Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43865   clinical trials with a EudraCT protocol, of which   7286   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase II open-label, roll-over study of the long-term tolerability, safety and efficacy of oral BIBF 1120 in patients with idiopathic pulmonary fibrosis

    Summary
    EudraCT number
    		 2009-013788-21
    Trial protocol
    		 ES   BE   FR   PT   IT   DE   IE   HU   CZ   BG   GB   GR  
    Global end of trial date
    26 Sep 2016

    Results information
    Results version number
    		 v1
    This version publication date
    14 Oct 2017
    First version publication date
    14 Oct 2017
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1199.35
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01170065
    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
    08 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to establish the long-term tolerability and safety profile of nintedanib in patients with idiopathic pulmonary fibrosis (IPF) who had completed parent trial 1199.30 (NCT00514683).
    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
    25 Jun 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Ethical reason
    Long term follow-up duration
    		 6 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Brazil: 7
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    China: 16
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    France: 32
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Greece: 6
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Russian Federation: 4
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United Kingdom: 13
    Worldwide total number of subjects
    199
    EEA total number of subjects
    138
    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)
    69
    From 65 to 84 years
    127
    85 years and over
    3

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Treatment groups are displayed according to dose at randomisation in 1199.30 (NCT00514683).

    Pre-assignment
    Screening details
    		 Patients were not randomised to study medication in trial 1199.35 but were to receive open-label nintedanib, either at the dose received in period 2 of parent trial 1199.30 (NCT00514683) or they could increase their dose to nintedanib 150 mg twice daily (bid) after implementation of protocol amendment 1.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Trial was open-label. The treatment allocation of patients in parent trial 1199.30 was unblinded prior to the start of trial 1199.35.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Patients were treated with oral administration of placebo in period 1 of the parent trial and with soft gelatine capsules of Nintedanib 50 mg once daily (qd) in the second period of the 1199.30 (parent trial). In the 1199.35 trial they could remain on this last dose or increase to Nintedanib 150 mg twice daily (bid)
    Arm type
    		 Placebo in 1199.30 and Experimental in 1199.35

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were treated with oral administration of placebo in period 1 of the parent trial and with soft gelatine capsules of Nintedanib 50 mg once daily (qd) in the second period of the 1199.30 (parent trial). In the 1199.35 trial they could remain on this last dose or increase to Nintedanib 150 mg twice daily (bid). Continuous daily dosing until the patient met one of the withdrawal criteria.

    Arm title
    		 Nintedanib 50 mg- 100 mg
    Arm description
    		 Patients were treated with oral administration of soft gelatine capsules of Nintedanib 50 mg qd, 50 mg bid or 100 mg bid in the parent trial. In the 1199.35 trial they could remain on their last dose in the parent trial or increase to Nintedanib 150 mg bid.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were treated with oral administration of soft gelatine capsules of Nintedanib 50 mg qd, 50 mg bid or 100 mg bid in the parent trial. In the 1199.35 trial they could remain on their last dose in the parent trial or increase to Nintedanib 150 mg bid. Continuous daily dosing until the patient met one of the withdrawal criteria

    Arm title
    		 Nintedanib 150 mg
    Arm description
    		 Patients were treated with oral administration of soft gelatine capsules of Nintedanib 150 mg bid and could step down to 100 mg bid. In the 1199.35 trial they could remain on their last dose in the parent trial.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were treated with oral administration of soft gelatine capsules of Nintedanib 150 mg bid and could step down to 100 mg bid. In the 1199.35 trial they could remain on their last dose in the parent trial. Continuous daily dosing until the patient met one of the withdrawal criteria.

    Number of subjects in period 1 [1]
    		Placebo Nintedanib 50 mg- 100 mg Nintedanib 150 mg
    Started
    37
    126
    35
    Completed
    9
    34
    9
    Not completed
    28
    92
    26
         Adverse event, serious fatal
    14
    42
    7
         Adverse event, non-fatal
    3
    8
    3
         Consent withdrawn, not due to AE
    2
    4
    2
         Reason other than specified
    3
    8
    3
         Lost to follow-up
    1
    4
    1
         Ongoing after planned observation time
    5
    26
    10
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients were treated with oral administration of placebo in period 1 of the parent trial and with soft gelatine capsules of Nintedanib 50 mg once daily (qd) in the second period of the 1199.30 (parent trial). In the 1199.35 trial they could remain on this last dose or increase to Nintedanib 150 mg twice daily (bid)

    Reporting group title
    Nintedanib 50 mg- 100 mg
    Reporting group description
    		 Patients were treated with oral administration of soft gelatine capsules of Nintedanib 50 mg qd, 50 mg bid or 100 mg bid in the parent trial. In the 1199.35 trial they could remain on their last dose in the parent trial or increase to Nintedanib 150 mg bid.

