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    Clinical Trial Results:
    INBUILD®: A double-blind, randomised, placebo-controlled trial evaluating the efficacy and safety of nintedanib over 52 weeks in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD)

    Summary
    EudraCT number
    		 2015-003360-37
    Trial protocol
    		 FR   ES   BE   DE   GB   PL   IT  
    Global end of trial date
    12 Aug 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    11 Jan 2022
    First version publication date
    23 Aug 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1199.247
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02999178
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim Call Center, QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, +1 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the current study was to investigate the efficacy and safety of nintedanib over 52 weeks in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD) defined as patients who present with features of diffuse fibrosing lung disease of >10% extent on high-resolution computed tomography (HRCT) and whose lung function and respiratory symptoms or chest imaging have worsened despite treatment with unapproved medications used in clinical practice to treat ILD. There is currently no efficacious treatment available for PF-ILD. Based on its efficacy and safety in Idiopathic Pulmonary Fibrosis (IPF), it is anticipated that Nintedanib will be a new treatment option for patients with PF-ILD.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all subjects as required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jan 2017
    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
    China: 25
    Country: Number of subjects enrolled
    Japan: 166
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 39
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    United States: 211
    Country: Number of subjects enrolled
    Belgium: 29
    Country: Number of subjects enrolled
    Germany: 79
    Country: Number of subjects enrolled
    Spain: 65
    Country: Number of subjects enrolled
    France: 87
    Country: Number of subjects enrolled
    United Kingdom: 43
    Country: Number of subjects enrolled
    Italy: 56
    Country: Number of subjects enrolled
    Poland: 43
    Country: Number of subjects enrolled
    Russian Federation: 55
    Country: Number of subjects enrolled
    Argentina: 43
    Country: Number of subjects enrolled
    Chile: 52
    Worldwide total number of subjects
    1010
    EEA total number of subjects
    359
    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)
    404
    From 65 to 84 years
    593
    85 years and over
    13

    Subject disposition

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    Recruitment
    Recruitment details
    		 Randomised (1:1 ratio), placebo-controlled, double-blind, parallel-group trial comparing nintedanib to placebo over a 52-week treatment period (Part A). Subjects continued on blinded, randomised treatment beyond 52 weeks (Part B). Data base lock (DBL) one was on 6-June-2019, DBL two was on 11-September-2019. Overall Study Period=Part A and B.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 150 mg Nintedanib
    Arm description
    		 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, subjects continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, subjects continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).

    Arm title
    		 Placebo
    Arm description
    		 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, subjects continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, subjects continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).

    Number of subjects in period 1 [1]
    		150 mg Nintedanib Placebo
    Started
    332
    331
    Completed
    218
    231
    Not completed
    114
    100
         Other reason not defined above
    7
    13
         Adverse event, serious fatal
    15
    30
         Consent withdrawn by subject
    21
    21
         Adverse event, non-fatal
    70
    32
         Lost to follow-up
    -
    2
         Protocol deviation
    1
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    150 mg Nintedanib
    Reporting group description
    		 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, subjects continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).

    Reporting group title
    Placebo
    Reporting group description
    		 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, subjects continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).

    Reporting group values
    		 150 mg Nintedanib Placebo Total
    Number of subjects
    		 332 331 663
    Age categorical
    Subject set (=Treated set): This set included all randomised subjects who received at least 1 dose of trial medication.
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 139 121 260
        From 65-84 years
    		 189 205 394
        85 years and over
    		 4 5 9
    Age Continuous
    Subject set (=Treated set): This set included all randomised subjects who received at least 1 dose of trial medication.
    Units: years
        arithmetic mean (standard deviation)
    		 65.2 ( 9.7 ) 66.3 ( 9.8 ) -
    Sex: Female, Male
    Subject set (=Treated set): This set included all randomised subjects who received at least 1 dose of trial medication.
    Units:
        Female
    		 153 154 307
        Male
    		 179 177 356
    Race (NIH/OMB)
    Subject set (=Treated set): This set included all randomised subjects who received at least 1 dose of trial medication.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 83 80 163
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 5 5 10
        White
    		 242 246 488
        More than one race
    		 1 0 1
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Subject set (=Treated set): This set included all randomised subjects who received at least 1 dose of trial medication.
    Units: Subjects
        Hispanic or Latino
    		 47 49 96
        Not Hispanic or Latino
    		 285 282 567
        Unknown or Not Reported
    		 0 0 0
    Baseline High Resolution Computed Tomography (HRCT) fibrotic pattern
    HRCT fibrotic pattern, i.e. imaging pattern of the lung disease on high-resolution computed tomography assessed by central review. HRCT fibrotic pattern had two categories: 'Usual Interstitial Pneumonia (UIP)-like fibrotic pattern only', 'Other fibrotic patterns'. Subject set (=Treated set): This set included all randomised subjects who received at least 1 dose of trial medication.
    Units: Subjects
        UIP-like fibrotic pattern only
    		 206 206 412
        Other fibrotic patterns
    		 126 125 251
    Baseline Forced Vital Capacity (FVC) - Overall Population
    FVC is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Subject set (=Treated set): This set included all randomised subjects who received at least 1 dose of trial medication.
    Units: Milliliter (mL)
        arithmetic mean (standard deviation)
    		 2340.07 ( 740.19 ) 2321.15 ( 727.97 ) -
    Baseline FVC - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only
    FVC is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Subject set (=Treated set): This set included all randomised subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication. The arithmetic mean and Standard Deviation shown in the table below are based on: 206 subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern treated with 150 mg Nintedanib, 206 subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern treated with Placebo.
    Units: Milliliter (mL)
        arithmetic mean (standard deviation)
    		 2363.43 ( 762.89 ) 2373.59 ( 720.05 ) -

    End points

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    End points reporting groups
    Reporting group title
    150 mg Nintedanib
    Reporting group description
    		 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, subjects continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).

