lebrikizumab
    Reporting group description
    		 Lebrikizumab 125 milligrams (mg) was administered subcutaneously once in every 4 weeks for a total of 6 doses.

    Subject analysis set title
    Placebo: Biomarker-High
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Placebo matched to lebrikizumab was administered subcutaneously once in every 4 weeks for a total of 6 doses to the participants considered as biomarker-high. Biomarker-high participants were defined as the participants with baseline (Day -14) periostin greater than or equal to (>=) 50 nanograms per milliliter (ng/mL) or blood eosinophils >=300 cells per microliter (cells/mcL).

    Subject analysis set title
    Lebrikizumab: Biomarker-High
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Lebrikizumab 125 mg was administered subcutaneously once in every 4 weeks for a total of 6 doses to the participants considered as biomarker-high. Biomarker-high participants were defined as the participants with baseline (Day -14) periostin >=50 ng/mL or blood eosinophils >=300 cells/mcL.

    Subject analysis set title
    Placebo: Biomarker-Low
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Placebo matched to lebrikizumab was administered subcutaneously once in every 4 weeks for a total of 6 doses to the participants considered as biomarker-low. Biomarker-low participants were defined as the participants with baseline (Day -14) periostin less than (<) 50 ng/mL and blood eosinophils <300 cells/mcL.

    Subject analysis set title
    Lebrikizumab: Biomarker-Low
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Lebrikizumab 125 mg was administered subcutaneously once in every 4 weeks for a total of 6 doses to the participants considered as biomarker-low. Biomarker-low participants were defined as the participants with baseline (Day -14) periostin <50 ng/mL and blood eosinophils <300 cells/mcL.

    Primary: Change from Baseline in Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Week 12

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    End point title
    		 Change from Baseline in Pre-bronchodilator Forced Expiratory Volume in One Second (FEV1) at Week 12
    End point description
    Adjusted mean change from baseline in pre-bronchodilator FEV1 (assessed using spirometry) at Week 12 was calculated. Modified intent-to-treat (mITT) population included participants who were randomized and received at least one dose of any study drug, grouped according to the treatment assigned at randomization within biomarker-high and biomarker-low subgroups.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Placebo: Biomarker-High Lebrikizumab: Biomarker-High Placebo: Biomarker-Low Lebrikizumab: Biomarker-Low
    Number of subjects analysed
    80
    86
    74
    69
    Units: milliliters (mL)
        least squares mean (confidence interval 95%)
    46.4 (1.5 to 91.2)
    51.7 (8.2 to 95.1)
    -20.1 (-68.0 to 27.8)
    -8.1 (-56.8 to 40.5)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Adjusted mean difference was calculated as difference between adjusted mean values of lebrikizumab group minus placebo group.
    Comparison groups
    Placebo: Biomarker-High v Lebrikizumab: Biomarker-High
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.867
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    5.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57
         upper limit
    		 67.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    31.7
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Adjusted mean difference was calculated as difference between adjusted mean values of lebrikizumab group minus placebo group.
    Comparison groups
    Placebo: Biomarker-Low v Lebrikizumab: Biomarker-Low
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7308
    Method
    		 Mixed models analysis
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -56.4
         upper limit
    		 80.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    34.7

    Secondary: Rate of Moderate or Severe COPD Exacerbation

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    End point title
    		 Rate of Moderate or Severe COPD Exacerbation
    End point description
    A moderate COPD exacerbation was defined as new or increased COPD symptoms (for example, dyspnea, sputum volume, and sputum purulence) for at least 2 consecutive days that lead to treatment with systemic corticosteroids and/or antibiotics. A severe COPD exacerbation was defined as new or increased COPD symptoms (for example, dyspnea, sputum volume, and sputum purulence) for at least 2 consecutive days that lead to hospitalization. Adjusted exacerbation rate per year was calculated. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 24
    End point values
    		 Placebo: Biomarker-High Lebrikizumab: Biomarker-High Placebo: Biomarker-Low Lebrikizumab: Biomarker-Low
    Number of subjects analysed
    80
    86
    74
    69
    Units: exacerbations/year
        number (not applicable)
    0.78
    1.07
    0.93
    1.14
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Rate ratio was calculated as rate for lebrikizumab group/rate for placebo group.
    Comparison groups
    Placebo: Biomarker-High v Lebrikizumab: Biomarker-High
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Rate Ratio
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 2.36
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Rate ratio was calculated as rate for lebrikizumab group/rate for placebo group.
    Comparison groups
    Placebo: Biomarker-Low v Lebrikizumab: Biomarker-Low
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Rate Ratio
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 2.15