    Reporting group title
    Nintedanib 150 mg
    Reporting group description
    		 Patients were treated with oral administration of soft gelatine capsules of Nintedanib 150 mg bid and could step down to 100 mg bid. In the 1199.35 trial they could remain on their last dose in the parent trial.

    Reporting group values
    		 Placebo Nintedanib 50 mg- 100 mg Nintedanib 150 mg Total
    Number of subjects
    		 37 126 35
    Age categorical
    Units: Subjects
    Age Continuous
    Treated set (TS): The treated set which included all patients who received at least 1 dose of open-label study medication in trial 1199.35
    Units: years
        arithmetic mean (standard deviation)
    		 64.2 ( 7.3 ) 65.4 ( 8.6 ) 65.2 ( 7.2 ) -
    Gender, Male/Female
    Treated set (TS): The treated set which included all patients who received at least 1 dose of open-label study medication in trial 1199.35
    Units: Subjects
        Female
    		 14 36 7 57
        Male
    		 23 90 28 141

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients were treated with oral administration of placebo in period 1 of the parent trial and with soft gelatine capsules of Nintedanib 50 mg once daily (qd) in the second period of the 1199.30 (parent trial). In the 1199.35 trial they could remain on this last dose or increase to Nintedanib 150 mg twice daily (bid)

    Reporting group title
    Nintedanib 50 mg- 100 mg
    Reporting group description
    		 Patients were treated with oral administration of soft gelatine capsules of Nintedanib 50 mg qd, 50 mg bid or 100 mg bid in the parent trial. In the 1199.35 trial they could remain on their last dose in the parent trial or increase to Nintedanib 150 mg bid.

    Reporting group title
    Nintedanib 150 mg
    Reporting group description
    		 Patients were treated with oral administration of soft gelatine capsules of Nintedanib 150 mg bid and could step down to 100 mg bid. In the 1199.35 trial they could remain on their last dose in the parent trial.

    Primary: Annual rate of decline in forced vital capacity (FVC)

    		 Close Top of page
    End point title
    		 Annual rate of decline in forced vital capacity (FVC) [1]
    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. The full analysis set (FAS) which included all patients in the treated set who provided baseline data (for the first trial visit) for at least 1 endpoint in trial 1199.35 is the population set used for this endpoint
    End point type
    Primary
    End point timeframe
    From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    End point values
    		 Placebo Nintedanib 50 mg- 100 mg Nintedanib 150 mg
    Number of subjects analysed
    37 [2]
    126 [3]
    35 [4]
    Units: milliliters per year (mL/ yr)
        arithmetic mean (standard error)
    -129 ( 29.47 )
    -137.5 ( 14.6 )
    -132.9 ( 28.22 )
    Notes
    [2] - FAS
    [3] - FAS
    [4] - FAS
    No statistical analyses for this end point

    Secondary: Overall survival

    		 Close Top of page
    End point title
    		 Overall survival
    End point description
    Overall survival is defined as the time from the first intake of nintedanib in trial 1199.35 to death. For presentation of overall survival results, Kaplan-Meier estimates and confidence intervals (using Greenwood variance formula) for the overall on-treatment survival is calculated within each treatment arm.
    End point type
    Secondary
    End point timeframe
    From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months
    End point values
    		 Placebo Nintedanib 50 mg- 100 mg Nintedanib 150 mg
    Number of subjects analysed
    37 [5]
    126 [6]
    35 [7]
    Units: percentage
        arithmetic mean (confidence interval 95%)
    37.4 (16.8 to 58)
    46.8 (35.3 to 58.4)
    66.2 (46.9 to 85.5)
    Notes
    [5] - FAS
    [6] - FAS
    [7] - FAS
    No statistical analyses for this end point