    Reporting group title
    Placebo
    Reporting group description
    		 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, subjects continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).

    Primary: Annual rate of decline in Forced Vital Capacity - Overall population

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    End point title
    		 Annual rate of decline in Forced Vital Capacity - Overall population
    End point description
    Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Overall population consists of all randomized subjects with High Resolution Computed Tomography (HRCT) fibrotic pattern=UIP-like fibrotic pattern only or HRCT fibrotic pattern= Other fibrotic patterns. Annual rate of decline in Forced Vital Capacity in milliliter (mL) per year in the overall population is based on a random coefficient regression with fixed effects for treatment, HRCT fibrotic pattern, and baseline FVC [mL], and including treatment−by−time and baseline−by−time interactions. Within−subject errors are modelled by an unstructured variance−covariance matrix. Overall Population: All randomised subjects in the overall population who received at least 1 dose of trial medication.
    End point type
    Primary
    End point timeframe
    Baseline, 2, 4, 6, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    332 [1]
    331 [2]
    Units: Milliliter per year
        least squares mean (confidence interval 95%)
    -80.82 (-110.42 to -51.22)
    -187.78 (-216.92 to -158.64)
    Notes
    [1] - Overall Population
    [2] - Overall Population
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The decrease in FVC was assumed to be linear within each participant over 52 weeks. The intercepts and slopes were assumed to be normally distributed with unstructured covariance matrix. The within participant error was assumed to be independent and normally distributed with mean 0 and a common variance. The Kenward-Roger approximation was used to estimate denominator degrees of freedom and adjust standard errors (SEs).
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference of adjusted annual rates
    Point estimate
    106.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 65.42
         upper limit
    		 148.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    21.15
    Notes
    [3] - Fixed effects: Treatment, HRCT fibrotic pattern, baseline FVC (mL), treatment-by-time, baseline-by-time interactions. Random effects: time, intercept. Difference of adjusted annual rates of decline was calculated as Nintedanib – Placebo.
    [4] - Treatment comparison of slopes was assessed through the treatment-by-time interaction coefficient. P-value was not adjusted for multiple comparisons. P-value .0001 is actually <.0001.

    Primary: Annual rate of decline in Forced Vital Capacity - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only

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    End point title
    		 Annual rate of decline in Forced Vital Capacity - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only
    End point description
    Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Annual rate of decline in Forced Vital Capacity in milliliter (mL) per year in subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only is based on a random coefficient regression with fixed effects for treatment, baseline FVC [mL], and including treatment−by−time and baseline−by−time interactions. Within−subject errors are modelled by an unstructured variance−covariance matrix. Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only: All randomised subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.
    End point type
    Primary
    End point timeframe
    Baseline, 2, 4, 6, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    206 [5]
    206 [6]
    Units: Milliliter per year
        least squares mean (confidence interval 95%)
    -82.87 (-123.73 to -42.02)
    -211.07 (-251.38 to -170.77)
    Notes
    [5] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    [6] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The decrease in FVC was assumed to be linear within each participant over 52 weeks. The intercepts and slopes were assumed to be normally distributed with unstructured covariance matrix. The within participant error was assumed to be independent and normally distributed with mean 0 and a common variance. The Kenward-Roger approximation was used to estimate denominator degrees of freedom and adjust standard errors (SEs).
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    412
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.0001 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference of adjusted annual rates
    Point estimate
    128.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 70.81
         upper limit
    		 185.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    29.17
    Notes
    [7] - Fixed effects: Treatment, baseline FVC (mL), treatment-by-time, baseline-by-time interactions. Random effects: time, intercept. Difference of adjusted annual rates of decline was calculated as Nintedanib – Placebo.
    [8] - Treatment comparison of slopes was assessed through the treatment-by-time interaction coefficient. P-value was not adjusted for multiple comparisons. P-value .0001 is actually <.0001.

    Secondary: Absolute change from baseline in King's Brief Interstitial Lung Disease Questionnaire (K-BILD) Total score at week 52 - Overall population

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    End point title
    		 Absolute change from baseline in King's Brief Interstitial Lung Disease Questionnaire (K-BILD) Total score at week 52 - Overall population
    End point description
    King's Brief Interstitial Lung Disease questionnaire (K-BILD) consists of 15 items and 3 domains: breathlessness and activities, psychological, chest symptoms ranging from 0-100, with 100 representing the best health status. If missing items were >50% per domain, the domain score was set to missing. If any of the domain scores were missing, the total score was set to missing. Absolute change from baseline at week 52 was based on a Mixed Model Repeated Measures (MMRM), with fixed effects for baseline K-BILD Total score, HRCT fibrotic pattern, visit, treatment-by-visit interaction, baseline-by-visit interactions and random effect for subject. Visit was the repeated measure. Within-subject errors were modelled by unstructured variance-covariance matrix. Overall Population: All randomised subjects in the overall population who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    332 [9]
    330 [10]
    Units: Unit on scale
        least squares mean (confidence interval 95%)
    0.55 (-0.62 to 1.72)
    -0.79 (-1.94 to 0.37)
    Notes
    [9] - Overall Population
    [10] - Overall Population
    Statistical analysis title
    		 Statistical Analysis 3
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    662
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.1115
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted mean difference
    Point estimate
    1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.31
         upper limit
    		 2.98
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.84
    Notes
    [11] - No formal hypotheses were tested. Fixed effects: baseline K-BILD Total score, visit, treatment−by−visit and baseline−by−visit interactions, random effect: participant. Adjusted mean difference was calculated as Nintedanib – Placebo.

    Secondary: Absolute change from baseline in King's Brief Interstitial Lung Disease (K-BILD) Questionnaire Total score at week 52 - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only

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    End point title
    		 Absolute change from baseline in King's Brief Interstitial Lung Disease (K-BILD) Questionnaire Total score at week 52 - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only
    End point description
    King's Brief Interstitial Lung Disease questionnaire (K-BILD) consists of 15 items and 3 domains: breathlessness, activities, psychological, chest symptoms ranging from 0-100, with 100 representing best health status. If missing items were >50% per domain, the domain score was set to missing. If any of the domain scores were missing, the total score was set to missing. Absolute change from baseline at week 52 was based on a Mixed Model Repeated Measures (MMRM), with fixed effects for baseline K-BILD Total score, HRCT fibrotic pattern, visit, treatment-by-visit interaction, baseline-by-visit interactions and random effect for subject and visit as repeated measure. Within-subject errors were modelled by unstructured variance-covariance matrix. Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only: All randomised subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    206 [12]
    205 [13]
    Units: Unit on scale
        least squares mean (confidence interval 95%)
    0.75 (-0.82 to 2.31)
    -0.78 (-2.34 to 0.78)
    Notes
    [12] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    [13] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    Statistical analysis title
    		 Statistical Analysis 4
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    411
    Analysis specification
    Pre-specified
    Analysis type
    		 [14]
    P-value
    		 = 0.1747
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted mean difference
    Point estimate
    1.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.68
         upper limit
    		 3.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.12
    Notes
    [14] - No formal hypotheses were tested. Fixed effects: baseline K-BILD Total score, visit, treatment−by−visit and baseline−by−visit interactions, random effect: participant. Adjusted mean difference was calculated as Nintedanib – Placebo.

    Secondary: Time to first acute Interstitial Lung Disease (ILD) exacerbation or death over 52 weeks - Overall population

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    End point title
    		 Time to first acute Interstitial Lung Disease (ILD) exacerbation or death over 52 weeks - Overall population
    End point description
    Time to first acute ILD exacerbation or death over 52 weeks was defined as time to first acute ILD exacerbation or death due to any cause within the first 52 weeks and was computed as earliest of date of first documented acute ILD exacerbation or death – date of first drug intake + 1. Subjects alive who did not experience any ILD exacerbation event or with unknown status within the first 52 weeks were censored. The value '99999' stands for non-calculable because the 25 percentile was not reached. Overall Population: All randomised subjects in the overall population who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    From first drug intake until date of first acute ILD exacerbation or date of death or last contact date, up to 372 days
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    332 [15]
    331 [16]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [15] - Overall Population
    [16] - Overall Population
    Statistical analysis title
    		 Statistical Analysis 5
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 [17]
    P-value
    		 = 0.3948
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.34
    Notes
    [17] - No formal hypotheses were tested. Stratified by HRCT fibrotic pattern. A Cox proportional hazards model, stratified by HRCT fibrotic pattern, was used to estimate the hazard ratio calculated as Nintedanib divided by Placebo.

    Secondary: Time to first acute Interstitial Lung Disease (ILD) exacerbation or death over 52 weeks – Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only

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    End point title
    		 Time to first acute Interstitial Lung Disease (ILD) exacerbation or death over 52 weeks – Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only
    End point description
    Time to first acute ILD exacerbation or death over 52 weeks was defined as time to first acute ILD exacerbation or death due to any cause within the first 52 weeks and was computed as earliest of date of first documented acute ILD exacerbation or death – date of first drug intake + 1. Subjects alive who did not experience any ILD exacerbation event or with unknown status within the first 52 weeks were censored. The value '99999' stands for non-calculable because the 25 percentile was not reached. Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only: All randomised subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    From first drug intake until date of first acute ILD exacerbation or date of death or last contact date, up to 372 days
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    206 [18]
    206 [19]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [18] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    [19] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    Statistical analysis title
    		 Statistical Analysis 6
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    412
    Analysis specification
    Pre-specified
    Analysis type
    		 [20]
    P-value
    		 = 0.1985
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 1.24
    Notes
    [20] - No formal hypotheses were tested. A Cox proportional hazards model was used to estimate the hazard ratio calculated as Nintedanib divided by Placebo.

    Secondary: Time to death over 52 weeks - Overall population

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    End point title
    		 Time to death over 52 weeks - Overall population
    End point description
    Time to death over 52 weeks defined as the time from date of first drug intake until date of death from any cause for subjects with known date of death (from any cause) within the first 52 weeks. Subjects with no event (death from any cause) or unknown status within the first 52 weeks were censored. The value '99999' stands for non-calculable because the 25 percentile was not reached. Overall Population: All randomised subjects in the overall population who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    From first drug intake until date of death or last contact date, up to 372 days
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    332 [21]
    331 [22]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [21] - Overall Population
    [22] - Overall Population
    Statistical analysis title
    		 Statistical Analysis 7
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 [23]
    P-value
    		 = 0.8544
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.86
    Notes
    [23] - No formal hypotheses were tested. Stratified by HRCT fibrotic pattern. A Cox proportional hazards model, stratified by HRCT fibrotic pattern, was used to estimate the hazard ratio calculated as Nintedanib divided by Placebo.

    Secondary: Time to death over 52 weeks - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only

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    End point title
    		 Time to death over 52 weeks - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only
    End point description
    Time to death over 52 weeks defined as the time from date of first drug intake until date of death from any cause for subjects with known date of death (from any cause) within the first 52 weeks. Subjects with no event (death from any cause) or unknown status within the first 52 weeks were censored. The value '99999' stands for non-calculable because the 25 percentile was not reached. Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only: All randomised subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    From first drug intake until date of death or last contact date, up to 372 days
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    206 [24]
    206 [25]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [24] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    [25] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    Statistical analysis title
    		 Statistical Analysis 8
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    412
    Analysis specification
    Pre-specified
    Analysis type
    		 [26]
    P-value
    		 = 0.3291
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 1.47
    Notes
    [26] - No formal hypotheses were tested. A Cox proportional hazards model was used to estimate the hazard ratio calculated as Nintedanib divided by Placebo.

    Secondary: Time to death due to respiratory cause over 52 weeks - Overall population

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    End point title
    		 Time to death due to respiratory cause over 52 weeks - Overall population
    End point description
    Time to death due to respiratory cause over 52 weeks is defined as the time from date of first drug intake until date of death attributed to respiratory causes (determined by an independent Adjudication Committee) for subjects with known date of death (from respiratory causes) within the first 52 weeks. Subjects with no event (death from respiratory causes) or unknown status within the first 52 weeks were censored. As less than 4.95% of the total of subjects in the analysis population experienced an event, only descriptive statistics were performed, as pre-specified. The value '99999' stands for non-calculable because the 25 percentile was not reached. No statistical analysis provided for Time to death due to respiratory cause over 52 weeks. Overall Population: All randomised subjects in the overall population who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    From date of first trial drug intake up to date of death from respiratory causes or last contact date, up to 372 days
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    332 [27]
    331 [28]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [27] - Overall population
    [28] - Overall population
    No statistical analyses for this end point

    Secondary: Time to death due to respiratory cause over 52 weeks - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only

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    End point title
    		 Time to death due to respiratory cause over 52 weeks - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only
    End point description
    Time to death due to respiratory cause over 52 weeks is defined as the time from date of first drug intake until date of death attributed to respiratory causes (determined by an independent Adjudication Committee) for subjects with known date of death (from respiratory causes) within the first 52 weeks. Subjects with no event (death from respiratory causes) or unknown status within the first 52 weeks were censored. As less than 4.95% of the total of subjects in the analysis population experienced an event, only descriptive statistics were performed, as pre-specified. The value '99999' stands for non-calculable because the 25 percentile was not reached. No statistical analysis provided for Time to death due to respiratory cause over 52. Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only: All randomised subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    From date of first trial drug intake up to date of death from respiratory causes or last contact date, up to 372 days
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    206 [29]
    206 [30]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    Notes
    [29] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    [30] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    No statistical analyses for this end point

    Secondary: Time to progression or death over 52 weeks - Overall population

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    End point title
    		 Time to progression or death over 52 weeks - Overall population
    End point description
    Time to progression or death over 52 weeks is as the time from date of first drug intake to date of progression, or date of death (from any cause) if a subject died earlier. Subjects with no event (progression or death from any cause) or unknown status were censored. Date of progression defined as the date when ≥ 10% of absolute decline in FVC percent predicted compared to baseline occurred for the first time. Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent. The value '99999' stands for non-calculable because the 50 percentile was not reached. Overall Population: All randomised subjects in the overall population who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    From first drug intake until date of progression or date of death or last contact date, up to 372 days
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    332 [31]
    331 [32]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    99999 (367 to 99999)
    99999 (269 to 99999)
    Notes
    [31] - Overall Population
    [32] - Overall Population
    Statistical analysis title
    		 Statistical Analysis 9
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 [33]
    P-value
    		 = 0.0017
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 0.85
    Notes
    [33] - No formal hypotheses were tested. Stratified by HRCT fibrotic pattern. A Cox proportional hazards model, stratified by HRCT fibrotic pattern, was used to estimate the hazard ratio calculated as Nintedanib divided by Placebo.

    Secondary: Time to progression or death over 52 weeks - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only

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    End point title
    		 Time to progression or death over 52 weeks - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only
    End point description
    Time to progression or death over 52 weeks defined as time from date of first drug intake to date of progression, or date of death (from any cause) if a participant died earlier. Subjects with no event (progression or death from any cause) or unknown status were censored. Date of progression defined as the date when ≥ 10% of absolute decline in FVC percent predicted compared to baseline occurred for the first time. FVC is the volume of air (measured in milliliter) forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent. The value '99999' stands for non-calculable because the 50 percentile was not reached. Subjects with HRCT fibrotic pattern= UIP-like fibrotic pattern (HRCT=UIP FP) only: All randomised subjects with HRCT=UIP FP only who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    From first drug intake until date of progression or date of death or last contact date, up to 372 days
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    206 [34]
    206 [35]
    Units: Days
        median (inter-quartile range (Q1-Q3))
    99999 (365 to 99999)
    99999 (254 to 99999)
    Notes
    [34] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    [35] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    Statistical analysis title
    		 Statistical Analysis 10
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    412
    Analysis specification
    Pre-specified
    Analysis type
    		 [36]
    P-value
    		 = 0.0081
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 0.89
    Notes
    [36] - No formal hypotheses were tested. A Cox proportional hazards model was used to estimate the hazard ratio calculated as Nintedanib divided by Placebo.

    Secondary: Percentage of subjects with a relative decline from baseline in FVC percent predicted of more than 10 percent at week 52 - Overall population

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    End point title
    		 Percentage of subjects with a relative decline from baseline in FVC percent predicted of more than 10 percent at week 52 - Overall population
    End point description
    Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent. Subjects with relative decline from baseline in FVC % pred greater than 10% at week 52 were those subjects with a negative relative change from baseline in FVC % pred at week 52 the absolute value of which being greater than 10% and those subjects with missing data (worst case analysis). Overall Population: All randomised subjects in the overall population who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 52 weeks after first drug intake
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    332 [37]
    331 [38]
    Units: Percentage of subjects
        number (not applicable)
    40.7
    48.9
    Notes
    [37] - Overall Population
    [38] - Overall Population
    Statistical analysis title
    		 Statistical Analysis 11
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 [39]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.96
    Notes
    [39] - No formal hypotheses were tested. Logistic regression model with continuous covariate baseline FVC % pred and binary covariate HRCT fibrotic pattern. Adjusted Odds Ratio calculated as Nintedanib divided by Placebo.

    Secondary: Percentage of subjects with a relative decline from baseline in FVC percent predicted of more than 10 percent at week 52 - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only

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    End point title
    		 Percentage of subjects with a relative decline from baseline in FVC percent predicted of more than 10 percent at week 52 - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only
    End point description
    Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent. Subjects with relative decline from baseline in FVC % pred greater than 10% at week 52 were those subjects with a negative relative change from baseline in FVC % pred at week 52 the absolute value of which being greater than 10% and those subjects with missing data (worst case analysis). Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only: All randomised subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 52 weeks after first drug intake
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    206 [40]
    206 [41]
    Units: Percentage of participants
        number (not applicable)
    41.3
    52.4
    Notes
    [40] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    [41] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    Statistical analysis title
    		 Statistical Analysis 12
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    412
    Analysis specification
    Pre-specified
    Analysis type
    		 [42]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.94
    Notes
    [42] - No formal hypotheses were tested. Logistic regression model with continuous covariate baseline FVC % pred. Ratio calculated as Nintedanib divided by Placebo.

    Secondary: Percentage of subjects with a relative decline from baseline in FVC percent predicted of more than 5 percent at week 52 - Overall population

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    End point title
    		 Percentage of subjects with a relative decline from baseline in FVC percent predicted of more than 5 percent at week 52 - Overall population
    End point description
    Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent. Subjects with relative decline from baseline in FVC % pred greater than 5% at week 52 were those subjects with a negative relative change from baseline in FVC % pred at week 52 the absolute value of which being greater than 5% and those subjects with missing data (worst case analysis). Overall Population: All randomised subjects in the overall population who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 52 weeks after first drug intake
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    332 [43]
    331 [44]
    Units: Percentage of subjects
        number (not applicable)
    52.4
    68.6
    Notes
    [43] - Overall population
    [44] - Overall population
    Statistical analysis title
    		 Statistical Analysis 13
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    663
    Analysis specification
    Pre-specified
    Analysis type
    		 [45]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 0.68
    Notes
    [45] - No formal hypotheses were tested. Logistic regression model with continuous covariate baseline FVC % pred and binary covariate HRCT fibrotic pattern. Ratio calculated as Nintedanib divided by Placebo.

    Secondary: Percentage of subjects with a relative decline from baseline in FVC percent predicted of more than 5 percent at week 52 - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only

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    End point title
    		 Percentage of subjects with a relative decline from baseline in FVC percent predicted of more than 5 percent at week 52 - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only
    End point description
    Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. Predicted normal values of FVC were calculated according to the Global Lung Initiative. FVC percent predicted (FVC % pred) is the FVC divided by its predicted value in percent. Subjects with relative decline from baseline in FVC % pred greater than 5% at week 52 were those subjects with a negative relative change from baseline in FVC % pred at week 52 the absolute value of which being greater than 5% and those subjects with missing data (worst case analysis). Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only: All randomised subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 52 weeks after first drug intake
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    206 [46]
    206 [47]
    Units: Percentage of subjects
        number (not applicable)
    52.4
    70.4
    Notes
    [46] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    [47] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    Statistical analysis title
    		 Statistical Analysis 14
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    412
    Analysis specification
    Pre-specified
    Analysis type
    		 [48]
    Method
    		 Regression, Logistic
    Parameter type
    		 Adjusted Odds Ratio
    Point estimate
    0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 0.69
    Notes
    [48] - No formal hypotheses were tested. Logistic regression model with continuous covariate baseline FVC % pred. Ratio calculated as Nintedanib divided by Placebo.

    Secondary: Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms dyspnea domain score at week 52 - Overall population

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    End point title
    		 Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms dyspnea domain score at week 52 - Overall population
    End point description
    Living with Pulmonary Fibrosis (L-PF) questionnaire with 44 items in two modules: Symptoms (23 items with three domains: dyspnea, cough and fatigue and a total score) and Impacts (21 items as a single score). L-PF Symptoms dyspnea domain score (dyspnea score) ranges from 0-100, with higher scores indicating greater impairment. A score was set to missing if ≥50 % items were missing. Absolute change from baseline at week 52 based on a Mixed Model Repeated Measures, with fixed effects for baseline dyspnea score, HRCT fibrotic pattern, visit, treatment-by-visit interaction, baseline dyspnea score-by-visit interaction and random effect for subject, visit as repeated measure. Adjusted mean is based on all analysed subjects in the model (not only subjects with a baseline and measurement at week 52). Overall Population: All randomised subjects in the overall population who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    329 [49]
    323 [50]
    Units: Unit on scale
        least squares mean (confidence interval 95%)
    4.28 (2.43 to 6.14)
    7.81 (5.97 to 9.66)
    Notes
    [49] - Overall Population
    [50] - Overall Population
    Statistical analysis title
    		 Statistical Analysis 15
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    652
    Analysis specification
    Pre-specified
    Analysis type
    		 [51]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -3.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.14
         upper limit
    		 -0.92
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.33
    Notes
    [51] - No formal hypotheses were tested. Fixed effects: baseline, HRCT fibrotic pattern, visit, treatment−by−visit interaction, baseline−by−visit interaction, random effect: participant. Adjusted mean difference was calculated as Nintedanib – Placebo.

    Secondary: Absolute change from baseline in L-PF Symptoms dyspnea domain score at week 52 - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only

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    End point title
    		 Absolute change from baseline in L-PF Symptoms dyspnea domain score at week 52 - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only
    End point description
    Living with Pulmonary Fibrosis (L-PF) questionnaire with 44 items in two modules: Symptoms (23 items with three domains: dyspnea, cough and fatigue and a total score) and Impacts (21 items as a single score). L-PF Symptoms dyspnea domain score (dyspnea score) ranges from 0-100, with higher scores indicating greater impairment. A score was set to missing if ≥50 % items were missing. Absolute change from baseline at week 52 based on a Mixed Model Repeated Measures, with fixed effects for baseline dyspnea score, visit, treatment-by-visit interaction, baseline dyspnea score treatment-by-visit interaction and random effect for subject, visit as repeated measure. Adjusted mean is based on all analysed subjects in the model (not only subjects with a baseline and measurement at week 52). Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only: All randomised subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    204 [52]
    201 [53]
    Units: Unit on scale
        least squares mean (confidence interval 95%)
    4.14 (1.81 to 6.47)
    8.32 (5.99 to 10.66)
    Notes
    [52] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    [53] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    Statistical analysis title
    		 Statistical Analysis 16
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    		 [54]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -4.18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.48
         upper limit
    		 -0.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.68
    Notes
    [54] - No formal hypotheses were tested. Fixed effects: baseline, visit, treatment−by−visit interaction, baseline−by−visit interaction, random effect: participant. Adjusted mean difference was calculated as Nintedanib – Placebo.

    Secondary: Absolute change from baseline in L-PF Symptoms cough domain score at week 52 - Overall population

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    End point title
    		 Absolute change from baseline in L-PF Symptoms cough domain score at week 52 - Overall population
    End point description
    Living with Pulmonary Fibrosis (L-PF) questionnaire with 44 items in two modules: Symptoms (23 items with three domains: dyspnea, cough and fatigue and a total score) and Impacts (21 items as a single score). L-PF Symptoms cough domain score (cough score) ranges from 0-100, higher scores indicating greater impairment. A score was set to missing if ≥50 % items were missing. Absolute change from baseline at week 52 based on a Mixed Model Repeated Measures, with fixed effects for baseline cough score, HRCT fibrotic pattern, visit, treatment-by-visit interaction, baseline cough score-by-visit interaction and random effect for subject, visit as repeated measure. Adjusted mean is based on all analysed subjects in the model (not only subjects with a baseline and measurement at week 52). Overall Population: All randomised subjects in the overall population who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    327 [55]
    320 [56]
    Units: Unit on scale
        least squares mean (confidence interval 95%)
    -1.84 (-4.36 to 0.69)
    4.25 (1.74 to 6.76)
    Notes
    [55] - Overall population
    [56] - Overall population
    Statistical analysis title
    		 Statistical Analysis 17
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    647
    Analysis specification
    Pre-specified
    Analysis type
    		 [57]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -6.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.65
         upper limit
    		 -2.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.81
    Notes
    [57] - No formal hypotheses were tested. Fixed effects: baseline, HRCT fibrotic pattern, visit, treatment−by−visit interaction, baseline−by−visit interaction, random effect: participant. Adjusted mean difference was calculated as Nintedanib – Placebo.

    Secondary: Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms cough domain score at week 52 - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only

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    End point title
    		 Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms cough domain score at week 52 - Subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only
    End point description
    Living with Pulmonary Fibrosis (L-PF) with 44 items in two modules: Symptoms (23 items with three domains: dyspnea, cough and fatigue and a total score) and Impacts (21 items as a single score). L-PF Symptoms cough domain score (cough score) ranges from 0-100, higher scores indicating greater impairment. A score was set to missing if ≥50 % items were missing. Absolute change from baseline at week 52 based on a Mixed Model Repeated Measures, with fixed effects for baseline cough score, visit, treatment-by-visit interaction, baseline cough score-by-visit interaction and random effect for subject, visit as repeated measure. Adjusted mean is based on all analysed subjects in the model (not only subjects with a baseline and measurement at week 52). Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only: All randomised subjects with HRCT fibrotic pattern=UIP-like fibrotic pattern only who received at least 1 dose of trial medication.
    End point type
    Secondary
    End point timeframe
    Baseline, 12, 24, 36, 52 weeks after first drug intake (planned post-baseline visits)
    End point values
    		 150 mg Nintedanib Placebo
    Number of subjects analysed
    203 [58]
    199 [59]
    Units: Unit on scale
        least squares mean (confidence interval 95%)
    -3.20 (-6.43 to 0.04)
    4.09 (0.85 to 7.32)
    Notes
    [58] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    [59] - Subjects with HRCT fibrotic pattern = UIP-like fibrotic pattern only
    Statistical analysis title
    		 Statistical Analysis 18
    Comparison groups
    150 mg Nintedanib v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 [60]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -7.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.86
         upper limit
    		 -2.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.33
    Notes
    [60] - No formal hypotheses were tested. Fixed effects: baseline, visit, treatment−by−visit interaction, baseline−by−visit interaction, random effect: participant. Adjusted mean difference was calculated as Nintedanib – Placebo.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment period plus 28 days (residual effect period), up to 836 days. Time frame for All-Cause-Mortality: Treatment period plus Follow-up, up to 900 days.
    Adverse event reporting additional description
    All participants who signed the informed consent.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    150 mg Nintedanib
    Reporting group description
    		 150 milligram (mg) Nintedanib as soft gelatine capsule, administered orally, twice daily (bid), with optional dose reduction to 100 mg bid to manage adverse events (AEs). Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).

    Reporting group title
    Placebo
    Reporting group description
    		 150 mg Nintedanib matching placebo, soft gelatine capsule, administered orally, bid, with optional dose reduction to 100 mg bid to manage AEs. Continuous daily dosing over a 52-week treatment period (Part A). After completion of the 52-week treatment period, participants continued on blinded treatment until the end of the trial or until a reason for treatment withdrawal was met (Part B).

    Serious adverse events
    		 150 mg Nintedanib Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    147 / 332 (44.28%)
    164 / 331 (49.55%)
         number of deaths (all causes)
    36
    45
         number of deaths resulting from adverse events
    15
    30
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    2 / 332 (0.60%)
    4 / 331 (1.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder adenocarcinoma
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lung squamous cell carcinoma metastatic
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Salivary gland adenoma
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm rupture
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Arteritis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 332 (0.60%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic vascular disorder
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Vasculitis
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac death
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Chest pain
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Discomfort
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sudden death
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    16 / 332 (4.82%)
    7 / 331 (2.11%)
         occurrences causally related to treatment / all
    0 / 19
    0 / 8
         deaths causally related to treatment / all
    0 / 5
    0 / 2
    Asthma
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    1 / 332 (0.30%)
    6 / 331 (1.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cough
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 332 (1.81%)
    13 / 331 (3.93%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 20
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Eosinophilic pneumonia chronic
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity pneumonitis
         subjects affected / exposed
    2 / 332 (0.60%)
    4 / 331 (1.21%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    3 / 332 (0.90%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic interstitial pneumonia
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    19 / 332 (5.72%)
    45 / 331 (13.60%)
         occurrences causally related to treatment / all
    0 / 22
    1 / 53
         deaths causally related to treatment / all
    0 / 2
    0 / 7
    Lung disorder
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    6 / 332 (1.81%)
    6 / 331 (1.81%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 332 (0.30%)
    5 / 331 (1.51%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    7 / 332 (2.11%)
    5 / 331 (1.51%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    5 / 332 (1.51%)
    9 / 331 (2.72%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 332 (0.00%)
    3 / 331 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Respiratory failure
         subjects affected / exposed
    11 / 332 (3.31%)
    10 / 331 (3.02%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 11
         deaths causally related to treatment / all
    0 / 4
    0 / 5
    Psychiatric disorders
    Anxiety disorder
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug abuse
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram Q wave abnormal
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotavirus test positive
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic stenosis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery restenosis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    3 / 332 (0.90%)
    4 / 331 (1.21%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    3 / 332 (0.90%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 332 (0.60%)
    3 / 331 (0.91%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    5 / 332 (1.51%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block left
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 332 (0.90%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chronic right ventricular failure
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cor pulmonale acute
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 332 (0.30%)
    3 / 331 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Long QT syndrome
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 332 (0.60%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prinzmetal angina
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systolic anterior motion of mitral valve
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar infarction
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cerebral infarction
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokinesia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 332 (0.00%)
    3 / 331 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood loss anaemia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mixed deafness
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Amaurosis fugax
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vascular thrombosis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 332 (0.90%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis haemorrhagic
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 332 (0.90%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 332 (0.00%)
    3 / 331 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    6 / 332 (1.81%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    6 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Liver injury
         subjects affected / exposed
    3 / 332 (0.90%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Henoch-Schonlein purpura
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyoderma gangrenosum
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 332 (0.90%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Connective tissue disorder
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Groin pain
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporosis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyositis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scleroderma
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sjogren's syndrome
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic scleroderma
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Winged scapula
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    4 / 332 (1.20%)
    5 / 331 (1.51%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    2 / 332 (0.60%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster oticus
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Influenza
         subjects affected / exposed
    4 / 332 (1.20%)
    4 / 331 (1.21%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leishmaniasis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 332 (0.30%)
    3 / 331 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    3 / 332 (0.90%)
    3 / 331 (0.91%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal infection
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    24 / 332 (7.23%)
    16 / 331 (4.83%)
         occurrences causally related to treatment / all
    0 / 27
    0 / 19
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Pneumonia bacterial
         subjects affected / exposed
    1 / 332 (0.30%)
    3 / 331 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia legionella
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 332 (0.00%)
    3 / 331 (0.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 332 (0.90%)
    3 / 331 (0.91%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 331 (0.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 331 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 331 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 150 mg Nintedanib Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    308 / 332 (92.77%)
    266 / 331 (80.36%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    47 / 332 (14.16%)
    12 / 331 (3.63%)
         occurrences all number
    53
    17
    Aspartate aminotransferase increased
         subjects affected / exposed
    41 / 332 (12.35%)
    12 / 331 (3.63%)
         occurrences all number
    49
    16
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    22 / 332 (6.63%)
    6 / 331 (1.81%)
         occurrences all number
    29
    6
    Weight decreased
         subjects affected / exposed
    49 / 332 (14.76%)
    18 / 331 (5.44%)
         occurrences all number
    53
    18
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    19 / 332 (5.72%)
    15 / 331 (4.53%)
         occurrences all number
    34
    16
    Headache
         subjects affected / exposed
    37 / 332 (11.14%)
    27 / 331 (8.16%)
         occurrences all number
    52
    37
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    18 / 332 (5.42%)
    14 / 331 (4.23%)
         occurrences all number
    20
    17
    Chest pain
         subjects affected / exposed
    17 / 332 (5.12%)
    14 / 331 (4.23%)
         occurrences all number
    21
    14
    Fatigue
         subjects affected / exposed
    34 / 332 (10.24%)
    21 / 331 (6.34%)
         occurrences all number
    38
    25
    Oedema peripheral
         subjects affected / exposed
    18 / 332 (5.42%)
    22 / 331 (6.65%)
         occurrences all number
    18
    28
    Pyrexia
         subjects affected / exposed
    17 / 332 (5.12%)
    18 / 331 (5.44%)
         occurrences all number
    19
    20
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    34 / 332 (10.24%)
    9 / 331 (2.72%)
         occurrences all number
    42
    10
    Abdominal pain upper
         subjects affected / exposed
    33 / 332 (9.94%)
    6 / 331 (1.81%)
         occurrences all number
    46
    6
    Constipation
         subjects affected / exposed
    25 / 332 (7.53%)
    32 / 331 (9.67%)
         occurrences all number
    29
    36
    Diarrhoea
         subjects affected / exposed
    239 / 332 (71.99%)
    85 / 331 (25.68%)
         occurrences all number
    577
    115
    Nausea
         subjects affected / exposed
    100 / 332 (30.12%)
    33 / 331 (9.97%)
         occurrences all number
    173
    45
    Vomiting
         subjects affected / exposed
    64 / 332 (19.28%)
    16 / 331 (4.83%)
         occurrences all number
    129
    20
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    19 / 332 (5.72%)
    3 / 331 (0.91%)
         occurrences all number
    27
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    40 / 332 (12.05%)
    50 / 331 (15.11%)
         occurrences all number
    48
    66
    Dyspnoea
         subjects affected / exposed
    49 / 332 (14.76%)
    46 / 331 (13.90%)
         occurrences all number
    54
    56
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    12 / 332 (3.61%)
    18 / 331 (5.44%)
         occurrences all number
    14
    19
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    18 / 332 (5.42%)
    18 / 331 (5.44%)
         occurrences all number
    19
    19
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 332 (3.61%)
    23 / 331 (6.95%)
         occurrences all number
    13
    24
    Back pain
         subjects affected / exposed
    28 / 332 (8.43%)
    26 / 331 (7.85%)
         occurrences all number
    31
    34
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    44 / 332 (13.25%)
    62 / 331 (18.73%)
         occurrences all number
    62
    86
    Nasopharyngitis
         subjects affected / exposed
    54 / 332 (16.27%)
    48 / 331 (14.50%)
         occurrences all number
    72
    68
    Respiratory tract infection
         subjects affected / exposed
    18 / 332 (5.42%)
    12 / 331 (3.63%)
         occurrences all number
    28
    19
    Upper respiratory tract infection
         subjects affected / exposed
    26 / 332 (7.83%)
    25 / 331 (7.55%)
         occurrences all number
    31
    29
    Urinary tract infection
         subjects affected / exposed
    22 / 332 (6.63%)
    20 / 331 (6.04%)
         occurrences all number
    29
    22
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    54 / 332 (16.27%)
    22 / 331 (6.65%)
         occurrences all number
    69
    22

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Dec 2016
    To address a recommendation by the FDA, the primary analysis of the primary endpoint was also planned to be performed in the complementary population of patients with other High Resolution Computed Tomography (HRCT) fibrotic patterns; Serum banking was changed from mandatory to optional to ensure that the trial could be conducted according to regulatory and ethical requirements in the participating countries; Flow chart Part B was updated to ensure that Electrocardiogram (ECG) was also performed at end of trial part B (EOTB); Scoring instructions for Living with Pulmonary Fibrosis (L-PF) domains were updated; Information was added to adapt informed consent handling for specific regulatory requirements in Japan;
    08 Jun 2018
    Following main changes were introduced: End of trial (EOT) and roll over in the open-label extension trial: After BI communicated end of the trial, EOTB Visit was performed in all ongoing patients. Patients receiving trial medication until end of Part B could be eligible for open-label treatment with nintedanib in a separate trial. Trial 1199.247 was planned to last until all patients completed EOTB Visit and Follow-up Visit as applicable; End of trial part A (EOTA) was done in cases of premature trial medication discontinuation during Part A of the trial with a Follow-up Visit 4 weeks later. A scheduled visit (V3-V9) could be skipped if EOTA or Follow-up Visit occurred within 4 weeks prior to scheduled visits; In case of premature discontinuation of trial medication during Part B, EOTB was done as soon as possible after last drug intake and a Follow-up Visit was to be completed 4 weeks after EOTB. A scheduled visit could be skipped if EOTB or Follow-up Visit occurred within 4 weeks prior to scheduled visits. For patients completing the trial regularly, EOTB was scheduled after BI’s communication of the end of the trial. For patients not rolling over in the separate open-label trial, a Follow-up Visit was completed 4 weeks after EOTB. The specific time window for EOTB was removed, time intervals for Visits X and Xa corrected, and the need for Interactive Response Technology (IRT) call included; All adverse events (AE)s (non-serious and serious), all AE of special interest (AESIs) were collected after the EOT, including the residual effect period until the individual patient’s end of trial; Additional AE analyses were specified to take the half-life of the trial drug into account: AEs that occurred between start of treatment and up to 7 days after date of last dose of trial medication were analysed in addition; Details were added regarding drug induced liver injury (DILI) handling: Potential DILI cases were defined as AESIs and a DILI checklist had to be completed.

    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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