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    Clinical Trial Results:
    A 52 weeks, double blind, randomized, placebo-controlled trial evaluating the effect of oral BIBF 1120, 150 mg twice daily, on Forced Vital Capacity decline , in patients with Idiopathic Pulmonary Fibrosis (IPF)

    Summary
    EudraCT number
    2010-024252-29
    Trial protocol
    FI   DE   PT   GR   NL   ES  
    Global end of trial date
    15 Oct 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Jun 2016
    First version publication date
    01 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1199.34
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01335477
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173 , Ingelheim am Rhein , Germany,
    Public contact
    QRPE Processes and Systems Coordination , Boehringer Ingelheim Pharma GmbH & Co. KG , +1 800243 0127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination, Boehringer Ingelheim Pharma GmbH & Co. KG , +1 800243 0127, 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
    18 Nov 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate a reduction of lung function decline, as measured by a change of the yearly rate of decline of forced vital capacity (FVC).
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were 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 patients as required.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 May 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    7 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Chile: 11
    Country: Number of subjects enrolled
    China: 84
    Country: Number of subjects enrolled
    Finland: 21
    Country: Number of subjects enrolled
    France: 76
    Country: Number of subjects enrolled
    Germany: 52
    Country: Number of subjects enrolled
    Greece: 28
    Country: Number of subjects enrolled
    India: 35
    Country: Number of subjects enrolled
    Japan: 83
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 97
    Country: Number of subjects enrolled
    Mexico: 7
    Country: Number of subjects enrolled
    Netherlands: 23
    Country: Number of subjects enrolled
    Portugal: 28
    Country: Number of subjects enrolled
    Russian Federation: 4
    Country: Number of subjects enrolled
    Spain: 28
    Country: Number of subjects enrolled
    Turkey: 55
    Country: Number of subjects enrolled
    United States: 142
    Worldwide total number of subjects
    794
    EEA total number of subjects
    256
    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)
    314
    From 65 to 84 years
    475
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    All subjects were screened for eligibility to participate in the trial. Subjects attended one specialist site which would then ensure that they (the subjects) met all inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Oral administration of placebo matching nintedanib soft gelatine capsules. One patient was randomised to the placebo arm, however this patient was not treated. Consequently, number of subject that started is 220 but only 219 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.
    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
    Oral administration of placebo matching nintedanib soft gelatine capsules. twice daily (bid)

    Arm title
    Nintedanib 150mg
    Arm description
    Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events. Two patients were randomised to the placebo arm, however those two patients were not treated. Consequently, number of subject that started is 331 but only 329 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.
    Arm type
    Experimental

    Investigational medicinal product name
    Nintedanib 150mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    twice daily (bid)

    Number of subjects in period 1 [1]
    Placebo Nintedanib 150mg
    Started
    219
    329
    Completed
    179
    272
    Not completed
    40
    57
         Adverse event, serious fatal
    23
    24
         Non compliant with protocol
    -
    2
         Reason other than those stated above
    2
    2
         Adverse event, non-fatal
    7
    18
         Consent withdrawn, not due to AE
    7
    9
         Lost to follow-up
    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 of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Oral administration of placebo matching nintedanib soft gelatine capsules. One patient was randomised to the placebo arm, however this patient was not treated. Consequently, number of subject that started is 220 but only 219 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

    Reporting group title
    Nintedanib 150mg
    Reporting group description
    Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events. Two patients were randomised to the placebo arm, however those two patients were not treated. Consequently, number of subject that started is 331 but only 329 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

    Reporting group values
    Placebo Nintedanib 150mg Total
    Number of subjects
    219 329 548
    Age categorical
    Units: Subjects
    Age continuous
    Treated set (TS): The TS consisted of randomised patients who were dispensed study medication and were documented to have taken at least one dose of investigational treatment
    Units: years
        arithmetic mean (standard deviation)
    67.1 ± 7.5 66.4 ± 7.9 -
    Gender categorical
    Treated set (TS): The TS consisted of randomised patients who were dispensed study medication and were documented to have taken at least one dose of investigational treatment
    Units: Subjects
        Female
    48 73 121
        Male
    171 256 427

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Oral administration of placebo matching nintedanib soft gelatine capsules. One patient was randomised to the placebo arm, however this patient was not treated. Consequently, number of subject that started is 220 but only 219 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

    Reporting group title
    Nintedanib 150mg
    Reporting group description
    Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events. Two patients were randomised to the placebo arm, however those two patients were not treated. Consequently, number of subject that started is 331 but only 329 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

    Primary: Annual Rate of Decline in Forced Vital Capacity (FVC) Over 52 Weeks.