    Secondary: Progression−free survival

    		 Close Top of page
    End point title
    		 Progression−free survival
    End point description
    Progression-free survival was defined as the time from the first nintedanib intake in trial 1199.35 to disease progression. For presentation of progression−free survival results, Kaplan-Meier estimates and confidence intervals (using Greenwood variance formula) for the overall on-treatment progression-free survival is calculated within each treatment arm.
    End point type
    Secondary
    End point timeframe
    From first trial drug intake in 1199.35 to disease progression; up to 61.8 months
    End point values
    		 Placebo Nintedanib 50 mg- 100 mg Nintedanib 150 mg
    Number of subjects analysed
    37 [8]
    126 [9]
    35 [10]
    Units: percentage
        arithmetic mean (confidence interval 95%)
    9.6 (0 to 22)
    3.5 (0 to 7.4)
    12.2 (0 to 24.9)
    Notes
    [8] - FAS
    [9] - FAS
    [10] - FAS
    No statistical analyses for this end point

    Secondary: Annual rate of decline in haemoglobin corrected diffusing capacity of the lung for carbon monoxide (DLCO) decrease

    		 Close Top of page
    End point title
    		 Annual rate of decline in haemoglobin corrected diffusing capacity of the lung for carbon monoxide (DLCO) decrease
    End point description
    Haemoglobin corrected DLCO decrease was a secondary endpoint for the trial. It was considered important that all investigators used the same method of testing and recording data at each visit for each patient. Haemoglobin corrected DLCO was calculated for each patient using the following formulae: Males: Hb corrected DLCO = measured DLCO x (10.22 + Hb concentration) / (1.7 x Hb concentration) Females: Hb corrected DLCO = measured DLCO x (9.38 + Hb concentration) / (1.7 x Hb concentration). Annual rate of decline in haemoglobin corrected diffusing capacity of the lung for carbon monoxide (DLCO) decrease is presented.
    End point type
    Secondary
    End point timeframe
    From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months
    End point values
    		 Placebo Nintedanib 50 mg- 100 mg Nintedanib 150 mg
    Number of subjects analysed
    37 [11]
    126 [12]
    35 [13]
    Units: mmol/min/kPa/yr
        arithmetic mean (standard error)
    -0.4 ( 0.08 )
    -0.3 ( 0.04 )
    -0.2 ( 0.07 )
    Notes
    [11] - FAS
    [12] - FAS
    [13] - FAS
    No statistical analyses for this end point

    Secondary: Percentage of patients with at least one acute idiopathic pulmonary fibrosis (IPF) exacerbation

    		 Close Top of page
    End point title
    		 Percentage of patients with at least one acute idiopathic pulmonary fibrosis (IPF) exacerbation
    End point description
    Percentage of patients with at least one acute idiopathic pulmonary fibrosis (IPF) exacerbation are presented. An exacerbation was defined as otherwise unexplained clinical features occurring within 1 month including all of the following: -Progression of dyspnoea over several days to 4 weeks -New diffuse pulmonary infiltrates on chest X-ray and/or high-resolution computerised tomography (HRCT) Parenchymal abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) since the last visit -A decrease in arterial oxygen partial pressure (PaO2) of ≥10 mmHg or PaO2/fraction of inspired oxygen (FiO2) of <225 mmHg since the last visit -Exclusion of infection based on routine clinical practice and microbiological studies -Absence of other contributory causes such as congestive heart failure, pulmonary embolism, etc.
    End point type
    Secondary
    End point timeframe
    From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months
    End point values
    		 Placebo Nintedanib 50 mg- 100 mg Nintedanib 150 mg
    Number of subjects analysed
    37 [14]
    126 [15]
    35 [16]
    Units: Percentage of participants
        number (not applicable)
    13.5
    19.8
    20
    Notes
    [14] - FAS
    [15] - FAS
    [16] - FAS
    No statistical analyses for this end point

    Secondary: Incidence of patients with at least one acute IPF exacerbation over time

