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    Clinical Trial Results:
    A Phase III, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Lebrikizumab in Adult Patients with Mild-to-Moderate Asthma

    Summary
    EudraCT number
    		 2013-004625-81
    Trial protocol
    		 CZ   BG   GB   SK  
    Global end of trial date
    22 Jan 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Mar 2017
    First version publication date
    30 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WA29249
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02104674
    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 Ltd., Roche Trial Information Hotline, 41 616878333, global.trial_information@roche.com
    Scientific contact
    F.Hoffmann-La Roche Ltd., Roche Trial Information Hotline, 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
    18 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    A Phase III, randomized, double-blind, placebo-controlled study to evaluate the efficacy of lebrikizumab compared with placebo in improving lung function in adult participants with mild-to-moderate asthma.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the Declaration of Helsinki, International Conference on Harmonisation (ICH) E6 guideline for Good Clinical Practice (GCP) and investigators were trained according to applicable Sponsor standard operating procedures (SOPs). Roche and the investigators strictly adhered to the stated provisions in these 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 ICH GCP guidelines for good clinical practice.
    Background therapy
    		 Participants could only receive short-acting beta agonists (SABA) therapy for asthma treatment at study entry (less than [<] 10 puffs daily).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jun 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
    Poland: 36
    Country: Number of subjects enrolled
    Romania: 14
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Bulgaria: 33
    Country: Number of subjects enrolled
    Czech Republic: 9
    Country: Number of subjects enrolled
    United States: 138
    Country: Number of subjects enrolled
    Brazil: 10
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    New Zealand: 7
    Country: Number of subjects enrolled
    Russian Federation: 23
    Country: Number of subjects enrolled
    South Africa: 31
    Worldwide total number of subjects
    313
    EEA total number of subjects
    95
    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)
    293
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Out of 313 enrolled participants, 3 were randomized but not treated during a 12-week treatment period where participants received blinded lebrikizumab/placebo or an open-label active comparator (Montelukast sodium).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lebrikizumab
    Arm description
    		 Lebrikizumab 125 milligrams (mg) administered as subcutaneous (SC) injection on Day 1, 29, and 57 during the 12-week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lebrikuzimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled injector
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lebrikizumab administered as SC injection during the 12-week treatment period.

    Arm title
    		 Montelukast
    Arm description
    		 Montelukast 10 mg tablet administered orally once daily during the 12-week treatment period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Montelukast
    Investigational medicinal product code
    Other name
    Singulair
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Montelukast administered orally during the 12-week treatment period.

    Arm title
    		 Placebo
    Arm description
    		 Placebo matched to Lebrikuzimab as SC injection administered on Day 1, 29, and 57 during the 12-week treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled injector
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matched to Lebrikuzimab as SC injection administered during the 12-week treatment period.

    Number of subjects in period 1
    		Lebrikizumab Montelukast Placebo
    Started
    105
    102
    106
    Completed
    98
    91
    98
    Not completed
    7
    11
    8
         Consent withdrawn by subject
    5
    7
    4
         Adverse Event
    1
    1
    1
         Unspecified
    1
    -
    1
         Lost to follow-up
    -
    2
    1
         Lack of efficacy
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lebrikizumab
    Reporting group description
    		 Lebrikizumab 125 milligrams (mg) administered as subcutaneous (SC) injection on Day 1, 29, and 57 during the 12-week treatment period.

    Reporting group title
    Montelukast
    Reporting group description
    		 Montelukast 10 mg tablet administered orally once daily during the 12-week treatment period.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to Lebrikuzimab as SC injection administered on Day 1, 29, and 57 during the 12-week treatment period.

    Reporting group values
    		 Lebrikizumab Montelukast Placebo Total
    Number of subjects
    		 105 102 106 313
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 98 98 97 293
        From 65-84 years
    		 7 4 9 20
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 64 61 66 191
        Male
    		 41 41 40 122

    End points

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    End points reporting groups
    Reporting group title
    Lebrikizumab
    Reporting group description
    		 Lebrikizumab 125 milligrams (mg) administered as subcutaneous (SC) injection on Day 1, 29, and 57 during the 12-week treatment period.

    Reporting group title
    Montelukast
    Reporting group description
    		 Montelukast 10 mg tablet administered orally once daily during the 12-week treatment period.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matched to Lebrikuzimab as SC injection administered on Day 1, 29, and 57 during the 12-week treatment period.

    Subject analysis set title
    Lebrikizumab-Modified Intent to Treat (mITT)
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Lebrikizumab 125 mg administered as SC injection on Day 1, 29 and 57 during the 12-week treatment period.

    Subject analysis set title
    Montelukast-mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Montelukast 10 mg tablet administered orally once daily during the 12-week treatment period.

    Subject analysis set title
    Placebo-mITT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Placebo matched to Lebrikuzimab administered as SC injection on Day 1, 29 and 57 during the 12-week treatment period.

    Subject analysis set title
    Montelukast-Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Montelukast 10 mg tablet administered orally once daily during the 12 week treatment period. Participants were followed up further for 8 weeks during the safety follow-up period.

    Subject analysis set title
    Placebo-Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Placebo matched to Lebrikuzimab administered as SC injection on Day 1, 29 and 57 during the 12-week treatment period. Participants were followed up further for 8 weeks during the safety follow-up period.

    Subject analysis set title
    Lebrikizumab-Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Lebrikuzimab administered as SC injection on Day 1, 29 and 57 during the 12-week treatment period. Participants were followed up further for 8 weeks during the safety follow-up period.

    Primary: Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 12

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    End point title
    		 Change From Baseline in Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Week 12
    End point description
    FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. Modified intent to treat (mITT) population included all randomized participants who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Lebrikizumab-Modified Intent to Treat (mITT) Montelukast-mITT Placebo-mITT
    Number of subjects analysed
    104
    101
    105
    Units: Liters
        arithmetic mean (standard error)
    0.15 ( 0.033 )
    0.05 ( 0.032 )
    0.07 ( 0.03 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The model used absolute change from baseline in pre-bronchodilator in FEV1 as response and the following covariates: Baseline pre-bronchodilator in FEV1, Region, Treatment, Week, and a 4-level categorical variable using Periostin (PERI) and Eosonophil (EOS) levels as (PERI High/EOS High, PERI High/EOS Low, PERI Low/EOS High, and PERI Low/EOS Low)
    Comparison groups
    Lebrikizumab-Modified Intent to Treat (mITT) v Placebo-mITT
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06 [1]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.044
    Notes
    [1] - Mixed effects model for repeated measures (MMRM) was used to model the absolute change from baseline.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The model used absolute change from baseline in pre-bronchodilator in FEV1 as response and the following covariates: Baseline pre-bronchodilator in FEV1, Region, Treatment, Week, and a 4-level categorical variable using PERI and EOS levels as (PERI High/EOS High, PERI High/EOS Low, PERI Low/EOS High, and PERI Low/EOS Low).
    Comparison groups
    Placebo-mITT v Montelukast-mITT
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6954 [2]
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.043
    Notes
    [2] - MMRM was used to model the absolute change from baseline.

    Secondary: Change From Baseline in Asthma Reliever Medication use at Week 12

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    End point title
    		 Change From Baseline in Asthma Reliever Medication use at Week 12
    End point description
    Participants could only receive SABA therapy for asthma treatment as asthma reliever medication (<10 puffs daily). SABA use was recorded in the eDiary. mITT population. Here, "Number of subjects analysed" indicates the total number of participants who provided evaluable data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Lebrikizumab-Modified Intent to Treat (mITT) Placebo-mITT
    Number of subjects analysed
    102
    101
    Units: Puffs/day
        arithmetic mean (standard error)
    -0.51 ( 0.108 )
    -0.55 ( 0.108 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    MMRM was used to model the absolute change from baseline. The model used absolute change from baseline asthma reliever medication (ARM) as response and the following covariates: Baseline ARM, Region, Baseline % of predicted FEV1, Treatment, Week, and a 4-level categorical variable using PERI and EOS levels as (PERI High/EOS High, PERI High/EOS Low, PERI Low/EOS High, and PERI Low/EOS Low)
    Comparison groups
    Lebrikizumab-Modified Intent to Treat (mITT) v Placebo-mITT
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0.32
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.144

    Secondary: Change From Baseline in the Standardized Asthma Quality of Life Questionnaire (AQLQ[S]) Overall Score at Week 12

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    End point title
    		 Change From Baseline in the Standardized Asthma Quality of Life Questionnaire (AQLQ[S]) Overall Score at Week 12
    End point description
    The AQLQ[S]) was used to assess the participant’s asthma-specific health-related quality of life. The 32-item questionnaire contains four domains: activity limitations, symptoms, emotional function, and environmental stimuli. The AQLQ[S]) has a recall specification of 2 weeks. Participants were asked to think about how they had been during the previous 2 weeks and to respond to each of the 32 questions on a 7-point scale (7 = not impaired at all; 1 = severely impaired). An increase in the AQLQ score indicates a better quality of life. The overall AQLQ score is the mean of all 32 responses and the individual domain scores are the means of the items in those domains. mITT population. Here, "Number of subjects analysed" indicates the total number of participants who provided evaluable data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Lebrikizumab-Modified Intent to Treat (mITT) Placebo-mITT
    Number of subjects analysed
    102
    102
    Units: Units on scale
        arithmetic mean (standard error)
    0.62 ( 0.088 )
    0.68 ( 0.086 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    MMRM was used to model the absolute change from baseline. The model used absolute change from baseline AQLQ[S]) as response and the following covariates: Baseline AQLQ[S]), Region, Baseline % of predicted FEV1, Treatment, Week, and a 4-level categorical variable using PERI and EOS levels as (PERI High/EOS High, PERI High/EOS Low, PERI Low/EOS High, and PERI Low/EOS Low)
    Comparison groups
    Lebrikizumab-Modified Intent to Treat (mITT) v Placebo-mITT
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.115

    Secondary: Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) Levels at Week 12

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    End point title
    		 Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) Levels at Week 12
    End point description
    Safety population included all participants who received at least one dose of study drug and who were grouped according to the treatment they received. Here, number (n)= number of participants evaluable for the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Montelukast-Safety Placebo-Safety Lebrikizumab-Safety
    Number of subjects analysed
    103
    103
    104
    Units: parts per billion (ppb)
    arithmetic mean (standard deviation)
        Baseline (n= 103, 103, 104)
    65.89 ( 67.81 )
    50.66 ( 44.49 )
    52.85 ( 44.98 )
        Change at Week 12 (n= 92, 86, 84)
    -13.21 ( 33.28 )
    -10.86 ( 28.41 )
    -31.85 ( 36.13 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Blood Eosinophil Count at Week 12

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    End point title
    		 Change From Baseline in Blood Eosinophil Count at Week 12
    End point description
    Safety population. Here, number (n)= number of participants evaluable for the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Montelukast-Safety Placebo-Safety Lebrikizumab-Safety
    Number of subjects analysed
    103
    103
    104
    Units: cells/microliter (cells/mcL)
    arithmetic mean (standard deviation)
        Baseline (n= 103, 103, 104)
    262.04 ( 169.84 )
    233.3 ( 152.61 )
    230.1 ( 149.9 )
        Change at Week 12 (n= 90, 91, 84)
    -32.67 ( 165.94 )
    33.52 ( 173.87 )
    55.12 ( 215.83 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Serum Periostin at Week 12

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    End point title
    		 Change From Baseline in Serum Periostin at Week 12
    End point description
    Safety population. Here, number (n)= number of participants evaluable for the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Montelukast-Safety Placebo-Safety Lebrikizumab-Safety
    Number of subjects analysed
    103
    103
    104
    Units: Nanogram/milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Baseline (n= 103, 103, 104)
    54.6 ( 16.18 )
    55.37 ( 19.15 )
    53.85 ( 16.71 )
        Change at Week 12 (n= 90, 91, 88)
    -1.3 ( 7.72 )
    0.33 ( 8.13 )
    -3.92 ( 9.68 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total Immunoglobulin E (IgE) Levels at Week 12

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    End point title
    		 Change From Baseline in Total Immunoglobulin E (IgE) Levels at Week 12
    End point description
    Safety population. Here, "Number of subjects analysed" indicates the total number of participants who provided evaluable data for this outcome measure and number (n)= number of participants evaluable for the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Montelukast-Safety Placebo-Safety Lebrikizumab-Safety
    Number of subjects analysed
    103
    102
    103
    Units: Microgram (Mcg)/mL
    arithmetic mean (standard deviation)
        Baseline (n= 103, 102, 103)
    565.42 ( 1051.63 )
    868.28 ( 1422.97 )
    994.46 ( 2032.99 )
        Change at Week 12 (n= 89, 89, 86)
    26.1 ( 408.43 )
    -80.28 ( 582.12 )
    -200.71 ( 643.46 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in C-C Motif Chemokine Ligand 13 (CCL-13) Levels at Week 12

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    End point title
    		 Change From Baseline in C-C Motif Chemokine Ligand 13 (CCL-13) Levels at Week 12
    End point description
    Safety population. Here, "Number of subjects analysed" indicates the total number of participants who provided evaluable data for this outcome measure and number (n)= number of participants evaluable for the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Montelukast-Safety Placebo-Safety Lebrikizumab-Safety
    Number of subjects analysed
    103
    102
    104
    Units: Picogram/mL (pg/mL)
    arithmetic mean (standard deviation)
        Baseline (n= 103, 102, 104)
    201.34 ( 81.13 )
    206.19 ( 91.04 )
    192.79 ( 87.77 )
        Change at Week 12 (n= 90, 90, 88)
    0.19 ( 51.31 )
    4.36 ( 72 )
    -35.79 ( 57.72 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in CCL-17 Levels at Week 12

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    End point title
    		 Change From Baseline in CCL-17 Levels at Week 12
    End point description
    Safety population included all participants who received at least one dose of study drug and who were grouped according to the treatment they received. Here, "Number of subjects analysed" indicates the total number of participants who provided evaluable data for this outcome measure and number (n)= number of participants evaluable for the specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Montelukast-Safety Placebo-Safety Lebrikizumab-Safety
    Number of subjects analysed
    103
    102
    104
    Units: pg/mL
    arithmetic mean (standard deviation)
        Baseline (n= 103, 102, 104)
    326.09 ( 189.33 )
    365.48 ( 206.23 )
    506.49 ( 1476.14 )
        Change at Week 12 (n= 90, 90, 87)
    5.79 ( 134.93 )
    23.93 ( 169.01 )
    -133.93 ( 764.14 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Plasma Lebrikizumab Concentration After the First Dose (Cmax)

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    End point title
    		 Maximum Observed Plasma Lebrikizumab Concentration After the First Dose (Cmax)
    End point description
    Pharmacokinetic (PK)-evaluable population included participants who had received at least one subcutaneous dose of lebrikizumab and had at least one lebrikizumab PK sample. Here, N (number of participants analyzed) indicates the total number of participants who provided evaluable data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Postdose on Day 8
    End point values
    		 Lebrikizumab-Modified Intent to Treat (mITT)
    Number of subjects analysed
    103
    Units: Mcg/mL
        arithmetic mean (standard deviation)
    14.9 ( 5.91 )
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Lebrikizumab Concentration After the First Dose (Tmax)

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    End point title
    		 Time to Reach Maximum Lebrikizumab Concentration After the First Dose (Tmax)
    End point description
    PK-evaluable population. Here, N (number of participants analyzed) indicates the total number of participants who provided evaluable data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Postdose on Day 8
    End point values
    		 Lebrikizumab-Modified Intent to Treat (mITT)
    Number of subjects analysed
    103
    Units: Days
        arithmetic mean (standard deviation)
    7.04 ( 1.17 )
    No statistical analyses for this end point

    Secondary: Predose Serum Lebrikizumab Concentration (Cmin) at Week 4

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    End point title
    		 Predose Serum Lebrikizumab Concentration (Cmin) at Week 4
    End point description
    PK-evaluable population. Here, "Number of subjects analysed" indicates the total number of participants who provided evaluable data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Predose (at Hour 0) on Week 4
    End point values
    		 Lebrikizumab-Modified Intent to Treat (mITT)
    Number of subjects analysed
    101
    Units: Mcg/mL
        arithmetic mean (standard deviation)
    9.58 ( 4.12 )
    No statistical analyses for this end point

    Secondary: Predose Serum Lebrikizumab Concentration (Cmin) at Week 12

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    End point title
    		 Predose Serum Lebrikizumab Concentration (Cmin) at Week 12
    End point description
    PK-evaluable population. Here, "Number of subjects analysed" indicates the total number of participants who provided evaluable data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Predose (at Hour 0) on Week 12
    End point values
    		 Lebrikizumab-Modified Intent to Treat (mITT)
    Number of subjects analysed
    82
    Units: Mcg/mL
        arithmetic mean (standard deviation)
    18.1 ( 6.46 )
    No statistical analyses for this end point

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

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    End point title
    		 Plasma Elimination Half-Life (t1/2) of Lebrikizumab
    End point description
    PK-evaluable population. Here, "Number of subjects analysed" indicates the total number of participants who provided evaluable data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Predose (at Hour 0) on Day 57, Days 85, 113, 141
    End point values
    		 Lebrikizumab-Modified Intent to Treat (mITT)
    Number of subjects analysed
    90
    Units: Days
        arithmetic mean (standard deviation)
    23.7 ( 7.24 )
    No statistical analyses for this end point

    Secondary: Change Fom Baseline in Morning Pre-bronchodilator Peak Expiratory Flow (PEF) at Week 12: Placebo Versus Montelukast

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    End point title
    		 Change Fom Baseline in Morning Pre-bronchodilator Peak Expiratory Flow (PEF) at Week 12: Placebo Versus Montelukast
    End point description
    PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. mITT population. Here, "Number of subjects analysed" indicates the total number of participants who provided evaluable data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Montelukast-mITT Placebo-mITT
    Number of subjects analysed
    98
    101
    Units: Liters/minute
        arithmetic mean (standard error)
    5.92 ( 5.973 )
    4.69 ( 5.872 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    MMRM was used to model the absolute change from baseline. The model used absolute change from baseline PEF as response and the following covariates: Baseline PEF, Region, Baseline % of predicted FEV1, Treatment, Week, and a 4-level categorical variable using PERI and EOS levels as (PERI High/EOS High, PERI High/EOS Low, PERI Low/EOS High,and PERI Low/EOS Low).
    Comparison groups
    Montelukast-mITT v Placebo-mITT
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.57
         upper limit
    		 17.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.012

    Secondary: Change From Baseline in Morning Pre-bronchodilator PEF at Week 12: Placebo Versus Lebrikizumab

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    End point title
    		 Change From Baseline in Morning Pre-bronchodilator PEF at Week 12: Placebo Versus Lebrikizumab
    End point description
    PEF is defined as the maximum airflow during a forced expiration beginning with the lungs fully inflated. mITT population. Here, "Number of subjects analysed" indicates the total number of participants who provided evaluable data for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12
    End point values
    		 Lebrikizumab-Modified Intent to Treat (mITT) Placebo-mITT
    Number of subjects analysed
    102
    101
    Units: Liters/minute
        arithmetic mean (standard error)
    1.63 ( 5.551 )
    5.25 ( 5.565 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    MMRM was used to model the absolute change from baseline. The model used absolute change from baseline PEF as response and the following covariates: Baseline PEF, Region, Baseline % of predicted FEV1, Treatment, Week, and a 4-level categorical variable using PERI and EOS levels as (PERI High/EOS High, PERI High/EOS Low, PERI Low/EOS High, and PERI Low/EOS Low).
    Comparison groups
    Lebrikizumab-Modified Intent to Treat (mITT) v Placebo-mITT
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.46
         upper limit
    		 11.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.523

    Secondary: Number of Participants With Treatment Failure

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    End point title
    		 Number of Participants With Treatment Failure
    End point description
    Treatment failure was defined as a worsening of asthma symptoms (per investigator’s assessment of participant report) in association with either relative decline in pre-bronchodilator FEV1 >=20%; or >=20% decline in morning pre-bronchodilator PEF on 2 consecutive days compared with baseline; or use of >=10 puffs of albuterol metered dose inhaler (MDI); or >=2 additional administrations (or any new use) of nebulized short-acting β-agonist (SABA) therapy within any calendar day; or need for any inhaled, oral, or parenteral corticosteroid or for a controller medication. The hazard ratio from the Cox Proportional Hazards model compared the risk of treatment failure for the lebrikizumab-treated and placebo participants. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    End point values
    		 Lebrikizumab-Modified Intent to Treat (mITT) Placebo-mITT
    Number of subjects analysed
    104
    105
    Units: Participants with treatment failure
    9
    11
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Multivariate Cox proportional hazards regression was used to estimate Hazard Ratios. Confidence intervals (CI) calculated according to Wald. Covariates: treatment, region, baseline periostin and eosinophil category, and baseline percentage FEV1 category.
    Comparison groups
    Placebo-mITT v Lebrikizumab-Modified Intent to Treat (mITT)
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 2.42

    Secondary: Time to Treatment Failure

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    End point title
    		 Time to Treatment Failure
    End point description
    Treatment failure was defined as a worsening of asthma symptoms (per investigator’s assessment of participant report) in association with either relative decline in pre-bronchodilator FEV1 >=20%; or >=20% decline in morning pre-bronchodilator PEF on 2 consecutive days compared with baseline; or use of >=10 puffs of albuterol metered dose inhaler (MDI); or >=2 additional administrations (or any new use) of nebulized short-acting β-agonist (SABA) therapy within any calendar day; or need for any inhaled, oral, or parenteral corticosteroid or for a controller medication. Time to treatment failure was estimated using Kaplan-Meier method. mITT population. Median and corresponding 95% CI could not be estimated due to higher number (>50%) of censored participants who have been reported as 99999.
    End point type
    Secondary
    End point timeframe
    Basleine up to Week 12
    End point values
    		 Lebrikizumab-Modified Intent to Treat (mITT) Placebo-mITT
    Number of subjects analysed
    104
    105
    Units: Days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    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 20
    Adverse event reporting additional description
    Safety population.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Lebrikizumab-Safety
    Reporting group description
    		 Lebrikizumab 125 mg SC administered as injection on Day 1, 29 and 57 during the 12-week treatment period. Participants were followed up further for 8 weeks during the safety follow-up period.

    Reporting group title
    Montelukast-Safety
    Reporting group description
    		 Montelukast 10 mg tablet administered orally once daily during the 12-week treatment period. Participants were followed up further for 8 weeks during the safety follow-up period.

    Reporting group title
    Placebo-Safety
    Reporting group description
    		 Placebo matched to lebrikizumab 125 mg SC administered as injection on Day 1, 29 and 57 during the 12-week treatment period. Participants were followed up further for 8 weeks during the safety follow-up period.

    Serious adverse events
    		 Lebrikizumab-Safety Montelukast-Safety Placebo-Safety
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 104 (1.92%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma in situ
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrospinal fluid leakage
         subjects affected / exposed
    0 / 104 (0.00%)
    0 / 103 (0.00%)
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 104 (0.96%)
    0 / 103 (0.00%)
    0 / 103 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lebrikizumab-Safety Montelukast-Safety Placebo-Safety
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 104 (24.04%)
    33 / 103 (32.04%)
    24 / 103 (23.30%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 104 (2.88%)
    5 / 103 (4.85%)
    6 / 103 (5.83%)
         occurrences all number
    3
    6
    6
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    6 / 104 (5.77%)
    12 / 103 (11.65%)
    12 / 103 (11.65%)
         occurrences all number
    6
    12
    15
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 104 (8.65%)
    11 / 103 (10.68%)
    5 / 103 (4.85%)
         occurrences all number
    10
    13
    5
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 104 (8.65%)
    8 / 103 (7.77%)
    5 / 103 (4.85%)
         occurrences all number
    9
    8
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Sep 2015
    - Description of completed and ongoing clinical trials with lebrikizumab was updated. - Biomarker subgroups for analysis to include blood eosinophil count was updated. - Secondary efficacy endpoints, pharmacokinetic and pharmacodynamic endpoints, and exploratory efficacy endpoints were updated. - Statistical analyses details were updated.

    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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