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    End point title
    Annual Rate of Decline in Forced Vital Capacity (FVC) Over 52 Weeks.
    End point description
    Forced vital capacity (FVC) is the total amount of air exhaled during the lung function test. For this endpoint reported means represent the adjusted rate.
    End point type
    Primary
    End point timeframe
    52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    219 [1]
    329 [2]
    Units: mL/year
        arithmetic mean (standard error)
    -207.32 ± 19.309
    -113.59 ± 15.726
    Notes
    [1] - Treated Set (Only patients with observed cases (OC) values were analysed)
    [2] - Treated Set (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Random coefficient regression with fixed effects for treatment, gender, age, height and random effect of patient specific intercept and time. A hierarchical procedure was used in order to demonstrate the superiority of nintedanib over placebo for the primary and two key secondary endpoints. The consecutive steps of the hierarchy were only considered if the previous step was significant at the one-sided 2.5% level and the results were in favour of nintedanib.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.0002
    Method
    Random coefficient regression
    Parameter type
    Mean difference (final values)
    Point estimate
    93.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    44.78
         upper limit
    142.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    24.907
    Notes
    [3] - The Roger-Kenward approximation was used to estimate denominators degrees of freedom. Within-patient errors are modelled by an Unstructured variance-covariance matrix. Inter-individual variability is modelled by a Variance-components variance-covariance matrix. Nintedanib 150 mg bid versus Placebo.

    Secondary: Change From Baseline in Saint George’s Respiratory Questionnaire (SGRQ) Total Score at 52 Weeks

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    End point title
    Change From Baseline in Saint George’s Respiratory Questionnaire (SGRQ) Total Score at 52 Weeks
    End point description
    This is a key secondary endpoint. SGRQ is a health-related quality of life questionnaire divided into 3 components : symptoms, activity and impact. The total score (summed weights) can range from 0 to 100 with a lower score denoting a better health status. Means provided are the adjusted means based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).
    End point type
    Secondary
    End point timeframe
    Baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    213 [4]
    320 [5]
    Units: points on a scale
        arithmetic mean (standard error)
    5.48 ± 0.891
    2.8 ± 0.73
    Notes
    [4] - TS (Only patients with observed cases (OC) values were analysed)
    [5] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline SGRQ Total score, baseline SGRQ Total score-by-visit and random effect for patient.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    533
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.0197
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.95
         upper limit
    -0.43
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.151
    Notes
    [6] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix.

    Secondary: Time to First Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbation

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    End point title
    Time to First Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbation
    End point description
    Due to rare events, the median of time to event is not calculable, thus the percentages of patients with (IPF) exacerbation are reported and represented as a key secondary endpoint. An acute exacerbation (reported as an AE by the investigator) was defined as follows: Otherwise unexplained clinical features including all of the following: - Unexplained worsening or development of dyspnoea within 30 days - New diffuse pulmonary infiltrates on chest X-ray, and/or new HRCT parenchymal abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) since the last visit - Exclusion of infection as per routine clinical practice and microbiological studies - Exclusion of alternative causes as per routine clinical practice including left heart failure, pulmonary embolism and identifiable cause of acute lung injury. Failure is the proportion of patients with at least one acute IPF exacerbation over 52 weeks (up to randomisation + 372 days), based on all investigator-
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    219 [7]
    329 [8]
    Units: percentage of participants
    number (not applicable)
        Failure
    9.6
    3.6
        Censored
    90.4
    96.4
    Notes
    [7] - Treated Set (Only patients with observed cases (OC) values were analysed)
    [8] - Treated Set (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard Ratio is based on a Cox's regression model with terms for treatment, gender, age and height.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.005
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.19
         upper limit
    0.77
    Notes
    [9] - Nintedanib 150 mg bid versus Placebo.

    Secondary: Absolute Change From Baseline in Forced Vital Capacity (FVC) Over 52 weeks

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    End point title
    Absolute Change From Baseline in Forced Vital Capacity (FVC) Over 52 weeks
    End point description
    Means provided are the adjusted means. Adjusted mean is based on all analysed patients in the model (not only patients with a change from baseline to week 52).
    End point type
    Secondary
    End point timeframe
    Baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    217 [10]
    327 [11]
    Units: mL
        arithmetic mean (standard error)
    -205.03 ± 16.629
    -95.26 ± 14.2
    Notes
    [10] - TS (Only patients with observed cases (OC) values were analysed)
    [11] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, gender, age, height, treatment-by-visit, baseline FVC, baseline FVC -by-visit and random effect for patient.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    544
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    109.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    70.92
         upper limit
    148.62
    Variability estimate
    Standard error of the mean
    Dispersion value
    19.808
    Notes
    [12] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix.

    Secondary: Absolute Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) Over 52 Weeks

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    End point title
    Absolute Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) Over 52 Weeks
    End point description
    Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).
    End point type
    Secondary
    End point timeframe
    Baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    217 [13]
    327 [14]
    Units: %predicted
        arithmetic mean (standard error)
    -6.15 ± 0.505
    -3.09 ± 0.433
    Notes
    [13] - TS (Only patients with observed cases (OC) values were analysed)
    [14] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, gender, age, height, treatment-by-visit, baseline FVC [%predicted], baseline FVC [%predicted]-by-visit and random effect for patient.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    544
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    3.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.87
         upper limit
    4.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.607
    Notes
    [15] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix.

    Secondary: Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 5% Threshold

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    End point title
    Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 5% Threshold
    End point description
    Absolute categorical change of FVC (% predicted) by categories at 52 weeks - 5% threshold (decrease by >5%, increase by >5%, and change within ≤5%).
    End point type
    Secondary
    End point timeframe
    Baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    180
    269
    Units: percentage of participants
    number (not applicable)
        Decrease > 5%
    52.2
    34.9
        Change within ≤ 5%
    45
    50.2
        Increase > 5%
    2.8
    14.9
    No statistical analyses for this end point

    Secondary: Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 10% Threshold

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    End point title
    Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 10% Threshold
    End point description
    Absolute categorical change of FVC (% predicted) by categories at 52 weeks - 10% threshold (decrease by > 10%, increase by >10%, and change within ≤10%)
    End point type
    Secondary
    End point timeframe
    Baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    180
    269
    Units: percentage of participants
    number (not applicable)
        Decrease > 10%
    22.2
    14.9
        Change within ≤ 10%
    77.2
    80.7
        Increase > 10%
    0.6
    4.5
    No statistical analyses for this end point

    Secondary: FVC Responders Using 10% Threshold at 52 Weeks

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    End point title
    FVC Responders Using 10% Threshold at 52 Weeks
    End point description
    FVC responders using 10% threshold at 52 weeks, defined as patients with absolute decline in FVC% predicted no greater than 10% and with an FVC evaluation at 52 weeks.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    219 [16]
    329 [17]
    Units: percentage of participants
        number (confidence interval 95%)
    63.93 (57.38 to 70)
    69.6 (64.43 to 74.33)
    Notes
    [16] - TS (Only patients with observed cases (OC) values were analysed)
    [17] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Logistic regression with terms treatment, age, gender, height and baseline FVC % predicted
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    superiority [18]
    P-value
    = 0.1833
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.286
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.86
    Notes
    [18] - Nintedanib 150 mg bid versus Placebo

    Secondary: Proportion of FVC Responders Using 5% Threshold at 52 Weeks

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    End point title
    Proportion of FVC Responders Using 5% Threshold at 52 Weeks
    End point description
    Proportion of FVC responders using 5% threshold at 52 weeks, defined as patients with absolute decline in FVC% predicted no greater than 5% and with an FVC evaluation at 52 weeks.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    219 [19]
    329 [20]
    Units: percentage of participants
        number (confidence interval 95%)
    39.27 (33.04 to 45.87)
    53.19 (47.79 to 58.52)
    Notes
    [19] - TS (Only patients with observed cases (OC) values were analysed)
    [20] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Logistic regression with terms treatment, age, gender, height and baseline FVC % predicted
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    superiority [21]
    P-value
    = 0.0011
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.794
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.26
         upper limit
    2.55
    Notes
    [21] - Nintedanib 150 mg bid versus Placebo

    Secondary: Proportion of SGRQ Responders at 52 Weeks: Patient Reported Outcomes (PROs)

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    End point title
    Proportion of SGRQ Responders at 52 Weeks: Patient Reported Outcomes (PROs)
    End point description
    Proportion of SGRQ Responders at 52 Weeks. Responders defined as <= -4 points change in change from baseline in SGRQ total score at 52 weeks.
    End point type
    Secondary
    End point timeframe
    Baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    219 [22]
    329 [23]
    Units: percentage of participants
        number (confidence interval 95%)
    16.89 (12.51 to 22.42)
    25.23 (20.84 to 30.19)
    Notes
    [22] - TS (Only patients with observed cases (OC) values were analysed)
    [23] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Logistic regression with terms treatment, baseline SGRQ total score
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    superiority [24]
    P-value
    = 0.0218
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.664
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.08
         upper limit
    2.57
    Notes
    [24] - Nintedanib 150 mg bid versus Placebo

    Secondary: Change From Baseline in SGRQ Symptom Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)

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    End point title
    Change From Baseline in SGRQ Symptom Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)
    End point description
    SGRQ Symptom score is a sub-component of SGRQ total score and is concerned with the effect of respiratory symptoms, their frequency and severity. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better symptom-related quality of life. Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).
    End point type
    Secondary
    End point timeframe
    baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    214 [25]
    323 [26]
    Units: points on a scale
        arithmetic mean (standard error)
    3.43 ± 1.297
    2.03 ± 1.061
    Notes
    [25] - TS (Only patients with observed cases (OC) values were analysed)
    [26] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline SGRQ Symptoms component, baseline SGRQ Symptoms component-by-visit and random effect for patient.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    superiority [27]
    P-value
    = 0.4019
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.69
         upper limit
    1.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.675
    Notes
    [27] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix.

    Secondary: Change From Baseline in SGRQ Activity Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)

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    End point title
    Change From Baseline in SGRQ Activity Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)
    End point description
    SGRQ Activity score is a sub-component of SGRQ total score and concerned with activities that cause or are limited by breathlessness. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better activity-related quality of life. Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).
    End point type
    Secondary
    End point timeframe
    baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    214 [28]
    322 [29]
    Units: points on a scale
        arithmetic mean (standard error)
    7.2 ± 1.052
    3.89 ± 0.863
    Notes
    [28] - TS (Only patients with observed cases (OC) values were analysed)
    [29] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline SGRQ Activities component, baseline SGRQ Activities component-by-visit and random effect for patient
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    536
    Analysis specification
    Pre-specified
    Analysis type
    superiority [30]
    P-value
    = 0.0152
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.97
         upper limit
    -0.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.36
    Notes
    [30] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix.

    Secondary: Change From Baseline in SGRQ Impact Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)

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    End point title
    Change From Baseline in SGRQ Impact Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)
    End point description
    SGRQ Impact score is a sub-component of SGRQ total score and covers a range of aspects concerned with social functioning and psychological disturbances resulting from airway disease. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better impact-related quality of life.
    End point type
    Secondary
    End point timeframe
    baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    215 [31]
    320 [32]
    Units: points on a scale
        arithmetic mean (standard error)
    5.93 ± 1.036
    2.85 ± 0.852
    Notes
    [31] - TS (Only patients with observed cases (OC) values were analysed)
    [32] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline SGRQ impact component, baseline SGRQ impact component-by-visit and random effect for patient
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    535
    Analysis specification
    Pre-specified
    Analysis type
    superiority [33]
    P-value
    = 0.022
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.71
         upper limit
    -0.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.342
    Notes
    [33] - Nintedanib 150 mg bid versus Placebo. Within-patient error are modelled by compound symmetry covariance matrix.

    Secondary: Change From Baseline in Idiopathic Pulmonary Fibrosis (IPF) Specific Version of SGRQ (SGRQ-I) Total Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)

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    End point title
    Change From Baseline in Idiopathic Pulmonary Fibrosis (IPF) Specific Version of SGRQ (SGRQ-I) Total Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)
    End point description
    SGRQ-I is the IPF specific version of SGRQ comprises of selected items from the SGRQ divided into three components, Symptoms, Activity and Impact. Each component is scored separately. The weights for all items with a positive responses are summed and the weights from missed items are deducted from the maximum possible weight for the total score. The total score is calculated by dividing the summed weights from positive items in the questionnaire by maximum possible weight for all items in the questionnaire. The total score can range from 0 to 100 with a lower score denoting a better health-related quality of life. Change from baseline is calculated as the difference between total score at week 52 and total score at baseline as measured by the scale.
    End point type
    Secondary
    End point timeframe
    baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    213 [34]
    320 [35]
    Units: points on a scale
        arithmetic mean (standard error)
    5.84 ± 0.921
    2.72 ± 0.757
    Notes
    [34] - TS (Only patients with observed cases (OC) values were analysed)
    [35] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline SGRQ-I Total score, baseline SGRQ-I Total score-by-visit and random effect for patient.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    533
    Analysis specification
    Pre-specified
    Analysis type
    superiority [36]
    P-value
    = 0.0089
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.46
         upper limit
    -0.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.192
    Notes
    [36] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix.

    Secondary: Change From Baseline in Shortness of Breath Questionnaire (SOBQ) at 52 Weeks: Patient Reported Outcomes (PROs)

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    End point title
    Change From Baseline in Shortness of Breath Questionnaire (SOBQ) at 52 Weeks: Patient Reported Outcomes (PROs)
    End point description
    Shortness of Breath Questionnaire measures the shortness of breath. It comprises of 24 items. Each item is scored on a scale between 0-5 where 5 represents maximal breathlessness. The responses to all items are summed up to provide the overall score that can range from 0 (best outcome) to 120 (worst outcome). Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).
    End point type
    Secondary
    End point timeframe
    baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    204 [37]
    302 [38]
    Units: points on a scale
        arithmetic mean (standard error)
    9.07 ± 1.3
    6.69 ± 1.073
    Notes
    [37] - TS (Only patients with observed cases (OC) values were analysed)
    [38] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline SOBQ score, baseline SOBQ score-by-visit and random effect for patient.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    506
    Analysis specification
    Pre-specified
    Analysis type
    superiority [39]
    P-value
    = 0.1587
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.68
         upper limit
    0.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.685
    Notes
    [39] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix.

    Secondary: Change From Baseline in Cough Symptom Score of the Cough and Sputum Assessment Questionnaire (CASA-Q) Score at 52 Weeks: Patient Reported Outcomes (PROs)

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    End point title
    Change From Baseline in Cough Symptom Score of the Cough and Sputum Assessment Questionnaire (CASA-Q) Score at 52 Weeks: Patient Reported Outcomes (PROs)
    End point description
    The cough domains of the Cough and Sputum Assessment Questionnaire (CASAQ(CD)) assess the frequency and severity of cough and sputum and their impact on everyday life. It contains 4 domains cough/sputum symptom and impact with each scale ranging from 0 to 100 with lower scores indicating higher symptoms/impact levels (worst outcome). Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).
    End point type
    Secondary
    End point timeframe
    baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    215 [40]
    323 [41]
    Units: points on a scale
        arithmetic mean (standard error)
    -2.38 ± 1.325
    -0.33 ± 1.087
    Notes
    [40] - TS (Only patients with observed cases (OC) values were analysed)
    [41] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline CASA-Q Cough symptoms score, baseline CASAQ Cough symptoms score-by-visit and random effect for patient.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    538
    Analysis specification
    Pre-specified
    Analysis type
    superiority [42]
    P-value
    = 0.2326
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    2.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.31
         upper limit
    5.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.713
    Notes
    [42] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix.

    Secondary: Change From Baseline in Cough Impact Score of the Cough and Sputum Assessment Questionnaire (CASA-Q) Score at 52 Weeks: Patient Reported Outcomes (PROs)

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    End point title
    Change From Baseline in Cough Impact Score of the Cough and Sputum Assessment Questionnaire (CASA-Q) Score at 52 Weeks: Patient Reported Outcomes (PROs)
    End point description
    The cough domains of the Cough and Sputum Assessment Questionnaire (CASA-Q) assess the frequency and severity of cough and sputum and their impact on everyday life. It contains 4 domains cough/sputum symptom and impact with each scale ranging from 0 to 100 with lower scores indicating higher symptoms/impact levels (worst outcome). Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).
    End point type
    Secondary
    End point timeframe
    baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    215 [43]
    322 [44]
    Units: points on a scale
        arithmetic mean (standard error)
    -4.39 ± 1.209
    -2.58 ± 0.991
    Notes
    [43] - Treated set
    [44] - Treated set
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline CASA-Q Cough impact score, baseline CASA-Q Cough impact score-by-visit and random effect for patient.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    537
    Analysis specification
    Pre-specified
    Analysis type
    superiority [45]
    P-value
    = 0.2475
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    1.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.26
         upper limit
    4.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.564
    Notes
    [45] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix.

    Secondary: Proportion of Patient’s Global Impression of Change (PGI-C) Responders at 52 Weeks: Patient Reported Outcomes (PROs)

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    End point title
    Proportion of Patient’s Global Impression of Change (PGI-C) Responders at 52 Weeks: Patient Reported Outcomes (PROs)
    End point description
    Proportion of Patient's Global Impression of Change (PGI-C) responders at 52 weeks. Responders are defined as 'Very much better'/ 'Much better'/ 'A little better'/ 'No change'.
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    219 [46]
    329 [47]
    Units: percentage of participants
        number (confidence interval 95%)
    53.88 (47.27 to 60.36)
    61.7 (56.34 to 66.79)
    Notes
    [46] - TS (Only patients with observed cases (OC) values were analysed)
    [47] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Logistic regression with term treatment
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    superiority [48]
    P-value
    = 0.069
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.379
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.98
         upper limit
    1.95
    Notes
    [48] - Nintedanib 150 mg bid versus Placebo

    Secondary: Change From Baseline in EuroQol 5-Dimensional Quality of Life Questionnaire (EQ-5D) Health State up to 52 Weeks: Patient Reported Outcomes (PROs)

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    End point title
    Change From Baseline in EuroQol 5-Dimensional Quality of Life Questionnaire (EQ-5D) Health State up to 52 Weeks: Patient Reported Outcomes (PROs)
    End point description
    The EuroQol 5-dimensional Health State is based on a visual analog scale (EQ-VAS) representing the general patient's health state labelled from 100 (best imaginable health state) to 0 (worst imaginable health state). A higher score indicating a better health state. Change from baseline is calculated as the difference between health state at week 12, 24 and 52 respectively and health state at baseline as measured by the scale.
    End point type
    Secondary
    End point timeframe
    baseline, 12 weeks, 24 weeks and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    219 [49]
    329 [50]
    Units: points on a scale
    arithmetic mean (standard deviation)
        12 weeks (N=207, 306)
    -1.48 ± 15.6
    -0.57 ± 16.97
        24 weeks (N=204, 297)
    -4.86 ± 16.94
    -1.1 ± 16.81
        52 weeks (N=178, 265)
    -5.6 ± 17.67
    -2.52 ± 16.95
    Notes
    [49] - TS (Only patients with observed cases (OC) values were analysed)
    [50] - TS (Only patients with observed cases (OC) values were analysed)
    No statistical analyses for this end point

    Secondary: Time to Death Over 52 Weeks

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    End point title
    Time to Death Over 52 Weeks
    End point description
    Due to rare events, the median of time to event is not calculable, thus the percentages of patients who did or did not experienced death before or at 372 days after randomisation or last contact date (whichever occurs first) are reported. Failure is the proportion of patients who died over 52 weeks (up to 372 days after randomisation).
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    219 [51]
    329 [52]
    Units: percentage of participants
    number (not applicable)
        Failure
    9.1
    6.7
        Censored
    90.9
    93.3
    Notes
    [51] - TS (Only patients with observed cases (OC) values were analysed)
    [52] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard ratio is based on a Cox´s regression model with terms for treatment, gender, age and height.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    superiority [53]
    P-value
    = 0.2995
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    1.35
    Notes
    [53] - Nintedanib 150 mg bid versus Placebo

    Secondary: Time to Death Due to Respiratory Cause Over 52 Weeks (Adjudicated)

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    End point title
    Time to Death Due to Respiratory Cause Over 52 Weeks (Adjudicated)
    End point description
    Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experienced death due to respiratory causes before or at 372 days after randomisation or last contact date (whichever occurs first) are reported. Failure is the the proportion of patients who died due to respiratory causes over 52 weeks (up to 372 days after randomisation).
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    219 [54]
    329 [55]
    Units: percentage of participants
    number (not applicable)
        Failure
    5
    4.3
        Censored
    95
    95.7
    Notes
    [54] - TS (Only patients with observed cases (OC) values were analysed)
    [55] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard ratio is based on Cox´s regression model with terms for treatment, gender, age and height.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    superiority [56]
    P-value
    = 0.6654
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    1.9
    Notes
    [56] - Nintedanib 150 mg bid versus Placebo

    Secondary: Time to On-treatment Death

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    End point title
    Time to On-treatment Death
    End point description
    Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not die before or at last trial medication intake + 28 days were censored at last trial medication intake + 28 days and reported. Failure is the the proportion of patients who died on-treatment (up to 28 days after last treatment intake).
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    219 [57]
    329 [58]
    Units: percentage of participants
    number (not applicable)
        Failure
    7.8
    4.9
        Censored
    92.2
    95.1
    Notes
    [57] - TS (Only patients with observed cases (OC) values were analysed)
    [58] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard ratio is based on a Cox´s regression model with terms for treatment, gender, age and height.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    superiority [59]
    P-value
    = 0.2209
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.34
         upper limit
    1.35
    Notes
    [59] - Nintedanib 150 mg bid versus Placebo

    Secondary: Time to Death or Lung Transplant Over 52 Weeks

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    End point title
    Time to Death or Lung Transplant Over 52 Weeks
    End point description
    Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experience event (death or lung transplant) before or at 372 days after randomisation or last contact date (whichever occurs first) are reported. Failure is the proportion of patients who died or had lung transplant over 52 weeks (up to 372 days after randomisation).
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    219 [60]
    329 [61]
    Units: percentage of participants
    number (not applicable)
        Failure
    10
    6.7
        Censored
    90
    93.3
    Notes
    [60] - TS (Only patients with observed cases (OC) values were analysed)
    [61] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard ratio is based on Cox´s regression model with terms for treatment, gender, age and height.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    superiority [62]
    P-value
    = 0.1664
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.37
         upper limit
    1.21
    Notes
    [62] - Nintedanib 150 mg bid versus Placebo

    Secondary: Time to Death or Lung Transplant or Qualifying for Lung Transplant Over 52 Weeks.

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    End point title
    Time to Death or Lung Transplant or Qualifying for Lung Transplant Over 52 Weeks.
    End point description
    Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experienced death or lung transplant or qualifying for lung transplant over 52 weeks are reported. A patient was considered qualifying for lung transplant by the investigator if he or she fulfilled the following criteria: FVC <45% predicted or Carbon monoxide diffusion capacity (DL(CO)) <30% pred or Oxygen saturation on pulse oximetry (SpO2) <88% at rest, at sea level (to be adapted for other heights). These criteria were evaluated by investigators judgement. Failure is the proportion of patients who died or had lung transplant or qualified for lung transplant over 52 weeks (up to 372 days after randomisation).
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    219 [63]
    329 [64]
    Units: percentage of participants
    number (not applicable)
        Failure
    23.7
    19.5
        Censored
    76.3
    80.5
    Notes
    [63] - TS (Only patients with observed cases (OC) values were analysed)
    [64] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Hazard ratio is based on Cox´s regression model with terms for treatment, gender, age and height.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    superiority [65]
    P-value
    = 0.2123
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.55
         upper limit
    1.16
    Notes
    [65] - Nintedanib 150 mg bid versus Placebo

    Secondary: Change From Baseline in SpO2 (Oxygen Saturation, Expressed in Percent) at Rest up Over 52 Weeks

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    End point title
    Change From Baseline in SpO2 (Oxygen Saturation, Expressed in Percent) at Rest up Over 52 Weeks
    End point description
    Means presented are the adjusted means. Adjusted mean is based on all analyzed patients in the model (not only patients with a change from baseline to week 52)
    End point type
    Secondary
    End point timeframe
    baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    212 [66]
    320 [67]
    Units: percent of oxygen saturation
        arithmetic mean (standard error)
    -0.66 ± 0.174
    -0.39 ± 0.149
    Notes
    [66] - TS (Only patients with observed cases (OC) values were analysed)
    [67] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, gender, age, height, treatment-by-visit, baseline SpO2, baseline SpO2-by-visit and random effect for patient
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    532
    Analysis specification
    Pre-specified
    Analysis type
    superiority [68]
    P-value
    = 0.2032
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.15
         upper limit
    0.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.213
    Notes
    [68] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix.

    Secondary: Change From Baseline in Carbon Monoxide Diffusion Capacity (DLCO) at Rest Over 52 Weeks

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    End point title
    Change From Baseline in Carbon Monoxide Diffusion Capacity (DLCO) at Rest Over 52 Weeks
    End point description
    Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).
    End point type
    Secondary
    End point timeframe
    baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    202 [69]
    302 [70]
    Units: mmol/min/kPa
        arithmetic mean (standard error)
    -0.4 ± 0.0843
    -0.286 ± 0.0729
    Notes
    [69] - TS (Only patients with observed cases (OC) values were analysed)
    [70] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Mixed Model for Repeated Measures with fixed effects for treatment, visit, gender, age, height, treatment-by-visit, baseline DLCO (HGB Corrected) [mmol/min/kPa], baseline DLCO (HGB Corrected) [mmol/min/kPa]-by-visit and random effect for patient.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    504
    Analysis specification
    Pre-specified
    Analysis type
    superiority [71]
    P-value
    = 0.26
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.113
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.084
         upper limit
    0.31
    Notes
    [71] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix.

    Secondary: Relative Change From Baseline in Forced Vital Capacity (FVC) Over 52 Weeks

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    End point title
    Relative Change From Baseline in Forced Vital Capacity (FVC) Over 52 Weeks
    End point description
    Percentage change from baseline in FVC over 52 weeks. Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).
    End point type
    Secondary
    End point timeframe
    Baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    217 [72]
    327 [73]
    Units: percent change
        arithmetic mean (standard error)
    -8.14 ± 0.62
    -3.9 ± 0.528
    Notes
    [72] - Treated Set (Only patients with observed cases (OC) values were analysed)
    [73] - Treated Set (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, gender, age, height, treatment-by-visit, baseline FVC, baseline FVC-by visit and random effect for patient.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    544
    Analysis specification
    Pre-specified
    Analysis type
    superiority [74]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    4.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.78
         upper limit
    5.69
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.742
    Notes
    [74] - Within-patient errors are modelled by compound symmetry covariance matrix. Nintedanib 150 mg bid versus Placebo.

    Secondary: Relative Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) Over 52 Weeks

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    End point title
    Relative Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) Over 52 Weeks
    End point description
    Percentage change from baseline in FVC (% predicted) at 52 weeks. Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).
    End point type
    Secondary
    End point timeframe
    Baseline and 52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    217 [75]
    327 [76]
    Units: percent change
        arithmetic mean (standard error)
    -8.13 ± 0.614
    -3.92 ± 0.525
    Notes
    [75] - TS (Only patients with observed cases (OC) values were analysed)
    [76] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Based on Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, gender, age, height, treatment-by-visit, baseline FVC [%predicted], baseline FVC [%predicted]-by-visit and random effect for patient.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    544
    Analysis specification
    Pre-specified
    Analysis type
    superiority [77]
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    4.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.76
         upper limit
    5.67
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.743
    Notes
    [77] - Nintedanib 150 mg bid versus Placebo. Within-patient errors are modelled by compound symmetry covariance matrix. Clinical

    Secondary: Risk of an Acute IPF Exacerbation Over 52 Weeks

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    End point title
    Risk of an Acute IPF Exacerbation Over 52 Weeks
    End point description
    Incidence rate of exacerbations (calculated as the number of patients with at least 1 acute IPF exacerbation divided by the total number of years at risk *100)
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    Placebo Nintedanib 150mg
    Number of subjects analysed
    219 [78]
    329 [79]
    Units: Participants/Year *100
        number (not applicable)
    10.2
    3.9
    Notes
    [78] - TS (Only patients with observed cases (OC) values were analysed)
    [79] - TS (Only patients with observed cases (OC) values were analysed)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Risk ratio was calculated as the ratio of risk of exacerbation in both treatment groups. The log of the risk ratio was assumed to follow a normal distribution with mean 0 and variance equal to the sum of the reciprocals of the number of patients with at least one exacerbation in each treatment arm.
    Comparison groups
    Placebo v Nintedanib 150mg
    Number of subjects included in analysis
    548
    Analysis specification
    Pre-specified
    Analysis type
    superiority [80]
    P-value
    = 0.007
    Method
    Normal distribution
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.38
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.19
         upper limit
    0.77
    Notes
    [80] - Nintedanib 150 mg bid versus Placebo.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration until 28 days after the last drug administration, up to 428 days.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Oral administration of Placebo matching nintedanib soft gelatine capsules

    Reporting group title
    Nintedanib 150mg bid
    Reporting group description
    Oral administration of soft gelatine capsules of Nintedanib 150 mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

    Serious adverse events
    Placebo Nintedanib 150mg bid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    72 / 219 (32.88%)
    98 / 329 (29.79%)
         number of deaths (all causes)
    24
    30
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chloroma
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Colon cancer
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma metastatic
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (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
    2 / 219 (0.91%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurofibroma
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal cancer
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (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 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm rupture
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic intramural haematoma
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 219 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Coronary angioplasty
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung transplant
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheostomy
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 219 (0.91%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    3 / 219 (1.37%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Haemoptysis
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    3 / 219 (1.37%)
    4 / 329 (1.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    28 / 219 (12.79%)
    22 / 329 (6.69%)
         occurrences causally related to treatment / all
    1 / 32
    0 / 25
         deaths causally related to treatment / all
    0 / 12
    0 / 11
    Pleural effusion
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 219 (0.46%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 219 (0.00%)
    4 / 329 (1.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary hypertension
         subjects affected / exposed
    3 / 219 (1.37%)
    6 / 329 (1.82%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory acidosis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    5 / 219 (2.28%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract inflammation
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Arteriogram coronary
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest X-ray abnormal
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 219 (0.46%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Burns third degree
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 219 (0.46%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 219 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 219 (0.91%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 219 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (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 / 219 (0.46%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 219 (0.46%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiomegaly
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 219 (0.46%)
    3 / 329 (0.91%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pericardial effusion
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (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
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular dysfunction
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (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
    Aphasia
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 219 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Piriformis syndrome
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orbital apex syndrome
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 219 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 219 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-alcoholic steatohepatitis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Subcutaneous emphysema
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (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
    Renal colic
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (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 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 219 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (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
    Appendicitis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 219 (0.00%)
    2 / 329 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (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
    0 / 219 (0.00%)
    6 / 329 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (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
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex meningoencephalitis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective aneurysm
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycobacterial infection
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathogen resistance
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    11 / 219 (5.02%)
    18 / 329 (5.47%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 21
         deaths causally related to treatment / all
    0 / 1
    0 / 5
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (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 / 219 (1.37%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 219 (0.46%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    2 / 219 (0.91%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 219 (0.00%)
    1 / 329 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 219 (0.46%)
    0 / 329 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Nintedanib 150mg bid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    193 / 219 (88.13%)
    308 / 329 (93.62%)
    Investigations
    Weight decreased
         subjects affected / exposed
    2 / 219 (0.91%)
    37 / 329 (11.25%)
         occurrences all number
    2
    38
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 219 (5.02%)
    11 / 329 (3.34%)
         occurrences all number
    12
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 219 (3.20%)
    22 / 329 (6.69%)
         occurrences all number
    7
    27
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    20 / 219 (9.13%)
    26 / 329 (7.90%)
         occurrences all number
    21
    27
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 219 (3.20%)
    30 / 329 (9.12%)
         occurrences all number
    7
    37
    Abdominal pain upper
         subjects affected / exposed
    6 / 219 (2.74%)
    18 / 329 (5.47%)
         occurrences all number
    7
    18
    Constipation
         subjects affected / exposed
    10 / 219 (4.57%)
    19 / 329 (5.78%)
         occurrences all number
    10
    24
    Diarrhoea
         subjects affected / exposed
    39 / 219 (17.81%)
    207 / 329 (62.92%)
         occurrences all number
    56
    346
    Nausea
         subjects affected / exposed
    16 / 219 (7.31%)
    86 / 329 (26.14%)
         occurrences all number
    16
    114
    Vomiting
         subjects affected / exposed
    7 / 219 (3.20%)
    34 / 329 (10.33%)
         occurrences all number
    7
    49
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    31 / 219 (14.16%)
    38 / 329 (11.55%)
         occurrences all number
    37
    45
    Dyspnoea
         subjects affected / exposed
    22 / 219 (10.05%)
    25 / 329 (7.60%)
         occurrences all number
    22
    25
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    15 / 219 (6.85%)
    13 / 329 (3.95%)
         occurrences all number
    15
    13
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 219 (5.02%)
    8 / 329 (2.43%)
         occurrences all number
    13
    9
    Back pain
         subjects affected / exposed
    13 / 219 (5.94%)
    20 / 329 (6.08%)
         occurrences all number
    13
    22
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    17 / 219 (7.76%)
    26 / 329 (7.90%)
         occurrences all number
    25
    37
    Nasopharyngitis
         subjects affected / exposed
    34 / 219 (15.53%)
    48 / 329 (14.59%)
         occurrences all number
    44
    63
    Respiratory tract infection
         subjects affected / exposed
    13 / 219 (5.94%)
    18 / 329 (5.47%)
         occurrences all number
    15
    22
    Upper respiratory tract infection
         subjects affected / exposed
    24 / 219 (10.96%)
    30 / 329 (9.12%)
         occurrences all number
    32
    39
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    10 / 219 (4.57%)
    42 / 329 (12.77%)
         occurrences all number
    10
    48

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2011
    - ‘Acute IPF exacerbation’ was clarified each time ‘exacerbation’ was mentioned - Procedures and appropriate measures in case of suspicion of a ‘drug induced liver injury’ event were implemented - A re-test was allowed in case a laboratory parameter was found to be abnormal at Visit 1. This was to be conducted if laboratory tests were thought to be a measurement error and not related to the patient’s condition - Patients were to be excluded from the trial if they were not able to follow trial procedures including completion of self administered questionnaires without help - Instructions were included for Investigators on the reporting of DLCO in the eCRF - Addition of the ‘always serious AEs’ according to new BI standards to ensure proper reporting of these events - Inclusion criterion 4 was changed to: ‘Chest HRCT performed within 12 months of Visit 1’, instead of ‘Chest HRCT performed within 12 months of Visit 2’
    04 Sep 2012
    - Addition of exploratory biomarker analyses in order to explore the effect of nintedanib on biomarkers related to IPF pathology and prognostic markers of the disease. Exploratory analyses of samples from patients who gave specific informed consent were performed. Pharmacogenomic analysis was also added - The criterion for poor compliance was defined as a protocol violation

    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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