    		 Close Top of page
    End point title
    		 Incidence of patients with at least one acute IPF exacerbation over time
    End point description
    Incidence rate = (Patients with at least one acute IPF exacerbation / Total number of years at risk) x 100
    End point type
    Secondary
    End point timeframe
    From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months
    End point values
    		 Placebo Nintedanib 50 mg- 100 mg Nintedanib 150 mg
    Number of subjects analysed
    37 [17]
    126 [18]
    35 [19]
    Units: Exacerbations Per Year
        number (not applicable)
    6.1
    7.6
    7.8
    Notes
    [17] - FAS
    [18] - FAS
    [19] - FAS
    No statistical analyses for this end point

    Secondary: Time to first acute IPF exacerbation

    		 Close Top of page
    End point title
    		 Time to first acute IPF exacerbation
    End point description
    Time to acute IPF as 'time from the first nintedanib intake in trial 1199.35 to the first occurrence of an acute IPF exacerbation. For presentation of Time to first acute IPF exacerbation results, Kaplan-Meier estimates and confidence intervals (using Greenwood variance formula) for the overall time-to-event rate is calculated within each treatment arm.
    End point type
    Secondary
    End point timeframe
    From first drug administration in 1199.35 until database lock 15Oct2015, up to 61.8 Months
    End point values
    		 Placebo Nintedanib 50 mg- 100 mg Nintedanib 150 mg
    Number of subjects analysed
    37 [20]
    126 [21]
    35 [22]
    Units: percentage
        arithmetic mean (confidence interval 95%)
    67.7 (39.4 to 95.9)
    68.6 (56.8 to 80.4)
    73.5 (55.9 to 91.1)
    Notes
    [20] - FAS
    [21] - FAS
    [22] - FAS
    No statistical analyses for this end point

    Secondary: Percentage of patients with at least one Adverse events (AEs), with investigator defined drug−related AEs, AEs leading to discontinuation of trial drug, serious AEs

    		 Close Top of page
    End point title
    		 Percentage of patients with at least one Adverse events (AEs), with investigator defined drug−related AEs, AEs leading to discontinuation of trial drug, serious AEs
    End point description
    Percentage of patients with at least one Adverse events (AEs), with investigator defined drug−related AEs, AEs leading to discontinuation of trial drug, serious AEs are presented
    End point type
    Secondary
    End point timeframe
    From the first nintedanib intake in trial 1199.35 to the last nintedanib intake + 28 days; up to 61.8 months + 28 days
    End point values
    		 Placebo Nintedanib 50 mg- 100 mg Nintedanib 150 mg
    Number of subjects analysed
    37 [23]
    126 [24]
    35 [25]
    Units: Percentage of participants
    number (not applicable)
        AEs
    100
    99.2
    97.1
        Investigator defined drug−related AEs
    70.3
    65.9
    54.3
        AEs leading to discontinuation of trial drug
    48.6
    41.3
    34.3
        Serious AE
    67.6
    74.6
    62.9
    Notes
    [23] - TS
    [24] - TS
    [25] - TS
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From the first nintedanib intake in trial 1199.35 to the last nintedanib intake + 28 days; up to 61.8 months + 28 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients were treated with oral administration of placebo in period 1 of the parent trial and with soft gelatine capsules of Nintedanib 50 mg once daily (qd) in the second period of the 1199.30 (parent trial). In the 1199.35 trial they could remain on this last dose or increase to Nintedanib 150 mg twice daily (bid)

    Reporting group title
    Nintedanib 50 mg -100 mg
    Reporting group description
    		 Patients were treated with oral administration of soft gelatine capsules of Nintedanib 50 mg qd, 50 mg bid or 100 mg bid in the parent trial. In the 1199.35 trial they could remain on their last dose in the parent trial or increase to Nintedanib 150 mg bid.

    Reporting group title
    Nintedanib 150 mg
    Reporting group description
    		 Patients were treated with oral administration of soft gelatine capsules of Nintedanib 150 mg bid and could step down to 100 mg bid. In the 1199.35 trial they could remain on their last dose in the parent trial.

