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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 Idiopathic Pulmonary Fibrosis

    Summary
    EudraCT number
    2013-001163-24
    Trial protocol
    DE   IT   ES   PL   GB   BE   FR  
    Global end of trial date
    06 Nov 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Aug 2018
    First version publication date
    09 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GB28547
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01872689
    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
    06 Nov 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate lebrikizumab compared with placebo as monotherapy or as combination therapy with pirfenidone background compared with placebo in participants with idiopathic pulmonary fibrosis (IPF), as measured by the annualized rate of decline in percentage of predicted forced vital capacity (FVC) over 52 weeks.
    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. Approval from the Independent Ethics Committee/Institutional Review Board (IEC/IRB) 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. The Sponsor also obtained approval from the relevant Competent Authority prior to starting the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Oct 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 222
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Canada: 15
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    Germany: 31
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Poland: 43
    Country: Number of subjects enrolled
    Australia: 44
    Country: Number of subjects enrolled
    Japan: 49
    Country: Number of subjects enrolled
    Mexico: 13
    Country: Number of subjects enrolled
    Peru: 7
    Worldwide total number of subjects
    505
    EEA total number of subjects
    155
    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)
    120
    From 65 to 84 years
    382
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 505 participants (154 participants in Monotherapy Cohort and 351 participants in Combination Therapy Cohort) were enrolled in the study. Of the monotherapy cohort, 114 participants completed the double-blind period and only 108 of these participants continued into the 52-week open-label lebrikizumab treatment period.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Monotherapy (Cohort A): Placebo
    Arm description
    Participants received monotherapy with placebo matched to lebrikizumab administered via subcutaneous (SC) injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period. Participants were allowed to receive treatment with lebrikizumab at a dose of 250 milligrams (mg) administered via SC injection once every 4 weeks up to additional 52 weeks (that is, up to Week 104) in the open-label period.
    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 matched to lebrikizumab was administered via SC injection once every 4 weeks.

    Arm title
    Monotherapy (Cohort A): Lebrikizumab
    Arm description
    Participants received monotherapy with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period. Participants were allowed to receive treatment with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to additional 52 weeks (that is, up to Week 104) in the open-label period.
    Arm type
    Experimental

    Investigational medicinal product name
    Lebrikizumab
    Investigational medicinal product code
    Other name
    RO5490255
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lebrikizumab was administered at a dose of 250 mg via SC injection once every 4 weeks.

    Arm title
    Combination Therapy (Cohort B): Placebo + Pirfenidone
    Arm description
    Participants received pirfenidone at a stable dose of 2403 mg per day (three 267 mg capsules three times a day [9 capsules daily] for a total of 2403 mg/day) or at maximum tolerated dose (MTD) administered orally along with placebo matched to lebrikizumab administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period.
    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 matched to lebrikizumab was administered via SC injection once every 4 weeks.

    Investigational medicinal product name
    Pirfenidone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Pirfenidone was administered orally at a stable dose of 2403 mg per day or at MTD.

    Arm title
    Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Arm description
    Participants received pirfenidone at a stable dose of 2403 mg per day (three 267 mg capsules three times a day [9 capsules daily] for a total of 2403 mg/day) or at MTD administered orally along with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period.
    Arm type
    Experimental

    Investigational medicinal product name
    Lebrikizumab
    Investigational medicinal product code
    Other name
    RO5490255
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lebrikizumab was administered at a dose of 250 mg via SC injection once every 4 weeks.

    Investigational medicinal product name
    Pirfenidone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Pirfenidone was administered orally at a stable dose of 2403 mg per day or at MTD.

    Number of subjects in period 1
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Started
    76
    78
    177
    174
    Completed
    56
    58
    129
    136
    Not completed
    20
    20
    48
    38
         Protocol deviation
    -
    -
    1
    1
         Death
    3
    4
    14
    9
         Physician decision
    -
    3
    3
    1
         Lack of efficacy
    -
    1
    -
    -
         Consent withdrawn by subject
    9
    8
    14
    16
         Unspecified
    1
    1
    6
    3
         Adverse Event
    6
    3
    10
    7
         Lost to follow-up
    1
    -
    -
    1
    Period 2
    Period 2 title
    Open-Label Period (Only For Monotherapy)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Monotherapy (Cohort A): Placebo
    Arm description
    Participants received monotherapy with placebo matched to lebrikizumab administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period. Participants were allowed to receive treatment with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to additional 52 weeks (that is, up to Week 104) in the open-label period.
    Arm type
    Placebo

    Investigational medicinal product name
    Lebrikizumab
    Investigational medicinal product code
    Other name
    RO5490255
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lebrikizumab was administered at a dose of 250 mg via SC injection once every 4 weeks.

    Arm title
    Monotherapy (Cohort A): Lebrikizumab
    Arm description
    Participants received monotherapy with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period. Participants were allowed to receive treatment with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to additional 52 weeks (that is, up to Week 104) in the open-label period.
    Arm type
    Experimental

    Investigational medicinal product name
    Lebrikizumab
    Investigational medicinal product code
    Other name
    RO5490255
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Lebrikizumab was administered at a dose of 250 mg via SC injection once every 4 weeks.

    Number of subjects in period 2 [1]
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab
    Started
    52
    56
    Completed
    31
    33
    Not completed
    21
    23
         Death
    5
    3
         Physician decision
    -
    1
         Consent withdrawn by subject
    11
    12
         Unspecified
    2
    3
         Adverse Event
    2
    1
         Lost to follow-up
    1
    3
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: All participants who completed double-blind placebo-controlled period did not require to continue in the open-label period, so numbers may not match.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Monotherapy (Cohort A): Placebo
    Reporting group description
    Participants received monotherapy with placebo matched to lebrikizumab administered via subcutaneous (SC) injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period. Participants were allowed to receive treatment with lebrikizumab at a dose of 250 milligrams (mg) administered via SC injection once every 4 weeks up to additional 52 weeks (that is, up to Week 104) in the open-label period.

    Reporting group title
    Monotherapy (Cohort A): Lebrikizumab
    Reporting group description
    Participants received monotherapy with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period. Participants were allowed to receive treatment with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to additional 52 weeks (that is, up to Week 104) in the open-label period.

    Reporting group title
    Combination Therapy (Cohort B): Placebo + Pirfenidone
    Reporting group description
    Participants received pirfenidone at a stable dose of 2403 mg per day (three 267 mg capsules three times a day [9 capsules daily] for a total of 2403 mg/day) or at maximum tolerated dose (MTD) administered orally along with placebo matched to lebrikizumab administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period.

    Reporting group title
    Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Reporting group description
    Participants received pirfenidone at a stable dose of 2403 mg per day (three 267 mg capsules three times a day [9 capsules daily] for a total of 2403 mg/day) or at MTD administered orally along with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period.

