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    Clinical Trial Results:
    A 12-week, double-blind, randomised, placebo-controlled, parallel-group trial followed by a single active arm phase of 40 weeks evaluating the effect of oral nintedanib 150 mg twice daily on change in biomarkers of extracellular matrix (ECM) turnover in patients with idiopathic pulmonary fibrosis (IPF) and limited forced vital capacity (FVC) impairment

    Summary
    EudraCT number
    		 2015-003148-38
    Trial protocol
    		 ES   CZ   FI   HU   GB   BE   FR   DE   PL  
    Global end of trial date
    08 Jun 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jun 2019
    First version publication date
    15 Jun 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1199.227
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02788474
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, 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
    23 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jun 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This trial was conducted to examine for the first time the effects of nintedanib on the biomarkers indicative of ECM turnover to predict IPF progression. This trial also aimed to confirm the association between the change in these biomarkers during the first 12 weeks and disease progression over 52 weeks, and to assess whether nintedanib treatment could alter this association or not.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jun 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 26
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    Czech Republic: 21
    Country: Number of subjects enrolled
    Finland: 25
    Country: Number of subjects enrolled
    France: 39
    Country: Number of subjects enrolled
    Germany: 32
    Country: Number of subjects enrolled
    Hungary: 35
    Country: Number of subjects enrolled
    Japan: 70
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 60
    Country: Number of subjects enrolled
    Poland: 24
    Country: Number of subjects enrolled
    Spain: 54
    Country: Number of subjects enrolled
    United Kingdom: 51
    Country: Number of subjects enrolled
    United States: 18
    Worldwide total number of subjects
    471
    EEA total number of subjects
    297
    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)
    98
    From 65 to 84 years
    365
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial comprised of 2 treatment periods (52 weeks). The first treatment period was a 12-week, randomised, double-blind, placebo-controlled, parallel-group period whereas the second treatment period was a 40-week, single-arm, open-label, active treatment (nintedanib 150 milligram (mg) twice daily (bid)) period.

    Pre-assignment
    Screening details
    		 Participants with idiopathic pulmonary fibrosis (IPF) were eligible for trial if they fulfilled all of the inclusion criteria and none of the exclusion criteria. Subjects attended specialist sites to ensure that they met all implemented inclusion/exclusion criteria and were not to be randomized to drug if any of the specific criteria was violated.

    Period 1
    Period 1 title
    Double blind treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Subject, Carer, Data analyst, Assessor
    Blinding implementation details
    Patients, investigators and everyone involved in the trial conduct or analysis or with any other interest in this trial remained blinded with regard to randomised treatment assignments until after database lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo/Nintedanib
    Arm description
    		 Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period and Nintedanib 150 milligram (mg) twice daily (bid) for 40 weeks in open label period. 1 capsule of Nintedanib 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs). 1 patient was randomised to the this arm, however this patient was not treated. Consequently, number of subjects that started is 231 but only 230 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
    Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period

    Arm title
    		 Nintedanib/Nintedanib
    Arm description
    		 Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period and for 40 weeks in open label period. 1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period

    Number of subjects in period 1 [1]
    		Placebo/Nintedanib Nintedanib/Nintedanib
    Started
    230
    116
    Completed
    221
    112
    Not completed
    9
    4
         Patient's refusal
    3
    -
         Adverse event, non-fatal
    6
    4
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication
    Period 2
    Period 2 title
    Open label treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    The period was a 40-week, single arm, open-label, active treatment period during which all patients received nintedanib 150 mg bid

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo/Nintedanib
    Arm description
    		 Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period and Nintedanib 150 milligram (mg) twice daily (bid) for 40 weeks in open label period. 1 capsule of Nintedanib 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period.

    Arm title
    		 Nintedanib/Nintedanib
    Arm description
    		 Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period and for 40 weeks in open label period. 1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period and for 40 weeks in open label period. 1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)

    Number of subjects in period 2
    		Placebo/Nintedanib Nintedanib/Nintedanib
    Started
    221
    112
    Completed
    189
    100
    Not completed
    32
    12
         Patient's refusal
    1
    3
         Adverse event, serious fatal
    4
    3
         Other than reason specified
    1
    -
         Adverse event, non-fatal
    25
    6
         Non-compliance
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo/Nintedanib
    Reporting group description
    		 Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period and Nintedanib 150 milligram (mg) twice daily (bid) for 40 weeks in open label period. 1 capsule of Nintedanib 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs). 1 patient was randomised to the this arm, however this patient was not treated. Consequently, number of subjects that started is 231 but only 230 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