    Serious adverse events
    		 Placebo Nintedanib 50 mg -100 mg Nintedanib 150 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 37 (67.57%)
    94 / 126 (74.60%)
    22 / 35 (62.86%)
         number of deaths (all causes)
    15
    41
    8
         number of deaths resulting from adverse events
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 126 (1.59%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 126 (1.59%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 126 (1.59%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    Metastases to lung
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Renal neoplasm
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 126 (2.38%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery aneurysm
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 126 (1.59%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 126 (1.59%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 126 (1.59%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 126 (1.59%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchostenosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bullous lung disease
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 37 (5.41%)
    11 / 126 (8.73%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 14
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hypoventilation
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    11 / 37 (29.73%)
    41 / 126 (32.54%)
    10 / 35 (28.57%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 50
    0 / 12
         deaths causally related to treatment / all
    0 / 5
    0 / 20
    0 / 7
    Lung consolidation
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 37 (2.70%)
    6 / 126 (4.76%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 126 (3.97%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 37 (2.70%)
    7 / 126 (5.56%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Pancreatic enzymes increased
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin I
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 126 (1.59%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    3 / 37 (8.11%)
    2 / 126 (1.59%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 126 (2.38%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 126 (2.38%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 126 (1.59%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bundle branch block
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 126 (3.97%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 37 (2.70%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 126 (1.59%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 126 (1.59%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Coma
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 126 (2.38%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal haemorrhage
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 37 (8.11%)
    2 / 126 (1.59%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 126 (1.59%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Granuloma skin
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 126 (1.59%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary bladder polyp
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthropathy
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Exostosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Bronchitis
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 126 (2.38%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chlamydial infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fungal infection
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 37 (0.00%)
    4 / 126 (3.17%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 37 (2.70%)
    5 / 126 (3.97%)
    3 / 35 (8.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 9
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Pneumonia
         subjects affected / exposed
    3 / 37 (8.11%)
    6 / 126 (4.76%)
    2 / 35 (5.71%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    Pneumonia escherichia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 37 (2.70%)
    4 / 126 (3.17%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Nintedanib 50 mg -100 mg Nintedanib 150 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 37 (91.89%)
    111 / 126 (88.10%)
    32 / 35 (91.43%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 37 (0.00%)
    7 / 126 (5.56%)
    3 / 35 (8.57%)
         occurrences all number
    0
    7
    3
    Hypotension
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 126 (2.38%)
    2 / 35 (5.71%)
         occurrences all number
    0
    3
    2
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 37 (5.41%)
    10 / 126 (7.94%)
    1 / 35 (2.86%)
         occurrences all number
    2
    10
    1
    Condition aggravated
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 126 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    2
    0
    1
    Fatigue
         subjects affected / exposed
    2 / 37 (5.41%)
    9 / 126 (7.14%)
    4 / 35 (11.43%)
         occurrences all number
    2
    10
    5
    Influenza like illness
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 37 (8.11%)
    27 / 126 (21.43%)
    4 / 35 (11.43%)
         occurrences all number
    3
    38
    7
    Dyspnoea
         subjects affected / exposed
    5 / 37 (13.51%)
    19 / 126 (15.08%)
    3 / 35 (8.57%)
         occurrences all number
    6
    24
    3
    Epistaxis
         subjects affected / exposed
    2 / 37 (5.41%)
    8 / 126 (6.35%)
    1 / 35 (2.86%)
         occurrences all number
    3
    8
    2
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    0 / 37 (0.00%)
    22 / 126 (17.46%)
    3 / 35 (8.57%)
         occurrences all number
    0
    28
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 37 (0.00%)
    4 / 126 (3.17%)
    3 / 35 (8.57%)
         occurrences all number
    0
    4
    3
    Depression
         subjects affected / exposed
    2 / 37 (5.41%)
    4 / 126 (3.17%)
    1 / 35 (2.86%)
         occurrences all number
    3
    4
    1
    Insomnia
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 126 (1.59%)
    2 / 35 (5.71%)
         occurrences all number
    0
    2
    2
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 37 (5.41%)
    6 / 126 (4.76%)
    0 / 35 (0.00%)
         occurrences all number
    2
    8
    0
    Hepatic enzyme increased
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 126 (2.38%)
    0 / 35 (0.00%)