    Secondary: Change from Baseline in Post-bronchodilator FEV1 at Week 24

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    End point title
    		 Change from Baseline in Post-bronchodilator FEV1 at Week 24
    End point description
    Adjusted mean change from baseline in post-bronchodilator FEV1 at Week 24 was calculated. mITT population. ‘Number of Subjects Analysed’ = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo: Biomarker-High Lebrikizumab: Biomarker-High Placebo: Biomarker-Low Lebrikizumab: Biomarker-Low
    Number of subjects analysed
    76
    83
    71
    65
    Units: mL
        least squares mean (confidence interval 95%)
    20.6 (-24.5 to 65.6)
    31.2 (-12.0 to 74.5)
    -8.3 (-56.5 to 39.9)
    -10.7 (-60.2 to 38.8)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Adjusted mean difference was calculated as difference between adjusted mean values of lebrikizumab group minus placebo group.
    Comparison groups
    Placebo: Biomarker-High v Lebrikizumab: Biomarker-High
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    10.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.6
         upper limit
    		 72.9
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Adjusted mean difference was calculated as difference between adjusted mean values of lebrikizumab group minus placebo group.
    Comparison groups
    Placebo: Biomarker-Low v Lebrikizumab: Biomarker-Low
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -71.5
         upper limit
    		 66.6

    Secondary: Change from Baseline in Pre-bronchodilator FEV1 at Week 24

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    End point title
    		 Change from Baseline in Pre-bronchodilator FEV1 at Week 24
    End point description
    Adjusted mean change from baseline in pre-bronchodilator FEV1 at Week 24 was calculated. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo: Biomarker-High Lebrikizumab: Biomarker-High Placebo: Biomarker-Low Lebrikizumab: Biomarker-Low
    Number of subjects analysed
    80
    86
    74
    69
    Units: mL
        least squares mean (confidence interval 95%)
    17.5 (-26.4 to 61.5)
    46.8 (4.3 to 89.3)
    -31.4 (-78.3 to 15.5)
    1.9 (-46.1 to 49.9)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Adjusted mean difference was calculated as difference between adjusted mean values of lebrikizumab group minus placebo group.
    Comparison groups
    Placebo: Biomarker-High v Lebrikizumab: Biomarker-High
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    29.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -31.8
         upper limit
    		 90.3
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Adjusted mean difference was calculated as difference between adjusted mean values of lebrikizumab group minus placebo group.
    Comparison groups
    Placebo: Biomarker-Low v Lebrikizumab: Biomarker-Low
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    33.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.8
         upper limit
    		 100.4

    Secondary: Time to First COPD Exacerbation

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    End point title
    		 Time to First COPD Exacerbation
    End point description
    COPD exacerbation was defined as new or increased COPD symptoms (for example, dyspnea, sputum volume, and sputum purulence) for at least 2 consecutive days. Time to first COPD exacerbation was estimated using Kaplan-Meier analysis. mITT population. ‘99999’ indicates that data could not be estimated due to higher number of censored participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 24
    End point values
    		 Placebo: Biomarker-High Lebrikizumab: Biomarker-High Placebo: Biomarker-Low Lebrikizumab: Biomarker-Low
    Number of subjects analysed
    80
    86
    74
    69
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    25.9 (24.9 to 99999)
    99999 (25.0 to 99999)
    24.9 (24.0 to 99999)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo: Biomarker-High v Lebrikizumab: Biomarker-High
    Number of subjects included in analysis
    166
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5233
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.67
         upper limit
    		 2.1
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo: Biomarker-Low v Lebrikizumab: Biomarker-Low
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3085
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 2.28

    Secondary: Change from Baseline in Health-Related Quality of Life as Assessed by the Overall Score of the Saint George's Respiratory Questionnaire for COPD (SGRQ-C) at Week 24

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    End point title
    		 Change from Baseline in Health-Related Quality of Life as Assessed by the Overall Score of the Saint George's Respiratory Questionnaire for COPD (SGRQ-C) at Week 24
    End point description
    SGRQ-C was assessed by asking participants to recall their COPD-related experiences and to respond to 40 questions included within three domains: symptoms (7 items), activity (13 items), and impacts (20 items). Overall SGRQ-C score ranged from 0 to 100, where lower score indicated better health-related quality of life. Change from baseline in overall SGRQ-C score at Week 24 was reported. mITT population. ‘Number of Subjects Analysed’ = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo: Biomarker-High Lebrikizumab: Biomarker-High Placebo: Biomarker-Low Lebrikizumab: Biomarker-Low
    Number of subjects analysed
    76
    83
    70
    64
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -5.4 (-8.3 to -2.4)
    -4.6 (-7.5 to -1.7)
    -8.8 (-11.9 to -5.7)
    -2.4 (-5.6 to 0.9)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Adjusted mean difference was calculated as difference between adjusted mean values of lebrikizumab group minus placebo group.
    Comparison groups
    Placebo: Biomarker-High v Lebrikizumab: Biomarker-High
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 4.8
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Adjusted mean difference was calculated as difference between adjusted mean values of lebrikizumab group minus placebo group.
    Comparison groups
    Placebo: Biomarker-Low v Lebrikizumab: Biomarker-Low
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    6.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.9
         upper limit
    		 10.9

    Secondary: Change from Baseline in COPD Symptoms as Measured by the Overall Score of the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) at Week 24

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    End point title
    		 Change from Baseline in COPD Symptoms as Measured by the Overall Score of the Exacerbations of Chronic Pulmonary Disease Tool (EXACT) at Week 24
    End point description
    EXACT comprised of 14-item questionnaire containing four domains: breathlessness (5 items), cough and sputum (3 items), chest symptoms (3 items), and additional attributes (3 items). Overall EXACT score was the average of domain scores. It ranged from 0 to 100, where higher score indicated a more severe condition. Change from baseline in overall EXACT score at Week 24 was reported. mITT population. ‘Number of Subjects Analysed’ = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo: Biomarker-High Lebrikizumab: Biomarker-High Placebo: Biomarker-Low Lebrikizumab: Biomarker-Low
    Number of subjects analysed
    64
    60
    51
    48
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -2.4 (-4.4 to -0.4)
    -2.4 (-4.5 to -0.3)
    -1.9 (-4.2 to 0.4)
    -1.4 (-3.7 to 1.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Adjusted mean difference was calculated as difference between adjusted mean values of lebrikizumab group minus placebo group.
    Comparison groups
    Placebo: Biomarker-High v Lebrikizumab: Biomarker-High
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 2.9
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Adjusted mean difference was calculated as difference between adjusted mean values of lebrikizumab group minus placebo group.
    Comparison groups
    Placebo: Biomarker-Low v Lebrikizumab: Biomarker-Low
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 3.8

    Secondary: Change from Baseline in Cough and Sputum as Measured by the Cough and Sputum Domain Score of the EXACT at Week 24

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    End point title
    		 Change from Baseline in Cough and Sputum as Measured by the Cough and Sputum Domain Score of the EXACT at Week 24
    End point description
    EXACT comprised of 14-item questionnaire containing four domains: breathlessness (5 items), cough and sputum (3 items), chest symptoms (3 items), and additional attributes (3 items). Cough and Sputum domain score ranged from 0 to 100, where higher score indicated a more severe condition. Change from baseline in cough and sputum domain EXACT score at Week 24 was reported. mITT population. ‘Number of Subjects Analysed’ = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo: Biomarker-High Lebrikizumab: Biomarker-High Placebo: Biomarker-Low Lebrikizumab: Biomarker-Low
    Number of subjects analysed
    64
    60
    51
    48
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -4.0 (-6.9 to -1.2)
    -5.2 (-8.2 to -2.2)
    -5.6 (-8.9 to -2.3)
    -2.2 (-5.7 to 1.2)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Adjusted mean difference was calculated as difference between adjusted mean values of lebrikizumab group minus placebo group.
    Comparison groups
    Placebo: Biomarker-High v Lebrikizumab: Biomarker-High
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.3
         upper limit
    		 3
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Adjusted mean difference was calculated as difference between adjusted mean values of lebrikizumab group minus placebo group.
    Comparison groups
    Placebo: Biomarker-Low v Lebrikizumab: Biomarker-Low
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 8.2

    Secondary: Change from Baseline in Dyspnea as Assessed by the Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) at Week 24

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    End point title
    		 Change from Baseline in Dyspnea as Assessed by the Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) at Week 24
    End point description
    The BDI scores ranged from 0 (very severe impairment) to 4 (no impairment) for each of 3 domains (functional impairment, magnitude of task, and magnitude of effort) and were summed to determine the BDI total score (0 to 12). The TDI scores ranged from -3 (major deterioration) to +3 (major improvement) for each of the 3 domains (functional impairment, magnitude of task, and magnitude of effort). The sum of all domains yielded the TDI total score (-9 to +9). Change from baseline in BDI/TDI at Week 24 was reported. mITT population. ‘Number of Subjects Analysed’ = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo: Biomarker-High Lebrikizumab: Biomarker-High Placebo: Biomarker-Low Lebrikizumab: Biomarker-Low
    Number of subjects analysed
    72
    76
    66
    62
    Units: ratio
        arithmetic mean (standard deviation)
    1.0 ( 2.9 )
    1.4 ( 2.9 )
    2.3 ( 2.8 )
    1.6 ( 3.3 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Anti-Therapeutic Antibody (ATA) to Lebrikizumab

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    End point title
    		 Percentage of Participants with Anti-Therapeutic Antibody (ATA) to Lebrikizumab [1]
    End point description
    This outcome measure was planned to be analyzed only in overall lebrikizumab arm. Safety evaluable population included participants who received at least one dose of study treatment, grouped according to the actual treatment received. ‘Number of Subjects Analysed’ = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 36
    Notes
    [1] - 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: This endpoint was planned to be evaluated for lebrikizumab group only.
    End point values
    		 Lebrikizumab
    Number of subjects analysed
    154
    Units: percentage of participants
        number (not applicable)
    13.6
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Trough Concentration (Cmin) of Lebrikizumab

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    End point title
    		 Minimum Observed Serum Trough Concentration (Cmin) of Lebrikizumab [2]
    End point description
    This outcome measure was planned to be analyzed only in overall lebrikizumab arm. Pharmacokinetic (PK) population included participants who received at least one dose of lebrikizumab, and had available PK data. ‘n’ = participants evaluable for this endpoint at given timepoints.
    End point type
    Secondary
    End point timeframe
    Pre-dose (Hour 0) at Weeks 4 and 12, at Week 24
    Notes
    [2] - 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: This endpoint was planned to be evaluated for lebrikizumab group only.
    End point values
    		 Lebrikizumab
    Number of subjects analysed
    155
    Units: micrograms per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        Week 4 (n=152)
    9.09 ( 3.64 )
        Week 12 (n=147)
    14.7 ( 6.68 )
        Week 24 (n=143)
    15.2 ( 8.10 )
    No statistical analyses for this end point

    Secondary: Elimination Half-Life (t1/2) of Lebrikizumab

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    End point title
    		 Elimination Half-Life (t1/2) of Lebrikizumab [3]
    End point description
    Elimination half-life was defined as the time measured for the serum concentration to decrease by one half. This outcome measure was planned to be analyzed only in overall lebrikizumab arm. PK population. ‘Number of Subjects Analysed’ = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose (Hour 0) on Day 1 (Baseline) and Weeks 1, 4, 12, 24, 28, and 36
    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: This endpoint was planned to be evaluated for lebrikizumab group only.
    End point values
    		 Lebrikizumab
    Number of subjects analysed
    136
    Units: days
        arithmetic mean (standard deviation)
    25.1 ( 7.26 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Week 36
    Adverse event reporting additional description
    Safety evaluable population
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to lebrikizumab was administered subcutaneously once in every 4 weeks for a total of 6 doses.

    Reporting group title
    Lebrikizumab
    Reporting group description
    		 Lebrikizumab 125 milligrams (mg) was administered subcutaneously once in every 4 weeks for a total of 6 doses.

    Serious adverse events
    		 Placebo Lebrikizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 154 (14.94%)
    21 / 155 (13.55%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    1 / 154 (0.65%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chest injury
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Exomphalos
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
         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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    10 / 154 (6.49%)
    15 / 155 (9.68%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    2 / 154 (1.30%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary granuloma
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary necrosis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (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
    Pneumonia
         subjects affected / exposed
    3 / 154 (1.95%)
    3 / 155 (1.94%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 154 (0.65%)
    0 / 155 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 154 (0.00%)
    1 / 155 (0.65%)
         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
    		 Placebo Lebrikizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 154 (42.86%)
    57 / 155 (36.77%)
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    55 / 154 (35.71%)
    51 / 155 (32.90%)
         occurrences all number
    74
    76
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    10 / 154 (6.49%)
    7 / 155 (4.52%)
         occurrences all number
    10
    7
    Bronchitis
         subjects affected / exposed
    7 / 154 (4.55%)
    9 / 155 (5.81%)
         occurrences all number
    7
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2015
    The primary and secondary efficacy objectives were updated to reflect that these objectives will be evaluated within the biomarker-high and biomarker-low subgroups. The primary efficacy endpoint “absolute change in pre-bronchodilator FEV1 (liters) from baseline to Week 24” was changed to “absolute change in pre-bronchodilator FEV1 (liters) from baseline to Week 12”. Inclusion and exclusion criteria were modified.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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