    Reporting group values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone Total
    Number of subjects
    76 78 177 174 505
    Age, Customized
    Units: Subjects
        From 40 to <55 years
    2 1 6 2 11
        From 55 to <65 years
    18 10 40 41 109
        From 65 to <75 years
    38 44 99 92 273
        >/=75 years
    18 23 32 39 112
    Sex: Female, Male
    Units: Subjects
        Female
    13 13 30 37 93
        Male
    63 65 147 137 412
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    1 1 0 1 3
        Asian
    11 8 19 15 53
        Native Hawaiian or Other Pacific Islander
    1 0 1 0 2
        Black or African American
    0 0 1 1 2
        White
    60 66 149 151 426
        More than one race
    0 1 0 0 1
        Unknown or Not Reported
    3 2 7 6 18
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    9 6 13 15 43
        Not Hispanic or Latino
    64 68 160 155 447
        Unknown or Not Reported
    3 4 4 4 15

    End points

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    End points reporting groups
    Reporting group title
    Monotherapy (Cohort A): Placebo
    Reporting group description
    Participants received monotherapy with placebo matched to lebrikizumab administered via subcutaneous (SC) injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period. Participants were allowed to receive treatment with lebrikizumab at a dose of 250 milligrams (mg) administered via SC injection once every 4 weeks up to additional 52 weeks (that is, up to Week 104) in the open-label period.

    Reporting group title
    Monotherapy (Cohort A): Lebrikizumab
    Reporting group description
    Participants received monotherapy with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period. Participants were allowed to receive treatment with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to additional 52 weeks (that is, up to Week 104) in the open-label period.

    Reporting group title
    Combination Therapy (Cohort B): Placebo + Pirfenidone
    Reporting group description
    Participants received pirfenidone at a stable dose of 2403 mg per day (three 267 mg capsules three times a day [9 capsules daily] for a total of 2403 mg/day) or at maximum tolerated dose (MTD) administered orally along with placebo matched to lebrikizumab administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period.

    Reporting group title
    Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Reporting group description
    Participants received pirfenidone at a stable dose of 2403 mg per day (three 267 mg capsules three times a day [9 capsules daily] for a total of 2403 mg/day) or at MTD administered orally along with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period.
    Reporting group title
    Monotherapy (Cohort A): Placebo
    Reporting group description
    Participants received monotherapy with placebo matched to lebrikizumab administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period. Participants were allowed to receive treatment with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to additional 52 weeks (that is, up to Week 104) in the open-label period.

    Reporting group title
    Monotherapy (Cohort A): Lebrikizumab
    Reporting group description
    Participants received monotherapy with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period. Participants were allowed to receive treatment with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to additional 52 weeks (that is, up to Week 104) in the open-label period.

    Primary: Annualized Rate of Decrease in Percent Predicted Forced Vital Capacity (FVC) Over 52 Weeks

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    End point title
    Annualized Rate of Decrease in Percent Predicted Forced Vital Capacity (FVC) Over 52 Weeks
    End point description
    Annualized rates of decrease (slope throughout time from baseline to Week 52) for percent predicted FVC was assessed and reported. FVC is a standard pulmonary function test. FVC is defined as the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Predicted FVC is based on sex, age, and height of a person. Percent predicted FVC (in %) = [(observed FVC)/(predicted FVC)]*100. Analysis was performed on Intent-to-Treat (ITT) Population, which included all participants who were randomized in the study, with participants grouped according to the treatment assignment at randomization. Here 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure at Week 52.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 52 (assessed at Baseline, Weeks 1, 4, 12, 24, 36, 44, and 52)
    End point values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    53
    56
    120
    134
    Units: Percent predicted FVC/year
        arithmetic mean (standard error)
    -6.1876 ± 0.92597
    -5.2065 ± 0.92758
    -6.0430 ± 0.60633
    -5.5430 ± 0.59507
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Linear model comparing Lebrikizumab to Placebo, with assessment as the outcome variable; assessment time by treatment as fixed effects; and participant baseline FVC (<50%, 50 to 75%, >75%) and participant by assessment time as random effects with unstructured covariance.
    Comparison groups
    Monotherapy (Cohort A): Placebo v Monotherapy (Cohort A): Lebrikizumab
    Number of subjects included in analysis
    109
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4555
    Method
    Mixed models analysis
    Parameter type
    Median difference (final values)
    Point estimate
    0.98111
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.61
         upper limit
    3.57
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.31064
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Mixed Linear model comparing Lebrikizumab to Placebo, with assessment as the outcome variable; assessment time by treatment as fixed effects; and participant baseline FVC (<50%, 50 to 75%, >75%) and participant by assessment time as random effects with unstructured covariance.
    Comparison groups
    Combination Therapy (Cohort B): Placebo + Pirfenidone v Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5566
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.49998
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.17
         upper limit
    2.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.84946

    Secondary: Annualized Rate of Decline in 6-Minute Walk Test (6MWT) Distance Over 52 Weeks

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    End point title
    Annualized Rate of Decline in 6-Minute Walk Test (6MWT) Distance Over 52 Weeks
    End point description
    Annualized rates of decline (slope throughout time from baseline to Week 52) in 6MWT was assessed and reported. 6MWT was the distance (in meters [m]) that a participant could walk in 6 minutes. Analysis was performed on ITT Population. Here 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure at Week 52.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52 (assessed at Baseline, Weeks 1, 4, 12, 24, 36, 44, and 52)
    End point values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    52
    59
    120
    129
    Units: m/year
        arithmetic mean (standard error)
    -44.6512 ± 15.97862
    -22.7209 ± 15.34753
    -25.5683 ± 12.24923
    -46.9810 ± 11.84199
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Linear model comparing Lebrikizumab to Placebo, with assessment as the outcome variable; assessment time by treatment as fixed effects; and participant baseline FVC (<50%, 50 to 75%, >75%) and participant by assessment time as random effects with unstructured covariance.
    Comparison groups
    Monotherapy (Cohort A): Placebo v Monotherapy (Cohort A): Lebrikizumab
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3129
    Method
    Mixed models analysis
    Parameter type
    Median difference (final values)
    Point estimate
    21.93023
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.97
         upper limit
    64.83
    Variability estimate
    Standard error of the mean
    Dispersion value
    21.62248
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Mixed Linear model comparing Lebrikizumab to Placebo, with assessment as the outcome variable; assessment time by treatment as fixed effects; and participant baseline FVC (<50%, 50 to 75%, >75%) and participant by assessment time as random effects with unstructured covariance.
    Comparison groups
    Combination Therapy (Cohort B): Placebo + Pirfenidone v Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects included in analysis
    249
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2036
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -21.4127
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -54.5
         upper limit
    11.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    16.8016

    Secondary: Percentage of Participants with Event of Greater Than or Equal to (>/=) 10% Absolute Decline in Percent Predicted FVC or Death from Any Cause

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    End point title
    Percentage of Participants with Event of Greater Than or Equal to (>/=) 10% Absolute Decline in Percent Predicted FVC or Death from Any Cause
    End point description
    FVC is defined as the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Predicted FVC is based on sex, age, and height of a person. Percent predicted FVC (in %) = [(observed FVC)/(predicted FVC)]*100. Analysis was performed on ITT Population. Here 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to the event of >/=10% absolute decline in percent predicted FVC or death from any cause, whichever occurred first (up to Week 122)
    End point values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    76
    76
    175
    173
    Units: percentage of participants
        number (not applicable)
    34.2
    27.6
    30.3
    26.6
    No statistical analyses for this end point