         occurrences all number
    2
    3
    0
    Weight decreased
         subjects affected / exposed
    10 / 37 (27.03%)
    29 / 126 (23.02%)
    7 / 35 (20.00%)
         occurrences all number
    11
    33
    7
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    2 / 35 (5.71%)
         occurrences all number
    0
    1
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 37 (10.81%)
    11 / 126 (8.73%)
    2 / 35 (5.71%)
         occurrences all number
    4
    13
    2
    Paraesthesia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    2 / 35 (5.71%)
         occurrences all number
    0
    1
    2
    Sciatica
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    3 / 35 (8.57%)
         occurrences all number
    0
    1
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 126 (0.79%)
    2 / 35 (5.71%)
         occurrences all number
    2
    2
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 126 (0.79%)
    0 / 35 (0.00%)
         occurrences all number
    2
    1
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 37 (5.41%)
    9 / 126 (7.14%)
    3 / 35 (8.57%)
         occurrences all number
    2
    13
    4
    Glaucoma
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    2 / 35 (5.71%)
         occurrences all number
    0
    1
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 37 (5.41%)
    9 / 126 (7.14%)
    4 / 35 (11.43%)
         occurrences all number
    2
    9
    5
    Abdominal pain upper
         subjects affected / exposed
    2 / 37 (5.41%)
    4 / 126 (3.17%)
    0 / 35 (0.00%)
         occurrences all number
    2
    4
    0
    Constipation
         subjects affected / exposed
    2 / 37 (5.41%)
    11 / 126 (8.73%)
    1 / 35 (2.86%)
         occurrences all number
    4
    12
    1
    Diarrhoea
         subjects affected / exposed
    19 / 37 (51.35%)
    68 / 126 (53.97%)
    22 / 35 (62.86%)
         occurrences all number
    30
    111
    33
    Frequent bowel movements
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 126 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    1
    0
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 37 (8.11%)
    4 / 126 (3.17%)
    2 / 35 (5.71%)
         occurrences all number
    3
    4
    2
    Nausea
         subjects affected / exposed
    9 / 37 (24.32%)
    22 / 126 (17.46%)
    2 / 35 (5.71%)
         occurrences all number
    12
    37
    2
    Vomiting
         subjects affected / exposed
    7 / 37 (18.92%)
    17 / 126 (13.49%)
    3 / 35 (8.57%)
         occurrences all number
    8
    26
    4
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 126 (1.59%)
    2 / 35 (5.71%)
         occurrences all number
    1
    2
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 37 (2.70%)
    7 / 126 (5.56%)
    2 / 35 (5.71%)
         occurrences all number
    1
    9
    3
    Rash
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 126 (2.38%)
    0 / 35 (0.00%)
         occurrences all number
    2
    5
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 37 (0.00%)
    3 / 126 (2.38%)
    2 / 35 (5.71%)
         occurrences all number
    0
    4
    2
    Proteinuria
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 126 (1.59%)
    2 / 35 (5.71%)
         occurrences all number
    3
    2
    2
    Urinary retention
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 37 (5.41%)
    4 / 126 (3.17%)
    1 / 35 (2.86%)
         occurrences all number
    2
    6
    1
    Back pain
         subjects affected / exposed
    2 / 37 (5.41%)
    10 / 126 (7.94%)
    1 / 35 (2.86%)
         occurrences all number
    2
    13
    1
    Muscle spasms
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 126 (1.59%)
    1 / 35 (2.86%)
         occurrences all number
    2
    2
    1
    Osteoporosis
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 126 (0.79%)
    2 / 35 (5.71%)
         occurrences all number
    0
    1
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    12 / 37 (32.43%)
    27 / 126 (21.43%)
    6 / 35 (17.14%)
         occurrences all number
    24
    53
    11
    Cystitis
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 126 (1.59%)
    1 / 35 (2.86%)
         occurrences all number
    2
    2
    2
    Gastroenteritis
         subjects affected / exposed
    0 / 37 (0.00%)
    8 / 126 (6.35%)
    4 / 35 (11.43%)
         occurrences all number
    0
    11
    4
    Influenza
         subjects affected / exposed
    1 / 37 (2.70%)
    9 / 126 (7.14%)
    6 / 35 (17.14%)
         occurrences all number
    1
    10
    6
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 37 (10.81%)
    12 / 126 (9.52%)
    1 / 35 (2.86%)
         occurrences all number
    18
    28
    1
    Nasopharyngitis
         subjects affected / exposed
    8 / 37 (21.62%)
    24 / 126 (19.05%)
    6 / 35 (17.14%)
         occurrences all number
    14
    41
    6
    Pneumonia
         subjects affected / exposed
    2 / 37 (5.41%)
    3 / 126 (2.38%)
    1 / 35 (2.86%)
         occurrences all number
    2
    3
    2
    Respiratory tract infection
         subjects affected / exposed
    3 / 37 (8.11%)
    8 / 126 (6.35%)
    3 / 35 (8.57%)
         occurrences all number
    3
    10
    11
    Sinusitis
         subjects affected / exposed
    0 / 37 (0.00%)
    9 / 126 (7.14%)
    0 / 35 (0.00%)
         occurrences all number
    0
    16
    0
    Tinea pedis
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    2
    Tooth abscess
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 126 (1.59%)
    0 / 35 (0.00%)
         occurrences all number
    3
    2
    0
    Tracheobronchitis
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 126 (1.59%)
    2 / 35 (5.71%)
         occurrences all number
    2
    2
    3
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 37 (2.70%)
    10 / 126 (7.94%)
    1 / 35 (2.86%)
         occurrences all number
    1
    11
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 37 (5.41%)
    11 / 126 (8.73%)
    1 / 35 (2.86%)
         occurrences all number
    3
    14
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 37 (16.22%)
    17 / 126 (13.49%)
    2 / 35 (5.71%)
         occurrences all number
    6
    21
    2
    Hypokalaemia
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 126 (2.38%)
    2 / 35 (5.71%)
         occurrences all number
    1
    3
    2
    Hyponatraemia
         subjects affected / exposed
    0 / 37 (0.00%)
    0 / 126 (0.00%)
    2 / 35 (5.71%)
         occurrences all number
    0
    0
    3