    Reporting group title
    Nintedanib/Nintedanib
    Reporting group description
    		 Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period and for 40 weeks in open label period. 1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)

    Reporting group values
    		 Placebo/Nintedanib Nintedanib/Nintedanib Total
    Number of subjects
    		 230 116 346
    Age categorical
    Units: Subjects
    Age Continuous
    Treated Set (TS), consisting of participants who were randomised to a treatment group and received at least one dose of trial medication
    Units: years
        arithmetic mean (standard deviation)
    		 70.2 ± 7.2 70.5 ± 7.7 -
    Sex: Female, Male
    Treated Set (TS), consisting of participants who were randomised to a treatment group and received at least one dose of trial medication
    Units: Subjects
        Female
    		 61 23 84
        Male
    		 169 93 262
    Race (NIH/OMB)
    Unreported data: Data not collected at sites in France due to local regulation. Treated Set (TS), consisting of participants who were randomised to a treatment group and received at least one dose of trial medication
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 68 35 103
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 144 70 214
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 18 11 29
    Ethnicity (NIH/OMB)
    Unreported data: Data not collected at sites in France due to local regulation. Treated Set (TS), consisting of participants who were randomised to a treatment group and received at least one dose of trial medication
    Units: Subjects
        Hispanic or Latino
    		 19 9 28
        Not Hispanic or Latino
    		 193 96 289
        Unknown or Not Reported
    		 18 11 29

    End points

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    End points reporting groups
    Reporting group title
    Placebo/Nintedanib
    Reporting group description
    		 Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period and Nintedanib 150 milligram (mg) twice daily (bid) for 40 weeks in open label period. 1 capsule of Nintedanib 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs). 1 patient was randomised to the this arm, however this patient was not treated. Consequently, number of subjects that started is 231 but only 230 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

    Reporting group title
    Nintedanib/Nintedanib
    Reporting group description
    		 Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period and for 40 weeks in open label period. 1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)
    Reporting group title
    Placebo/Nintedanib
    Reporting group description
    		 Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period and Nintedanib 150 milligram (mg) twice daily (bid) for 40 weeks in open label period. 1 capsule of Nintedanib 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)

    Reporting group title
    Nintedanib/Nintedanib
    Reporting group description
    		 Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period and for 40 weeks in open label period. 1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)

    Primary: The rate of change (slope) in blood C-reactive protein degraded by matrix metalloproteinase-1/8 (CRPM) from baseline to week 12.

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    End point title
    		 The rate of change (slope) in blood C-reactive protein degraded by matrix metalloproteinase-1/8 (CRPM) from baseline to week 12.
    End point description
    The rate of change (slope) in blood C-reactive protein degraded by matrix metalloproteinase-1/8 (CRPM) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (CRPM log 10 transformed) with fixed effects for gender, age, height and random effect of patient specific intercept and time.
    End point type
    Primary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Placebo/Nintedanib Nintedanib/Nintedanib
    Number of subjects analysed
    229 [1]
    116 [2]
    Units: nanogram/ millitre/ month (ng/ mL/ mth)
        arithmetic mean (standard error)
    -0.00190 ± 0.00165
    -0.00257 ± 0.00232
    Notes
    [1] - TS including participants with available data for this endpoint.
    [2] - TS including participants with available data for this endpoint.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The rate of change (slope) in blood CRPM was assumed to be linear in each subject over the 12 weeks of treatment. The intercepts and slopes were assumed to be normally distributed with arbitrary covariance matrix. Since the distribution of the data was not normal, a log10 transformation was performed before conducting the statistical analyses. Significance tests were based on least-square means using 2-sided 95% confidence intervals (2-sided α=0.05).
    Comparison groups
    Placebo/Nintedanib v Nintedanib/Nintedanib
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.8146 [4]
    Method
    		 random coefficient regression
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.00066
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.00621
         upper limit
    		 0.00488
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.00282
    Notes
    [3] - The Kenward-Roger approximation was used to estimate denominators degrees of freedom. Difference calculated as Nintedanib minus Placebo
    [4] - random coefficient regression (random slopes and intercepts) model including sex, age and height as covariates (Due to the low number of measurements per patient, baseline CRPM was included as a response rather than as a covariate in the analysis)

    Secondary: Percentage of patients with disease progression as defined by absolute forced vital capacity (FVC) decline >=10% or death until week 52

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    End point title
    		 Percentage of patients with disease progression as defined by absolute forced vital capacity (FVC) decline >=10% or death until week 52
    End point description
    For this endpoint, disease progression was defined by absolute FVC (percentage of predicted) decline ≥10% or death up to Week 52 based on in-clinic supervised spirometry. CRPM was also log 10 transformed for this key secondary endpoint. Within group (for Placebo/Nintedanib) statistical analysis (Statistical analysis 1) for present outcome measure was defined and analysed in the clinical trial report (To assess the association between the change in the Extracellular matrix (ECM) biomarker CRPM in the first 12 weeks and disease progression over 52 weeks, a logistic regression analysis including baseline blood CRPM and the monthly rate of change (slope) in blood CRPM in the first 12 weeks as covariates was applied for placebo-treated patients only to evaluate the potential of CRPM as a prognostic biomarker). However, due to the platform limitation those could not be disclosed on EudraCT, but can be found on ct.gov under study number: NCT02788474
    End point type
    Secondary
    End point timeframe
    52 weeks
    End point values
    		 Placebo/Nintedanib Nintedanib/Nintedanib
    Number of subjects analysed
    230 [5]
    116 [6]
    Units: Percentage of participants
        number (confidence interval 95%)
    30.43 (24.85 to 36.66)
    25.00 (18.01 to 33.60)
    Notes
    [5] - TS
    [6] - TS
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    To assess how nintedanib treatment affected the association between the change in CRPM in the first 12 weeks and disease progression over 52 weeks, a logistic regression analysis including baseline blood CRPM, the monthly rate of change (slope) in blood CRPM up to Week 12, treatment and treatment-CRPM slope interaction as covariates was applied.
    Comparison groups
    Placebo/Nintedanib v Nintedanib/Nintedanib
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1537
    Method
    		 Regression, Logistic
    Parameter type
    		 slope estimate
    Point estimate
    -45.566
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -109.55
         upper limit
    		 16.37
    Statistical analysis title
    		 Statistical Analysis 3
    Statistical analysis description
    To assess whether the overall treatment regimen affected disease progression, a logistic regression analysis including baseline blood CRPM and randomised treatment as covariates was applied.
    Comparison groups
    Placebo/Nintedanib v Nintedanib/Nintedanib
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3116
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.769
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.27
    Statistical analysis title
    		 Statistical Analysis 4
    Statistical analysis description
    To assess whether the monthly rate of change (slope) in blood CRPM in the first 12 weeks could explain the effect of treatment on disease progression, a logistic regression analysis including baseline blood CRPM, the rate of change (slope) in blood CRPM in the first 12 weeks and randomised treatment as covariates was applied.
    Comparison groups
    Placebo/Nintedanib v Nintedanib/Nintedanib
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3175
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.772
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.27

    Secondary: The rate of change in blood Collagen 1 degraded by matrix metalloproteinase-2/9/13 (C1M) from baseline to week 12

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    End point title
    		 The rate of change in blood Collagen 1 degraded by matrix metalloproteinase-2/9/13 (C1M) from baseline to week 12
    End point description
    The rate of change in blood Collagen 1 degraded by matrix metalloproteinase-2/9/13 (C1M) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (C1M (negative reciprocal root transformation)) with fixed effects for gender, age, height and random effect of patient specific intercept and time.
    End point type
    Secondary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Placebo/Nintedanib Nintedanib/Nintedanib
    Number of subjects analysed
    229 [7]
    116 [8]
    Units: ng/ml/mth
        arithmetic mean (standard error)
    0.00041 ± 0.00127
    0.00162 ± 0.00172
    Notes
    [7] - Treated set (TS) including participants with available data for this endpoint.
    [8] - Treated set (TS) including participants with available data for this endpoint.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The rate of change (slope) in blood C1M was assumed to be linear in each subject over the 12 weeks of treatment. Within−patient errors are modelled by an Unstructured variance−covariance matrix.
    Comparison groups
    Placebo/Nintedanib v Nintedanib/Nintedanib
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.5469 [10]
    Method
    		 random coefficient regression
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.00121
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.00273
         upper limit
    		 0.00515
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.002
    Notes
    [9] - Difference calculated as Nintedanib minus Placebo. Inter−individual variability is modelled by a Variance−Components variance−covariance matrix.
    [10] - random coefficient regression model (C1M (negative reciprocal root-transformed)) with fixed effects for gender, age, height and random effect of patient specific intercept and time.

    Secondary: The rate of change in blood Collagen 3 degraded by matrix metalloproteinase-9 (C3M) from baseline to week 12

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    End point title
    		 The rate of change in blood Collagen 3 degraded by matrix metalloproteinase-9 (C3M) from baseline to week 12
    End point description
    The rate of change in blood Collagen 3 degraded by matrix metalloproteinase-9 (C3M) from baseline to week 12 is presented. The mean presented is the adjusted rate based on a random coefficient regression (C3M- log 10 transformation) with fixed effects for gender, age, height and random effect of patient specific intercept and time.
    End point type
    Secondary
    End point timeframe
    baseline and 12 weeks
    End point values
    		 Placebo/Nintedanib Nintedanib/Nintedanib
    Number of subjects analysed
    229 [11]
    116 [12]
    Units: ng/ml/mth
        arithmetic mean (standard error)
    -0.00091 ± 0.00158
    -0.00398 ± 0.00219
    Notes
    [11] - Treated set (TS) including participants with available data for this endpoint.
    [12] - Treated set (TS) including participants with available data for this endpoint.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The rate of change (slope) in blood C3M was assumed to be linear in each subject over the 12 weeks of treatment. Within−patient errors are modelled by an Unstructured variance−covariance matrix.
    Comparison groups
    Placebo/Nintedanib v Nintedanib/Nintedanib
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.2429 [14]
    Method
    		 random coefficient regression
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.00307
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.00823
         upper limit
    		 0.00209
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.00262
    Notes
    [13] - Difference calculated as Nintedanib minus Placebo. Inter−individual variability is modelled by a Variance−Components variance−covariance matrix.
    [14] - random coefficient regression model (C3M (log10-transformed)) with fixed effects for gender, age, height and random effect of patient specific intercept and time.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAE & Non SAE: Adverse events (AEs) that occurred between first drug intake and 28 days after last drug intake (end of the Residual effect period (REP));up to 53 weeks All cause mortality: AEs during the course of the clinical trial;up to 56 weeks
    Adverse event reporting additional description
    Treated set is used for reporting adverse events (Serious Adverse Event (SAE) & Non SAE)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Placebo/Nintedanib
    Reporting group description
    		 Participants received soft gelatin capsules of matching placebo for 12 weeks in double blind period and Nintedanib 150 milligram (mg) twice daily (bid) for 40 weeks in open label period. 1 capsule of Nintedanib 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs). 1 patient was randomised to the this arm, however this patient was not treated. Consequently, number of subjects that started is 231 but only 230 reported to ensure consistent reporting with baseline characteristics that includes only treated patients.

    Reporting group title
    Nintedanib/Nintedanib
    Reporting group description
    		 Participants received soft gelatin capsules of Nintedanib 150 mg bid for 12 weeks in double blind period and for 40 weeks in open label period. 1 capsule of 150 mg bid had possibility to be reduced to 100 mg bid to manage adverse events (AEs)

    Serious adverse events
    		 Placebo/Nintedanib Nintedanib/Nintedanib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    66 / 230 (28.70%)
    20 / 116 (17.24%)
         number of deaths (all causes)
    6
    3
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer recurrent
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 230 (0.43%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    3 / 230 (1.30%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microscopic polyangiitis
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (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
    Chest pain
         subjects affected / exposed
    2 / 230 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 230 (0.43%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Disease progression
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    5 / 230 (2.17%)
    2 / 116 (1.72%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 230 (0.43%)
    2 / 116 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    2 / 230 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 230 (0.43%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza B virus test positive
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    2 / 230 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 230 (0.87%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Pulmonary arteriovenous fistula
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (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
    2 / 230 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 230 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 230 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    2 / 230 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 230 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 230 (0.87%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Aplastic anaemia
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden hearing loss
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    2 / 230 (0.87%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (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
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 230 (0.87%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         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 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarthritis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    1 / 230 (0.43%)
    0 / 116 (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
    1 / 230 (0.43%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 230 (0.43%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 230 (1.74%)
    0 / 116 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 230 (1.74%)
    2 / 116 (1.72%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 230 (0.00%)
    1 / 116 (0.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo/Nintedanib Nintedanib/Nintedanib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    206 / 230 (89.57%)
    108 / 116 (93.10%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 230 (5.65%)
    12 / 116 (10.34%)
         occurrences all number
    15
    14
    Aspartate aminotransferase increased
         subjects affected / exposed
    14 / 230 (6.09%)
    10 / 116 (8.62%)
         occurrences all number
    17
    10
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    16 / 230 (6.96%)
    6 / 116 (5.17%)
         occurrences all number
    16
    7
    Weight decreased
         subjects affected / exposed
    22 / 230 (9.57%)
    11 / 116 (9.48%)
         occurrences all number
    23
    11
    Vascular disorders
    Hypertension
         subjects affected / exposed
    9 / 230 (3.91%)
    7 / 116 (6.03%)
         occurrences all number
    13
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 230 (4.35%)
    6 / 116 (5.17%)
         occurrences all number
    12
    7
    Headache
         subjects affected / exposed
    20 / 230 (8.70%)
    9 / 116 (7.76%)
         occurrences all number
    26
    11
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 230 (0.87%)
    6 / 116 (5.17%)
         occurrences all number
    2
    9
    Fatigue
         subjects affected / exposed
    11 / 230 (4.78%)
    6 / 116 (5.17%)
         occurrences all number
    11
    6
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    5 / 230 (2.17%)
    9 / 116 (7.76%)
         occurrences all number
    5
    9
    Abdominal pain
         subjects affected / exposed
    18 / 230 (7.83%)
    9 / 116 (7.76%)
         occurrences all number
    22
    15
    Abdominal pain upper
         subjects affected / exposed
    19 / 230 (8.26%)
    4 / 116 (3.45%)
         occurrences all number
    20
    4
    Constipation
         subjects affected / exposed
    10 / 230 (4.35%)
    10 / 116 (8.62%)
         occurrences all number
    12
    12
    Diarrhoea
         subjects affected / exposed
    158 / 230 (68.70%)
    92 / 116 (79.31%)
         occurrences all number
    366
    214
    Dyspepsia
         subjects affected / exposed
    8 / 230 (3.48%)
    6 / 116 (5.17%)
         occurrences all number
    8
    6
    Flatulence
         subjects affected / exposed
    7 / 230 (3.04%)
    6 / 116 (5.17%)
         occurrences all number
    8
    7
    Gastrooesophageal reflux disease
         subjects affected / exposed
    13 / 230 (5.65%)
    7 / 116 (6.03%)
         occurrences all number
    13
    7
    Nausea
         subjects affected / exposed
    55 / 230 (23.91%)
    23 / 116 (19.83%)
         occurrences all number
    78
    32
    Vomiting
         subjects affected / exposed
    34 / 230 (14.78%)
    18 / 116 (15.52%)
         occurrences all number
    58
    34
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    37 / 230 (16.09%)
    18 / 116 (15.52%)
         occurrences all number
    45
    23
    Dyspnoea
         subjects affected / exposed
    12 / 230 (5.22%)
    6 / 116 (5.17%)
         occurrences all number
    18
    8
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    23 / 230 (10.00%)
    8 / 116 (6.90%)
         occurrences all number
    25
    9
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    19 / 230 (8.26%)
    11 / 116 (9.48%)
         occurrences all number
    24
    16
    Influenza
         subjects affected / exposed
    7 / 230 (3.04%)
    6 / 116 (5.17%)
         occurrences all number
    9
    6
    Lower respiratory tract infection
         subjects affected / exposed
    13 / 230 (5.65%)
    8 / 116 (6.90%)
         occurrences all number
    22
    18
    Nasopharyngitis
         subjects affected / exposed
    44 / 230 (19.13%)
    25 / 116 (21.55%)
         occurrences all number
    56
    31
    Respiratory tract infection
         subjects affected / exposed
    12 / 230 (5.22%)
    6 / 116 (5.17%)
         occurrences all number
    15
    6
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 230 (8.70%)
    9 / 116 (7.76%)
         occurrences all number
    29
    11
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    38 / 230 (16.52%)
    21 / 116 (18.10%)
         occurrences all number
    41
    22

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Feb 2016
    The document number was corrected on the title page and headers.
    25 Feb 2016
    No content changes were introduced. A technical error during signature workflow was corrected.
    04 May 2017
    The following main changes in the conduct of the trial and clarifications were introduced: - Serum, plasma, RNA, PK and optional serum banking sample collections were added to the flow chart - Fingertip was added as a possibility to perform measurements of oxygen saturation - Further explanations were added concerning visit planning and conduct The below amendment exists but was issued after the global end of the trial date: Amendment dated: 09Jul2018 The following main changes in the analysis of the data were implemented: - The analysis of the PFT data was detailed further by adding 4 endpoints: the proportion of patients with absolute FVC decline ≥10% until Week 52, the proportion of patients with absolute FVC decline ≥5% until Week 52, the time to FVC decline ≥10%, and the time to FVC decline ≥5% - The analysis of the LOXL2 specific cross-linking fragment was deleted because the analysis kit had not been validated

    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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