    Secondary: Time to First Occurrence of a >/=10% Absolute Decline in Percent Predicted FVC or Death from Any Cause

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    End point title
    Time to First Occurrence of a >/=10% Absolute Decline in Percent Predicted FVC or Death from Any Cause
    End point description
    FVC is defined as the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Predicted FVC is based on sex, age, and height of a person. Percent predicted FVC = [(observed FVC)/(predicted FVC)]*100. Time from randomization to first occurrence of an event of >/=10% absolute decline in percent predicted FVC or death from any cause was reported. Participants without an event were censored at the last assessment during the double-blind treatment period. Any participant who underwent lung transplantation was censored at the date of the transplant. The median time to event was estimated using Kaplan-Meier method and 95% confidence interval (CI) was computed using the method of Brookmeyer and Crowley. Analysis was performed on ITT Population. 'Number of Subjects Analysed' = participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to the event of >/=10% absolute decline in percent predicted FVC or death from any cause, whichever occurred first (up to Week 122)
    End point values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    76 [1]
    76 [2]
    175 [3]
    173 [4]
    Units: weeks
        median (confidence interval 95%)
    53.1 (52.6 to 99999)
    99999 (99999 to 99999)
    99999 (52.9 to 99999)
    99999 (99999 to 99999)
    Notes
    [1] - ‘99999’ = CI could not be estimated due to high number of censored participants.
    [2] - ‘99999’ = median and CI could not be estimated due to high number of censored participants.
    [3] - ‘99999’ = median and CI could not be estimated due to high number of censored participants.
    [4] - ‘99999’ = median and CI could not be estimated due to high number of censored participants.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: stratified by baseline FVC (<50%, 50 to 75%, >75%)
    Comparison groups
    Monotherapy (Cohort A): Placebo v Monotherapy (Cohort A): Lebrikizumab
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4299
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    1.41
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Stratified Analysis: stratified by baseline FVC (<50%, 50 to 75%, >75%)
    Comparison groups
    Combination Therapy (Cohort B): Placebo + Pirfenidone v Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects included in analysis
    348
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3751
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.56
         upper limit
    1.24

    Secondary: Annualized Rate of Decrease in Diffusion Capacity of the Lung for Carbon Monoxide (DLco) Over 52 Weeks

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    End point title
    Annualized Rate of Decrease in Diffusion Capacity of the Lung for Carbon Monoxide (DLco) Over 52 Weeks
    End point description
    Annualized rates of decrease (slope throughout time from baseline to Week 52) in DLco was assessed and reported. DLco (in milliliters per minute/millimeters of mercury [mL/min/mmHg]) is a measure of the gas transfer. Analysis was performed on ITT Population. Here 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure at Week 52.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52 (assessed at Baseline, Weeks 1, 4, 12, 24, 36, 44, and 52)
    End point values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    50
    52
    112
    122
    Units: mL/min/mmHg/year
        arithmetic mean (standard error)
    -4.7818 ± 0.74479
    -4.2400 ± 0.73826
    -5.7552 ± 0.46561
    -5.5732 ± 0.45577
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Linear model comparing Lebrikizumab to Placebo, with assessment as the outcome variable; assessment time by treatment as fixed effects; and participant baseline FVC (<50%, 50 to 75%, >75%) and participant by assessment time as random effects with unstructured covariance.
    Comparison groups
    Monotherapy (Cohort A): Placebo v Monotherapy (Cohort A): Lebrikizumab
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6075
    Method
    Mixed models analysis
    Parameter type
    Median difference (final values)
    Point estimate
    0.54171
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.54
         upper limit
    2.62
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.05201
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Mixed Linear model comparing Lebrikizumab to Placebo, with assessment as the outcome variable; assessment time by treatment as fixed effects; and participant baseline FVC (<50%, 50 to 75%, >75%) and participant by assessment time as random effects with unstructured covariance.
    Comparison groups
    Combination Therapy (Cohort B): Placebo + Pirfenidone v Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects included in analysis
    234
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7803
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.18203
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    1.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.65206

    Secondary: Percentage of Participants with Event of Death, All Cause Hospitalization, or a Decrease from Baseline of >/=10% in FVC

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    End point title
    Percentage of Participants with Event of Death, All Cause Hospitalization, or a Decrease from Baseline of >/=10% in FVC
    End point description
    FVC is defined as the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Predicted FVC is based on sex, age, and height of a person. Percent predicted FVC = [(observed FVC)/(predicted FVC)]*100. Analysis was performed on ITT Population. Here 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to the event of death from any cause, all cause hospitalization, or a decrease from baseline of >/=10% in FVC, whichever occurred first (up to Week 122)
    End point values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    76
    76
    175
    173
    Units: percentage of participants
        number (not applicable)
    47.4
    32.9
    39.4
    39.9
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS)
    End point description
    FVC is defined as the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. Predicted FVC is based on sex, age, and height of a person. Percent predicted FVC = [(observed FVC)/(predicted FVC)]*100. PFS was defined as time from randomization to death from any cause, all cause hospitalization, or a decrease from baseline of >/=10% in FVC, whichever occurred first. Participants without an event were censored at the last assessment during the double-blind treatment period. Any participant who underwent lung transplantation was censored at the date of the transplant. The median PFS was estimated using Kaplan-Meier method. 95% CI for median was computed using the method of Brookmeyer and Crowley. Analysis was performed on ITT Population. Here 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to the event of death from any cause, all cause hospitalization, or a decrease from baseline of >/=10% in FVC, whichever occurred first (up to Week 122)
    End point values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    76 [5]
    76 [6]
    175 [7]
    173 [8]
    Units: weeks
        median (confidence interval 95%)
    52.6 (43.9 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (52.3 to 99999)
    Notes
    [5] - ‘99999’ = CI could not be estimated due to high number of censored participants.
    [6] - ‘99999’ = median and CI could not be estimated due to high number of censored participants.
    [7] - ‘99999’ = median and CI could not be estimated due to high number of censored participants.
    [8] - ‘99999’ = median and CI could not be estimated due to high number of censored participants.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: stratified by baseline FVC (<50%, 50 to 75%, >75%)
    Comparison groups
    Monotherapy (Cohort A): Placebo v Monotherapy (Cohort A): Lebrikizumab
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0972
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    1.09
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Stratified Analysis: stratified by baseline FVC (<50%, 50 to 75%, >75%)
    Comparison groups
    Combination Therapy (Cohort B): Placebo + Pirfenidone v Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects included in analysis
    348
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9344
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.72
         upper limit
    1.42

    Secondary: Annualized Rate of Decrease in FVC Over 52 Weeks

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    End point title
    Annualized Rate of Decrease in FVC Over 52 Weeks
    End point description
    Annualized rates of decrease (slope throughout time from baseline to Week 52) in FVC (in milliliters per year [mL/year]) was assessed and reported. FVC is defined as the volume of air that can forcibly be blown out after full inspiration in the upright position. Analysis was performed on ITT Population. Here 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure at Week 52.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52 (assessed at Baseline, Weeks 1, 4, 12, 24, 36, 44, and 52)
    End point values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    53
    57
    120
    134
    Units: mL/year
        arithmetic mean (standard error)
    -221.029 ± 34.87511
    -192.906 ± 34.93853
    -231.167 ± 22.67786
    -209.437 ± 22.25073
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Linear model comparing Lebrikizumab to Placebo, with assessment as the outcome variable; assessment time by treatment as fixed effects; and participant baseline FVC (<50%, 50 to 75%, >75%) and participant by assessment time as random effects with unstructured covariance.
    Comparison groups
    Monotherapy (Cohort A): Placebo v Monotherapy (Cohort A): Lebrikizumab
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5707
    Method
    Mixed models analysis
    Parameter type
    Median difference (final values)
    Point estimate
    28.12302
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -69.8
         upper limit
    126.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    49.47253
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Mixed Linear model comparing Lebrikizumab to Placebo, with assessment as the outcome variable; assessment time by treatment as fixed effects; and participant baseline FVC (<50%, 50 to 75%, >75%) and participant by assessment time as random effects with unstructured covariance.
    Comparison groups
    Combination Therapy (Cohort B): Placebo + Pirfenidone v Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4934
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    21.72972
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -40.65
         upper limit
    84.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    31.68767

    Secondary: Annualized Rate of Decrease in A Tool to Assess Quality of Life in IPF (ATAQ-IPF) Questionnaire Total Score Over 52 Weeks

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    End point title
    Annualized Rate of Decrease in A Tool to Assess Quality of Life in IPF (ATAQ-IPF) Questionnaire Total Score Over 52 Weeks
    End point description
    The ATAQ-IPF Version 3 was utilized that included 31 items within 5 domains: cough (6 items), dyspnea (7 items), exhaustion (6 items), emotional well-being (6 items), and independence (6 items). Each item was assessed on a scale ranging from 1 (Strongly disagree) to 4 (Strongly agree). The ATAQ-IPF had a recall specification of 2 weeks. Simple summation scoring was used to derive individual domain scores as well as a total score. ATAQ-IPF total score ranged from 31 to 124 with lower score indicating better quality of life (QoL). Annualized rates of decrease (slope throughout time from baseline to Week 52) in ATAQ-IPF questionnaire total score was assessed and reported. Analysis was performed on ITT Population. Here 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure at Week 52.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52 (assessed at Baseline, Weeks 1, 4, 12, 24, 36, 44, and 52)
    End point values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    58
    62
    136
    144
    Units: units on a scale/year
        arithmetic mean (standard error)
    6.8907 ± 1.71778
    4.7886 ± 1.70370
    5.6189 ± 0.99880
    5.4558 ± 0.97793
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Linear model comparing Lebrikizumab to Placebo, with assessment as the outcome variable; assessment time by treatment as fixed effects; and participant baseline FVC (<50%, 50 to 75%, >75%) and participant by assessment time as random effects with unstructured covariance.
    Comparison groups
    Monotherapy (Cohort A): Placebo v Monotherapy (Cohort A): Lebrikizumab
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3854
    Method
    Mixed models analysis
    Parameter type
    Median difference (final values)
    Point estimate
    -2.10204
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.88
         upper limit
    2.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.41325
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Mixed Linear model comparing Lebrikizumab to Placebo, with assessment as the outcome variable; assessment time by treatment as fixed effects; and participant baseline FVC (<50%, 50 to 75%, >75%) and participant by assessment time as random effects with unstructured covariance.
    Comparison groups
    Combination Therapy (Cohort B): Placebo + Pirfenidone v Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects included in analysis
    280
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9057
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.16313
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.87
         upper limit
    2.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.37698

    Secondary: Percentage of Participants with an Event of St. George's Respiratory Questionnaire (SGRQ) Total Score Worsening or Death from Any Cause

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    End point title
    Percentage of Participants with an Event of St. George's Respiratory Questionnaire (SGRQ) Total Score Worsening or Death from Any Cause [9]
    End point description
    The SGRQ is a 50-item health-related QoL instrument that measured health impairment. The questionnaire contains 3 domains: symptoms, activity, and impacts. Items were assessed on various response scales, including a 5-point Likert scale and True/False scale. The SGRQ had a recall specification of 4 weeks. The SGRQ total score (summed weights) ranged from 0 to 100 with a lower score denoting a better health status. Percentage of participants with an event of SGRQ total score worsening (defined as reaching minimal important difference [MID], that is, an increase in total score of >/=7) or death from any cause was reported. Analysis was performed on ITT Population for monotherapy cohort only. Here, 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to the event of SGRQ total score worsening or death from any cause, whichever occurred first (up to Week 122)
    Notes
    [9] - 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: Reported analysis was planned to be carried out in the indicated arms only.
    End point values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab
    Number of subjects analysed
    76
    76
    Units: percentage of participants
        number (not applicable)
    57.9
    48.7
    No statistical analyses for this end point

    Secondary: Time to First Occurrence of SGRQ Total Score Worsening or Death from Any Cause

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    End point title
    Time to First Occurrence of SGRQ Total Score Worsening or Death from Any Cause [10]
    End point description
    The SGRQ is a 50-item health-related QoL instrument that measured health impairment. The questionnaire contains 3 domains: symptoms, activity, and impacts. Items were assessed on various response scales, including a 5-point Likert scale and True/False scale. The SGRQ had a recall specification of 4 weeks. The SGRQ total score (summed weights) ranged from 0 to 100 with a lower score denoting a better health status. Time from randomization to first occurrence of an event of SGRQ total score worsening (defined as reaching minimal important difference [MID], that is, an increase in total score of >/=7) or death from any cause was reported. The median time to event was estimated using Kaplan-Meier method. 95% CI for median was computed using the method of Brookmeyer and Crowley. ITT Population for monotherapy cohort only; ‘Number of Subjects Analysed’ = number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to the event of SGRQ total score worsening or death from any cause, whichever occurred first (up to Week 122)
    Notes
    [10] - 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: Reported analysis was planned to be carried out in the indicated arms only.
    End point values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab
    Number of subjects analysed
    76
    76 [11]
    Units: weeks
        median (confidence interval 95%)
    51.7 (24.1 to 54.6)
    52.3 (35.7 to 99999)
    Notes
    [11] - ‘99999’ = upper limit of CI could not be estimated due to high number of censored participants.
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: stratified by baseline FVC (<50%, 50 to 75%, >75%)
    Comparison groups
    Monotherapy (Cohort A): Placebo v Monotherapy (Cohort A): Lebrikizumab
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4433
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.54
         upper limit
    1.31

    Secondary: Percentage of Participants with an Event of Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbation

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    End point title
    Percentage of Participants with an Event of Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbation
    End point description
    IPF exacerbation was defined as an event that met all of the following criteria as determined by the investigator: Unexplained worsening or development of dyspnea within the previous 30 days; And radiologic evidence of new bilateral ground-glass abnormality or consolidation, superimposed on a reticular or honeycomb background pattern, that is consistent with usual interstitial pneumonitis; And absence of alternative causes, such as left heart failure, pulmonary embolism, pulmonary infection (on the basis of endotracheal aspirate or bronchoalveolar lavage if available, or investigator judgment), or other events leading to acute lung injury (for example, sepsis, aspiration, trauma, reperfusion pulmonary edema). Analysis was performed on ITT Population. Here 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to the event of acute IPF exacerbation (up to Week 122)
    End point values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    76
    76
    175
    172
    Units: percentage of participants
        number (not applicable)
    3.9
    3.9
    6.3
    2.9
    No statistical analyses for this end point

    Secondary: Time to First Event of Acute IPF Exacerbation

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    End point title
    Time to First Event of Acute IPF Exacerbation
    End point description
    Time from randomization to first occurrence of an event of IPF exacerbation was reported. IPF exacerbation was defined as an event that met all of the following criteria as determined by the investigator: Unexplained worsening or development of dyspnea within the previous 30 days; And radiologic evidence of new bilateral ground-glass abnormality or consolidation, superimposed on a reticular or honeycomb background pattern, that is consistent with usual interstitial pneumonitis; And absence of alternative causes, or other events leading to acute lung injury. The median time to event was estimated using Kaplan-Meier method. 95% CI for median was computed using the method of Brookmeyer and Crowley. Analysis was performed on ITT Population. Here 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure. The data ‘99999’ in the results signifies that median and corresponding CI could not be estimated due to high number of censored participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to the event of acute IPF exacerbation (up to Week 122)
    End point values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    76
    76
    175
    172
    Units: weeks
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: stratified by baseline FVC (<50%, 50 to 75%, >75%)
    Comparison groups
    Monotherapy (Cohort A): Placebo v Monotherapy (Cohort A): Lebrikizumab
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9366
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.21
         upper limit
    5.3
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Stratified Analysis: stratified by baseline FVC (<50%, 50 to 75%, >75%)
    Comparison groups
    Combination Therapy (Cohort B): Placebo + Pirfenidone v Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1346
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.45
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.16
         upper limit
    1.31

    Secondary: Percentage of Participants with Respiratory-Related Hospitalization

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    End point title
    Percentage of Participants with Respiratory-Related Hospitalization [12]
    End point description
    Analysis was performed on ITT Population for combination therapy cohorts only. Here, 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to the event of respiratory-related hospitalization (up to Week 122)
    Notes
    [12] - 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: Reported analysis was planned to be carried out in the indicated arms only.
    End point values
    Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    175
    173
    Units: percentage of participants
        number (not applicable)
    15.4
    14.5
    No statistical analyses for this end point

    Secondary: Time to Respiratory-Related Hospitalization

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    End point title
    Time to Respiratory-Related Hospitalization [13]
    End point description
    Time from randomization to first occurrence of an event of respiratory-related hospitalization was reported. Participants without an event were censored at the last known alive day, study Day 368, or the last date during the double-blind period. The median time to event was estimated using Kaplan-Meier method. 95% CI for median was computed using the method of Brookmeyer and Crowley. Analysis was performed on ITT Population for combination therapy cohorts only. Here 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure. The data ‘99999’ in the results signifies that median and corresponding CI could not be estimated due to high number of censored participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to the event of respiratory-related hospitalization (up to Week 122)
    Notes
    [13] - 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: Reported analysis was planned to be carried out in the indicated arms only.
    End point values
    Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    175
    173
    Units: weeks
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: stratified by baseline FVC (<50%, 50 to 75%, >75%)
    Comparison groups
    Combination Therapy (Cohort B): Placebo + Pirfenidone v Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects included in analysis
    348
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6815
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.52
         upper limit
    1.54

    Secondary: Percentage of Participants with an Event of >/=15% Absolute Decrease in Percentage of Predicted DLco or Death from Any Cause

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    End point title
    Percentage of Participants with an Event of >/=15% Absolute Decrease in Percentage of Predicted DLco or Death from Any Cause
    End point description
    DLco (in mL/min/mmHg) is a measure of the gas transfer. Predicted DLco is based on sex, age, and height of a person. Percent of predicted DLco (in %) = [(observed DLco)/(predicted DLco)]*100. Analysis was performed on ITT Population. Here 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline up to the event of >/=15% absolute decrease in percentage of predicted DLco or death from any cause (up to Week 122)
    End point values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    76
    76
    175
    173
    Units: percentage of participants
        number (not applicable)
    9.2
    6.6
    14.9
    11.0
    No statistical analyses for this end point

    Secondary: Time to First Event of >/=15% Absolute Decrease in Percentage of Predicted DLco or Death from Any Cause

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    End point title
    Time to First Event of >/=15% Absolute Decrease in Percentage of Predicted DLco or Death from Any Cause
    End point description
    DLco is a measure of the gas transfer. Predicted DLco is based on sex, age, and height of a person. Percent of predicted DLco (in %) = [(observed DLco)/(predicted DLco)]*100. Time from randomization to first occurrence of >/=15% absolute decrease in percentage of predicted DLco or death from any cause was reported. The median time to event was estimated using Kaplan-Meier method. 95% CI for median was computed using the method of Brookmeyer and Crowley. Analysis was performed on ITT Population. Here 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure. The data ‘99999’ in the results signifies that median and corresponding CI could not be estimated due to high number of censored participants.
    End point type
    Secondary
    End point timeframe
    Baseline up to the event of >/=15% absolute decrease in percentage of predicted DLco or death from any cause (up to Week 122)
    End point values
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    76
    76
    175
    173
    Units: weeks
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Stratified Analysis: stratified by baseline FVC (<50%, 50 to 75%, >75%)
    Comparison groups
    Monotherapy (Cohort A): Placebo v Monotherapy (Cohort A): Lebrikizumab
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5685
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.23
         upper limit
    2.26
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Stratified Analysis: stratified by baseline FVC (<50%, 50 to 75%, >75%)
    Comparison groups
    Combination Therapy (Cohort B): Placebo + Pirfenidone v Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects included in analysis
    348
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1976
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.37
         upper limit
    1.23

    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 [14]
    End point description
    ATA to lebrikizumab was tested using a validated immunoassay. A positive ATA result was defined as one in which the presence of detectable ATAs could be confirmed by competitive binding with lebrikizumab. Percentage of participants with positive results for ATA at Baseline and at Post-baseline time points were reported. Only participants who received lebrikizumab were included in the analysis. Analysis was performed on Safety Population, which included all participants who received at least one dose of study drug and grouped according to the actual treatment received. Here, 'Number of Subjects Analysed' = participants evaluable for this outcome measure; ‘n’ = number of participants evaluable at indicated time points.
    End point type
    Secondary
    End point timeframe
    Baseline and Post-Baseline (assessed at multiple time points: Weeks 4, 12, 24, 36, 52, 56, 64, 76, and at safety follow-up up to Week 122)
    Notes
    [14] - 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: Reported analysis was planned to be carried out in the indicated arms only.
    End point values
    Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    75
    172
    Units: percentage of participants
    number (not applicable)
        Baseline (n=75,171)
    5.3
    1.8
        Post-Baseline (n=75,172)
    6.7
    5.2
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Concentration (Cmin) of Lebrikizumab at Week 52

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    End point title
    Minimum Observed Serum Concentration (Cmin) of Lebrikizumab at Week 52 [15]
    End point description
    Participants who received lebrikizumab were only included in the analysis. Analysis was performed on Pharmacokinetic (PK)-Evaluable Population, which included all participants who received at least one dose of study drug and had at least one non-missing PK observation. Here 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure at Week 52.
    End point type
    Secondary
    End point timeframe
    Predose (Hour 0) at Week 52
    Notes
    [15] - 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: Reported analysis was planned to be carried out in the indicated arms only.
    End point values
    Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    62
    137
    Units: micrograms per milliliter (mcg/mL)
        arithmetic mean (standard deviation)
    29.6 ± 14.0
    25.2 ± 12.7
    No statistical analyses for this end point

    Secondary: Minimum Observed Serum Concentration (Cmin) of Lebrikizumab

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    End point title
    Minimum Observed Serum Concentration (Cmin) of Lebrikizumab [16]
    End point description
    Participants who received lebrikizumab were only included in the analysis. Analysis was performed on PK-Evaluable Population. Here, 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure and ‘n signifies number of participants evaluable at specified time points for different arms, respectively
    End point type
    Secondary
    End point timeframe
    Predose (Hour 0) at Weeks 4, 12, 24, and 36
    Notes
    [16] - 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: Reported analysis was planned to be carried out in the indicated arms only.
    End point values
    Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    78
    174
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Cmin at Week 4 (n=74,170)
    14.0 ± 4.86
    14.9 ± 5.75
        Cmin at Week 12 (n=68,165)
    24.4 ± 9.86
    25.0 ± 11.0
        Cmin at Week 24 (n=65,153)
    28.5 ± 12.5
    25.7 ± 12.4
        Cmin at Week 36 (n=61,146)
    29.9 ± 14.1
    25.6 ± 13.8
    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 [17]
    End point description
    Elimination half-life is the time measured for the plasma drug concentration to decrease by one-half during the elimination phase of the drug. Analysis was performed on PK-Evaluable Population. Participants who received lebrikizumab were only included in the analysis. Analysis was performed on PK-Evaluable Population. Here, 'Number of Subjects Analysed' signifies number of participants evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Pre-dose (Hour 0) at Weeks 1, 4, 12, 24, 36, 64, 76, 88, 104; and at 4, 12, and 18 weeks post-last dose (last dose = Week 104)
    Notes
    [17] - 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: Reported analysis was planned to be carried out in the indicated arms only.
    End point values
    Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Number of subjects analysed
    35
    125
    Units: days
        arithmetic mean (standard deviation)
    23.5 ± 5.36
    21.9 ± 4.79
    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 122
    Adverse event reporting additional description
    Safety Population
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Monotherapy (Cohort A): Placebo
    Reporting group description
    Participants received monotherapy with placebo matched to lebrikizumab administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period. Participants were allowed to receive treatment with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to additional 52 weeks (that is, up to Week 104) in the open-label period.

    Reporting group title
    Monotherapy (Cohort A): Lebrikizumab
    Reporting group description
    Participants received monotherapy with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period. Participants were allowed to receive treatment with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to additional 52 weeks (that is, up to Week 104) in the open-label period.

    Reporting group title
    Combination Therapy (Cohort B): Placebo + Pirfenidone
    Reporting group description
    Participants received pirfenidone at a stable dose of 2403 mg per day (three 267 mg capsules three times a day [9 capsules daily] for a total of 2403 mg/day) or at MTD administered orally along with placebo matched to lebrikizumab administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period.

    Reporting group title
    Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Reporting group description
    Participants received pirfenidone at a stable dose of 2403 mg per day (three 267 mg capsules three times a day [9 capsules daily] for a total of 2403 mg/day) or at MTD administered orally along with lebrikizumab at a dose of 250 mg administered via SC injection once every 4 weeks up to 52 weeks during the placebo-controlled treatment period.

    Serious adverse events
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 76 (25.00%)
    23 / 78 (29.49%)
    47 / 177 (26.55%)
    56 / 174 (32.18%)
         number of deaths (all causes)
    4
    4
    15
    7
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Axillary vein thrombosis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Basosquamous carcinoma
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chondrosarcoma
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Adenocarcinoma Stage IV
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Neoplasm
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Lung squamous cell carcinoma Stage 0
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine carcinoma
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    3 / 177 (1.69%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Graft versus host disease
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    2 / 177 (1.13%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 78 (2.56%)
    3 / 177 (1.69%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiomegaly
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 78 (0.00%)
    2 / 177 (1.13%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    3 / 177 (1.69%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 78 (1.28%)
    1 / 177 (0.56%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperventilation
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    3 / 174 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    13 / 76 (17.11%)
    11 / 78 (14.10%)
    22 / 177 (12.43%)
    17 / 174 (9.77%)
         occurrences causally related to treatment / all
    2 / 15
    0 / 15
    3 / 27
    0 / 21
         deaths causally related to treatment / all
    1 / 7
    0 / 4
    1 / 11
    0 / 6
    Oropharyngeal discomfort
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 76 (2.63%)
    2 / 78 (2.56%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 76 (3.95%)
    2 / 78 (2.56%)
    1 / 177 (0.56%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 76 (2.63%)
    1 / 78 (1.28%)
    1 / 177 (0.56%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Epilepsy
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 78 (1.28%)
    1 / 177 (0.56%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal prolapse
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mesenteric vein thrombosis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 76 (1.32%)
    4 / 78 (5.13%)
    2 / 177 (1.13%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    1 / 177 (0.56%)
    2 / 174 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 76 (2.63%)
    3 / 78 (3.85%)
    7 / 177 (3.95%)
    7 / 174 (4.02%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
    2 / 9
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    Pneumonia bacterial
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 78 (1.28%)
    3 / 177 (1.69%)
    5 / 174 (2.87%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 78 (1.28%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Urinary tract infection enterococcal
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection bacterial
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mycobacterium avium complex infection
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 78 (0.00%)
    0 / 177 (0.00%)
    1 / 174 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 78 (2.56%)
    0 / 177 (0.00%)
    0 / 174 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Monotherapy (Cohort A): Placebo Monotherapy (Cohort A): Lebrikizumab Combination Therapy (Cohort B): Placebo + Pirfenidone Combination Therapy (Cohort B): Lebrikizumab + Pirfenidone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    70 / 76 (92.11%)
    73 / 78 (93.59%)
    158 / 177 (89.27%)
    142 / 174 (81.61%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 76 (5.26%)
    4 / 78 (5.13%)
    4 / 177 (2.26%)
    7 / 174 (4.02%)
         occurrences all number
    4
    4
    4
    7
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 76 (2.63%)
    5 / 78 (6.41%)
    3 / 177 (1.69%)
    0 / 174 (0.00%)
         occurrences all number
    2
    5
    3
    0
    Chest discomfort
         subjects affected / exposed
    5 / 76 (6.58%)
    2 / 78 (2.56%)
    3 / 177 (1.69%)
    3 / 174 (1.72%)
         occurrences all number
    9
    2
    3
    3
    Chest pain
         subjects affected / exposed
    5 / 76 (6.58%)
    7 / 78 (8.97%)
    7 / 177 (3.95%)
    10 / 174 (5.75%)
         occurrences all number
    6
    8
    7
    12
    Fatigue
         subjects affected / exposed
    12 / 76 (15.79%)
    15 / 78 (19.23%)
    22 / 177 (12.43%)
    28 / 174 (16.09%)
         occurrences all number
    17
    17
    24
    32
    Injection site erythema
         subjects affected / exposed
    1 / 76 (1.32%)
    4 / 78 (5.13%)
    1 / 177 (0.56%)
    1 / 174 (0.57%)
         occurrences all number
    1
    18
    1
    2
    Oedema peripheral
         subjects affected / exposed
    2 / 76 (2.63%)
    4 / 78 (5.13%)
    4 / 177 (2.26%)
    3 / 174 (1.72%)
         occurrences all number
    2
    5
    4
    3
    Pain
         subjects affected / exposed
    2 / 76 (2.63%)
    4 / 78 (5.13%)
    2 / 177 (1.13%)
    1 / 174 (0.57%)
         occurrences all number
    3
    4
    2
    1
    Pyrexia
         subjects affected / exposed
    2 / 76 (2.63%)
    6 / 78 (7.69%)
    5 / 177 (2.82%)
    1 / 174 (0.57%)
         occurrences all number
    2
    7
    7
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    5 / 76 (6.58%)
    3 / 78 (3.85%)
    1 / 177 (0.56%)
    2 / 174 (1.15%)
         occurrences all number
    6
    3
    1
    2
    Insomnia
         subjects affected / exposed
    3 / 76 (3.95%)
    7 / 78 (8.97%)
    4 / 177 (2.26%)
    8 / 174 (4.60%)
         occurrences all number
    3
    7
    4
    10
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    6 / 76 (7.89%)
    4 / 78 (5.13%)
    3 / 177 (1.69%)
    6 / 174 (3.45%)
         occurrences all number
    8
    5
    3
    7
    Investigations
    Forced vital capacity decreased
         subjects affected / exposed
    4 / 76 (5.26%)
    11 / 78 (14.10%)
    6 / 177 (3.39%)
    6 / 174 (3.45%)
         occurrences all number
    4
    12
    6
    6
    Weight decreased
         subjects affected / exposed
    5 / 76 (6.58%)
    2 / 78 (2.56%)
    9 / 177 (5.08%)
    11 / 174 (6.32%)
         occurrences all number
    5
    2
    9
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    19 / 76 (25.00%)
    21 / 78 (26.92%)
    46 / 177 (25.99%)
    33 / 174 (18.97%)
         occurrences all number
    22
    33
    59
    38
    Dysphonia
         subjects affected / exposed
    0 / 76 (0.00%)
    4 / 78 (5.13%)
    1 / 177 (0.56%)
    0 / 174 (0.00%)
         occurrences all number
    0
    4
    1
    0
    Dyspnoea
         subjects affected / exposed
    12 / 76 (15.79%)
    14 / 78 (17.95%)
    18 / 177 (10.17%)
    13 / 174 (7.47%)
         occurrences all number
    19
    14
    19
    14
    Dyspnoea exertional
         subjects affected / exposed
    4 / 76 (5.26%)
    6 / 78 (7.69%)
    4 / 177 (2.26%)
    5 / 174 (2.87%)
         occurrences all number
    4
    6
    4
    6
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    13 / 76 (17.11%)
    11 / 78 (14.10%)
    10 / 177 (5.65%)
    9 / 174 (5.17%)
         occurrences all number
    14
    12
    10
    9
    Oropharyngeal pain
         subjects affected / exposed
    7 / 76 (9.21%)
    4 / 78 (5.13%)
    5 / 177 (2.82%)
    2 / 174 (1.15%)
         occurrences all number
    7
    6
    5
    2
    Productive cough
         subjects affected / exposed
    3 / 76 (3.95%)
    8 / 78 (10.26%)
    8 / 177 (4.52%)
    6 / 174 (3.45%)
         occurrences all number
    3
    12
    8
    6
    Sinus congestion
         subjects affected / exposed
    1 / 76 (1.32%)
    5 / 78 (6.41%)
    1 / 177 (0.56%)
    2 / 174 (1.15%)
         occurrences all number
    1
    5
    1
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 76 (13.16%)
    14 / 78 (17.95%)
    14 / 177 (7.91%)
    11 / 174 (6.32%)
         occurrences all number
    15
    18
    18
    12
    Headache
         subjects affected / exposed
    9 / 76 (11.84%)
    10 / 78 (12.82%)
    17 / 177 (9.60%)
    11 / 174 (6.32%)
         occurrences all number
    14
    12
    21
    17
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 76 (2.63%)
    4 / 78 (5.13%)
    7 / 177 (3.95%)
    4 / 174 (2.30%)
         occurrences all number
    2
    5
    8
    5
    Dry eye
         subjects affected / exposed
    0 / 76 (0.00%)
    4 / 78 (5.13%)
    1 / 177 (0.56%)
    3 / 174 (1.72%)
         occurrences all number
    0
    4
    1
    3
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 76 (2.63%)
    4 / 78 (5.13%)
    3 / 177 (1.69%)
    3 / 174 (1.72%)
         occurrences all number
    2
    4
    3
    3
    Abdominal pain
         subjects affected / exposed
    3 / 76 (3.95%)
    4 / 78 (5.13%)
    2 / 177 (1.13%)
    1 / 174 (0.57%)
         occurrences all number
    4
    4
    2
    1
    Abdominal pain upper
         subjects affected / exposed
    4 / 76 (5.26%)
    4 / 78 (5.13%)
    4 / 177 (2.26%)
    6 / 174 (3.45%)
         occurrences all number
    4
    5
    6
    9
    Constipation
         subjects affected / exposed
    11 / 76 (14.47%)
    11 / 78 (14.10%)
    12 / 177 (6.78%)
    14 / 174 (8.05%)
         occurrences all number
    14
    14
    13
    15
    Diarrhoea
         subjects affected / exposed
    16 / 76 (21.05%)
    17 / 78 (21.79%)
    23 / 177 (12.99%)
    18 / 174 (10.34%)
         occurrences all number
    19
    25
    30
    20
    Dry mouth
         subjects affected / exposed
    0 / 76 (0.00%)
    6 / 78 (7.69%)
    2 / 177 (1.13%)
    4 / 174 (2.30%)
         occurrences all number
    0
    6
    2
    4
    Dyspepsia
         subjects affected / exposed
    2 / 76 (2.63%)
    4 / 78 (5.13%)
    5 / 177 (2.82%)
    8 / 174 (4.60%)
         occurrences all number
    2
    4
    5
    12
    Flatulence
         subjects affected / exposed
    0 / 76 (0.00%)
    4 / 78 (5.13%)
    1 / 177 (0.56%)
    1 / 174 (0.57%)
         occurrences all number
    0
    4
    1
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 76 (2.63%)
    3 / 78 (3.85%)
    9 / 177 (5.08%)
    9 / 174 (5.17%)
         occurrences all number
    3
    4
    11
    14
    Nausea
         subjects affected / exposed
    10 / 76 (13.16%)
    10 / 78 (12.82%)
    23 / 177 (12.99%)
    28 / 174 (16.09%)
         occurrences all number
    15
    12
    29
    30
    Toothache
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 78 (0.00%)
    2 / 177 (1.13%)
    1 / 174 (0.57%)
         occurrences all number
    4
    0
    2
    1
    Vomiting
         subjects affected / exposed
    6 / 76 (7.89%)
    3 / 78 (3.85%)
    9 / 177 (5.08%)
    8 / 174 (4.60%)
         occurrences all number
    11
    4
    10
    10
    Skin and subcutaneous tissue disorders
    Photosensitivity reaction
         subjects affected / exposed
    6 / 76 (7.89%)
    3 / 78 (3.85%)
    24 / 177 (13.56%)
    7 / 174 (4.02%)
         occurrences all number
    8
    4
    27
    9
    Pruritus
         subjects affected / exposed
    2 / 76 (2.63%)
    3 / 78 (3.85%)
    12 / 177 (6.78%)
    8 / 174 (4.60%)
         occurrences all number
    2
    7
    12
    8
    Rash
         subjects affected / exposed
    5 / 76 (6.58%)
    9 / 78 (11.54%)
    21 / 177 (11.86%)
    18 / 174 (10.34%)
         occurrences all number
    9
    15
    24
    24
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 76 (11.84%)
    9 / 78 (11.54%)
    8 / 177 (4.52%)
    10 / 174 (5.75%)
         occurrences all number
    15
    9
    10
    11
    Back pain
         subjects affected / exposed
    9 / 76 (11.84%)
    12 / 78 (15.38%)
    11 / 177 (6.21%)
    11 / 174 (6.32%)
         occurrences all number
    9
    15
    13
    11
    Muscle spasms
         subjects affected / exposed
    5 / 76 (6.58%)
    6 / 78 (7.69%)
    4 / 177 (2.26%)
    2 / 174 (1.15%)
         occurrences all number
    5
    6
    6
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 76 (1.32%)
    5 / 78 (6.41%)
    2 / 177 (1.13%)
    1 / 174 (0.57%)
         occurrences all number
    1
    5
    2
    1
    Musculoskeletal pain
         subjects affected / exposed
    10 / 76 (13.16%)
    5 / 78 (6.41%)
    8 / 177 (4.52%)
    2 / 174 (1.15%)
         occurrences all number
    11
    6
    8
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 76 (6.58%)
    9 / 78 (11.54%)
    22 / 177 (12.43%)
    17 / 174 (9.77%)
         occurrences all number
    8
    9
    22
    17
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    11 / 76 (14.47%)
    15 / 78 (19.23%)
    11 / 177 (6.21%)
    17 / 174 (9.77%)
         occurrences all number
    14
    21
    17
    19
    Influenza
         subjects affected / exposed
    4 / 76 (5.26%)
    5 / 78 (6.41%)
    10 / 177 (5.65%)
    3 / 174 (1.72%)
         occurrences all number
    5
    5
    12
    3
    Lower respiratory tract infection
         subjects affected / exposed
    5 / 76 (6.58%)
    11 / 78 (14.10%)
    13 / 177 (7.34%)
    10 / 174 (5.75%)
         occurrences all number
    9
    23
    21
    11
    Nasopharyngitis
         subjects affected / exposed
    19 / 76 (25.00%)
    17 / 78 (21.79%)
    25 / 177 (14.12%)
    31 / 174 (17.82%)
         occurrences all number
    33
    28
    35
    38
    Pneumonia
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 78 (1.28%)
    9 / 177 (5.08%)
    3 / 174 (1.72%)
         occurrences all number
    5
    1
    9
    3
    Respiratory tract infection
         subjects affected / exposed
    5 / 76 (6.58%)
    4 / 78 (5.13%)
    9 / 177 (5.08%)
    8 / 174 (4.60%)
         occurrences all number
    7
    4
    16
    9
    Rhinitis
         subjects affected / exposed
    4 / 76 (5.26%)
    4 / 78 (5.13%)
    7 / 177 (3.95%)
    2 / 174 (1.15%)
         occurrences all number
    4
    4
    9
    2
    Sinusitis
         subjects affected / exposed
    5 / 76 (6.58%)
    6 / 78 (7.69%)
    9 / 177 (5.08%)
    11 / 174 (6.32%)
         occurrences all number
    5
    6
    10
    13
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 76 (17.11%)
    18 / 78 (23.08%)
    38 / 177 (21.47%)
    31 / 174 (17.82%)
         occurrences all number
    17
    27
    47
    43
    Urinary tract infection
         subjects affected / exposed
    5 / 76 (6.58%)
    9 / 78 (11.54%)
    11 / 177 (6.21%)
    6 / 174 (3.45%)
         occurrences all number
    7
    14
    14
    9

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 May 2014
    The IPF diagnostic criteria required for eligibility were expanded to include participants with a diagnosis of definite IPF, probable IPF, possible IPF, or possible high-resolution computed tomography (HRCT) with no surgical lung biopsy (SLB) based on 2011 ATS/ERS/JRS/ALAT guidelines; A Multidisciplinary Discussion of Diagnosis (MDD) based on 2011 ATS/ERS/JRS/ALAT guidelines was utilized to finalize the diagnosis in the event of initial central review outcome results for HRCT and SLB were disparate; Time period for inclusion was extended to 5 years since initial diagnosis of IPF; Historical HRCT scans performed within 12 months of screening Visit 1 were allowed to be used to confirm IPF diagnosis and eligibility; Eligibility was expanded to include participants with minimal or no limitation in lung function indicated by FVC upper limit to 100% predicted.
    11 Feb 2015
    Two cohorts were included of participants to test lebrikizumab as monotherapy (Cohort A) or as combination therapy with pirfenidone (Cohort B); The primary endpoint for each cohort was changed from PFS to the absolute change from baseline to Week 52 in percent predicted FVC; The placebo-controlled study treatment duration was changed from a maximum of 2.5 years to 52 weeks; The statistical analysis considerations and plans were changed based upon the revised target participant populations, treatment duration, and primary endpoint; Open-label treatment (with lebrikizumab) period was added for participants in Cohort A who completed the 52-week placebo-controlled study period; The biosensor substudy was limited to participants who enrolled in the study prior to this version of the protocol.
    27 Mar 2015
    Clarity was provided with respect to protocol execution to ensure high quality data was captured throughout the study periods in both cohorts.
    02 Dec 2015
    Number of sites was updated from 110 to 120; The sample size of Cohort B was increased; Stratification for Cohort B was changed to by prior pirfenidone exposure, baseline lung function, and baseline serum periostin concentration; Updates were included to reflect the statistical power of each study cohort, to clarify the time period for the efficacy analysis of Cohort A, and how the missing data was handled for the analysis of primary endpoint.
    23 Oct 2016
    The objectives, endpoints, and statistical methods were updated; The randomization for Cohort B was modified to be stratified by region, baseline lung function, and baseline serum periostin concentration; The benefit-risk profile for lebrikizumab was updated based on the totality of data from completed studies.

    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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