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Sep 2010
    - Described findings derived from analysis of the data from parent trial 1199.30 that showed a clinically-relevant, beneficial effect for patients receiving the nintedanib 150 mg bid dose. - In the light of the new efficacy findings, the amendment recommended that patients in trial 1199.35 be offered the option to switch dose (if applicable) to nintedanib 150 mg bid; the amendment also specified procedures to be followed for patients undergoing the newly-permitted dose increase (including additional monitoring in the 17 weeks after dose increase). - Described procedures to be followed for patients who underwent dose increase to nintedanib 150 mg bid and experienced severe gastrointestinal AEs or liver enzyme elevations
    29 Nov 2012
    - Specified interim analysis of data from trial 1199.35, to support the regulatory submission for use of nintedanib as a treatment for patients with IPF. - Introduced a range of changes to harmonise the management of AEs with Phase III nintedanib studies, in particular: procedures for the identification and management of indicators of drug-induced liver injury were clarified, in line with nintedanib project specific procedures; procedures for managing severe gastrointestinal events were specified for patients receiving the different nintedanib doses. - Specified procedures for clinical evaluation of liver injury. - Specified procedures to be conducted in association with dose modification. - Revised the processes for reporting worsening underlying disease and other pre-existing conditions - Specified liver function impairment, severe gastrointestinal events, and pregnancy as necessitating discontinuation of nintedanib treatment - Clarified the reporting of pregnancy and clinically-relevant laboratory test results, and characterised some AEs as always serious. - Defined protocol-specified significant AEs and expected AEs. - The time required for use of highly-effective contraceptive measures after participation in trial 1199.35 was increased from 10 weeks to 3 months, to ensure standardised safety procedures across nintedanib IPF and oncology projects
    01 Jun 2015
    - Protocol amendment 3 was implemented following the awarding of market authorisation for nintedanib (Ofev®) for the treatment of IPF in the US in October 2014 and approval from the European Medicinal Agency in January 2015. While worldwide submissions were in progress, nintedanib had been made available by BI in the named-patient use and compassionate-use programmes and had become commercially available in some countries. As a result, it was anticipated that patients and physicians may want to discontinue participation in the study. The amendment allowed the final complete analysis to be conducted before the number of patients became too low to derive meaningful data summaries. - After completion of the final analysis, patients still participating in the trial were to be followed up with a limited assessment schedule, focussing on AEs, laboratory tests and physical examination. Patients receiving lower nintedanib doses could still undergo dose increase to nintedanib 150 mg and, in this case, would follow the flow-chart assessment schedule until the next complete visit and then start the limited-assessment schedule

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Mon Apr 29 05:49:25 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA