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    Clinical Trial Results:
    An open-label extension trial of the long-term safety of nintedanib in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD)

    Summary
    EudraCT number
    		 2018-000525-32
    Trial protocol
    		 ES   GB   DE   BE   IT  
    Global end of trial date
    30 Aug 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Sep 2023
    First version publication date
    03 Sep 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1199-0248
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03820726
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Aug 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this clinical trial was to assess long-term tolerability and safety of treatment with oral nintedanib in patients with Progressive Fibrosing-Interstitial Lung Disease (PF-ILD) who completed (and did not prematurely discontinue trial medication in) the Phase III parent trial, INBUILD® (1199-0247) NCT02999178.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all subjects as required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Jun 2019
    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
    Argentina: 21
    Country: Number of subjects enrolled
    Belgium: 16
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Chile: 27
    Country: Number of subjects enrolled
    China: 13
    Country: Number of subjects enrolled
    France: 42
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Japan: 65
    Country: Number of subjects enrolled
    Poland: 24
    Country: Number of subjects enrolled
    Russian Federation: 27
    Country: Number of subjects enrolled
    Korea, Republic of: 25
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    United States: 73
    Worldwide total number of subjects
    436
    EEA total number of subjects
    162
    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)
    173
    From 65 to 84 years
    258
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 A phase III, open label, extension trial. The study aimed to evaluate the long-term tolerability and safety of oral nintedanib treatment in patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD) who have completed (and did not prematurely discontinue trial medication in) the phase III parent trial, 1199.247 (INBUILD®) NCT02999178.

    Pre-assignment
    Screening details
    		 Only patients with PF-ILD who completed the parent trial (INBUILD®) on treatment (i.e., did not discontinue treatment early) were eligible and were included in this trial if they fulfilled all the inclusion criteria and did not present any of the exclusion criteria.

    Period 1
    Period 1 title
    Entered
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label trial, single-arm, treatment allocation was not concealed throughout the trial. The Case Report Form (CRF) contained information on actual treatment. The previous treatment received in INBUILD® (active drug or placebo) remained unknown to the investigator and patient until after the final database lock of INBUILD®

    Arms
    Arm title
    		 Nintedanib (Experimental)
    Arm description
    		 Patients taking 150 milligram (mg) bid blinded trial medication (active drug or placebo) at the end of INBUILD® started treatment with nintedanib 150 mg bid in this extension trial. Patients taking 100 mg bid blinded trial medication (active drug or placebo) at the end of INBUILD® started treatment with nintedanib in this extension trial either at 100 mg bid or at an increased dose of 150 mg bid at the discretion of the investigator orally as soft gelatine capsule, twice daily (bid), together with a glass of water (~250 mL), in a dose interval of 12 hours. With an optional dose reduction to 100 mg bid temporarily or permanently to manage adverse events (AEs). The treatment had a duration of 96 weeks or until nintedanib was made available to the patients outside of the clinical trial. Treatment was stopped if any reason for withdrawal was met.
    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 were administered 150 milligram (mg) nintedanib orally as soft gelatine capsule, twice daily (bid), together with a glass of water (~250 mL), in a dose interval of 12 hours. With an optional dose reduction to 100 mg bid temporarily or permanently to manage adverse events (AEs).

    Number of subjects in period 1
    		Nintedanib (Experimental)
    Started
    435
    Completed
    434
    Not completed
    1
         Patient not treated
    1
    Period 2
    Period 2 title
    Treated
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label trial, treatment allocation was not concealed throughout the trial. The CRF contained information on actual treatment. The previous treatment received in INBUILD® (active drug or placebo) remained unknown to the investigator and patient until after the final database lock of INBUILD®.

    Arms
    Arm title
    		 Nintedanib
    Arm description
    		 Patients taking 150 milligram (mg) bid blinded trial medication (active drug or placebo) at the end of INBUILD® started treatment with nintedanib 150 mg bid in this extension trial. Patients taking 100 mg bid blinded trial medication (active drug or placebo) at the end of INBUILD® started treatment with nintedanib in this extension trial either at 100 mg bid or at an increased dose of 150 mg bid at the discretion of the investigator orally as soft gelatine capsule, twice daily (bid), together with a glass of water (~250 mL), in a dose interval of 12 hours. With an optional dose reduction to 100 mg bid temporarily or permanently to manage adverse events (AEs). The treatment had a duration of 96 weeks or until nintedanib was made available to the patients outside of the clinical trial. Treatment was stopped if any reason for withdrawal was met.
    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 were administered 150 milligram (mg) nintedanib orally as soft gelatine capsule, twice daily (bid), together with a glass of water (~250 mL), in a dose interval of 12 hours. With an optional dose reduction to 100 mg bid temporarily or permanently to manage adverse events (AEs).

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 are the randomised subjects, period 2 the treated, baseline characteristics are reported for the treated subjects.
    Number of subjects in period 2 [2]
    		Nintedanib
    Started
    434
    Completed
    224
    Not completed
    210
         Consent withdrawn by subject
    37
         Adverse event, non-fatal
    146
         Protocol deviation
    1
         Lost to follow-up
    3
         Other than listed
    23
    Notes
    [2] - 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: Out of 436 subjects enrolled only 435 subjects entered the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nintedanib
    Reporting group description
    		 Patients taking 150 milligram (mg) bid blinded trial medication (active drug or placebo) at the end of INBUILD® started treatment with nintedanib 150 mg bid in this extension trial. Patients taking 100 mg bid blinded trial medication (active drug or placebo) at the end of INBUILD® started treatment with nintedanib in this extension trial either at 100 mg bid or at an increased dose of 150 mg bid at the discretion of the investigator orally as soft gelatine capsule, twice daily (bid), together with a glass of water (~250 mL), in a dose interval of 12 hours. With an optional dose reduction to 100 mg bid temporarily or permanently to manage adverse events (AEs). The treatment had a duration of 96 weeks or until nintedanib was made available to the patients outside of the clinical trial. Treatment was stopped if any reason for withdrawal was met.

    Reporting group values
    		 Nintedanib Total
    Number of subjects
    		 434 434
    Age categorical
    Treated Set (TS): This set included all patients who were dispensed trial medication (nintedanib) and were documented to have taken at least 1 dose of open-label trial medication (nintedanib).
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 172 172
        From 65-84 years
    		 257 257
        85 years and over
    		 5 5
    Age Continuous
    Treated Set (TS): This set included all patients who were dispensed trial medication (nintedanib) and were documented to have taken at least 1 dose of open-label trial medication (nintedanib).
    Units: years
        arithmetic mean (standard deviation)
    		 65.9 ( 9.9 ) -
    Sex: Female, Male
    Treated Set (TS): This set included all patients who were dispensed trial medication (nintedanib) and were documented to have taken at least 1 dose of open-label trial medication (nintedanib).
    Units: Participants
        Female
    		 211 211
        Male
    		 223 223
    Race (NIH/OMB)
    Treated Set (TS): This set included all patients who were dispensed trial medication (nintedanib) and were documented to have taken at least 1 dose of open-label trial medication (nintedanib).
    Units: Subjects
        American Indian or Alaska Native
    		 0 0
        Asian
    		 108 108
        Native Hawaiian or Other Pacific Islander
    		 1 1
        Black or African American
    		 4 4
        White
    		 279 279
        More than one race
    		 1 1
        Unknown or Not Reported
    		 41 41
    Ethnicity (NIH/OMB)
    Treated Set (TS): This set included all patients who were dispensed trial medication (nintedanib) and were documented to have taken at least 1 dose of open-label trial medication (nintedanib).
    Units: Subjects
        Hispanic or Latino
    		 65 65
        Not Hispanic or Latino
    		 328 328
        Unknown or Not Reported
    		 41 41

    End points

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    End points reporting groups
    Reporting group title
    Nintedanib (Experimental)
    Reporting group description
    		 Patients taking 150 milligram (mg) bid blinded trial medication (active drug or placebo) at the end of INBUILD® started treatment with nintedanib 150 mg bid in this extension trial. Patients taking 100 mg bid blinded trial medication (active drug or placebo) at the end of INBUILD® started treatment with nintedanib in this extension trial either at 100 mg bid or at an increased dose of 150 mg bid at the discretion of the investigator orally as soft gelatine capsule, twice daily (bid), together with a glass of water (~250 mL), in a dose interval of 12 hours. With an optional dose reduction to 100 mg bid temporarily or permanently to manage adverse events (AEs). The treatment had a duration of 96 weeks or until nintedanib was made available to the patients outside of the clinical trial. Treatment was stopped if any reason for withdrawal was met.
    Reporting group title
    Nintedanib
    Reporting group description
    		 Patients taking 150 milligram (mg) bid blinded trial medication (active drug or placebo) at the end of INBUILD® started treatment with nintedanib 150 mg bid in this extension trial. Patients taking 100 mg bid blinded trial medication (active drug or placebo) at the end of INBUILD® started treatment with nintedanib in this extension trial either at 100 mg bid or at an increased dose of 150 mg bid at the discretion of the investigator orally as soft gelatine capsule, twice daily (bid), together with a glass of water (~250 mL), in a dose interval of 12 hours. With an optional dose reduction to 100 mg bid temporarily or permanently to manage adverse events (AEs). The treatment had a duration of 96 weeks or until nintedanib was made available to the patients outside of the clinical trial. Treatment was stopped if any reason for withdrawal was met.

    Primary: Number of participants with any adverse events

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    End point title
    		 Number of participants with any adverse events [1]
    End point description
    Number of participants with adverse events over the course of the extension trial, AEs defined as any untoward medical occurrence in a patient administered with the investigational product and which does not necessarily have to have a causal relationship with this treatment. Treated Set (TS): This set included all patients who were dispensed trial medication (nintedanib) and were documented to have taken at least 1 dose of open-label trial medication (nintedanib).
    End point type
    Primary
    End point timeframe
    From first nintedanib intake until last nintedanib intake + 28 days of Residual effect period (REP), up to 1195 days.
    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: The Primary endpoint was planned to be only analyzed descriptively.
    End point values
    		 Nintedanib
    Number of subjects analysed
    434
    Units: Participants
    417
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first nintedanib intake until last nintedanib intake + 28 days of Residual effect period (REP), up to 1195 days.
    Adverse event reporting additional description
    Treated Set (TS): This set included all patients who were dispensed trial medication (nintedanib) and were documented to have taken at least 1 dose of open-label trial medication (nintedanib).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Nintedanib
    Reporting group description
    		 Patients taking 150 milligram (mg) bid blinded trial medication (active drug or placebo) at the end of INBUILD® started treatment with nintedanib 150 mg bid in this extension trial. Patients taking 100 mg bid blinded trial medication (active drug or placebo) at the end of INBUILD® started treatment with nintedanib in this extension trial either at 100 mg bid or at an increased dose of 150 mg bid at the discretion of the investigator orally as soft gelatine capsule, twice daily (bid), together with a glass of water (~250 mL), in a dose interval of 12 hours. With an optional dose reduction to 100 mg bid temporarily or permanently to manage adverse events (AEs). The treatment had a duration of 96 weeks or until nintedanib was made available to the patients outside of the clinical trial. Treatment was stopped if any reason for withdrawal was met.

    Serious adverse events
    		 Nintedanib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    234 / 434 (53.92%)
         number of deaths (all causes)
    83
         number of deaths resulting from adverse events
    77
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Carcinoid tumour pulmonary
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Bowen's disease
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuroendocrine tumour of the lung
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Extremity necrosis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Air embolism
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Aortic stenosis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Neurogenic shock
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vein disorder
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Asthenia
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    4 / 434 (0.92%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Death
         subjects affected / exposed
    4 / 434 (0.92%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    Disease progression
         subjects affected / exposed
    5 / 434 (1.15%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 3
    General physical health deterioration
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 2
    Sudden death
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lower respiratory tract inflammation
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Acute respiratory failure
         subjects affected / exposed
    15 / 434 (3.46%)
         occurrences causally related to treatment / all
    0 / 17
         deaths causally related to treatment / all
    0 / 7
    Chronic respiratory failure
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Chylothorax
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    12 / 434 (2.76%)
         occurrences causally related to treatment / all
    1 / 13
         deaths causally related to treatment / all
    0 / 1
    Hypercapnia
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypersensitivity pneumonitis
         subjects affected / exposed
    6 / 434 (1.38%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    Idiopathic interstitial pneumonia
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    35 / 434 (8.06%)
         occurrences causally related to treatment / all
    0 / 40
         deaths causally related to treatment / all
    0 / 10
    Lung disorder
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pneumomediastinum
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax
         subjects affected / exposed
    9 / 434 (2.07%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Pulmonary fibrosis
         subjects affected / exposed
    20 / 434 (4.61%)
         occurrences causally related to treatment / all
    0 / 23
         deaths causally related to treatment / all
    0 / 3
    Pulmonary hypertension
         subjects affected / exposed
    14 / 434 (3.23%)
         occurrences causally related to treatment / all
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Respiratory distress
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    17 / 434 (3.92%)
         occurrences causally related to treatment / all
    0 / 18
         deaths causally related to treatment / all
    0 / 8
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Delirium
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Mixed anxiety and depressive disorder
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oxygen consumption increased
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Weight decreased
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Compression fracture
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Poisoning
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Post procedural haematoma
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Postoperative wound complication
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Right ventricular failure
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    7 / 434 (1.61%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    4 / 434 (0.92%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 3
    Cardiac failure
         subjects affected / exposed
    7 / 434 (1.61%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    5 / 434 (1.15%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 5
    Cor pulmonale chronic
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    Pericarditis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prinzmetal angina
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinus arrest
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Nervous system disorders
    Cerebral infarction
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    5 / 434 (1.15%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    Ischaemic stroke
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mental impairment
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Vascular parkinsonism
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Age-related macular degeneration
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cataract
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Glaucoma
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Normal tension glaucoma
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diplopia
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Faecaloma
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    5 / 434 (1.15%)
         occurrences causally related to treatment / all
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Gallbladder rupture
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic cytolysis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Liver injury
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dermatomyositis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    IgA nephropathy
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary renal syndrome
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal failure
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Sjogren's syndrome
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Systemic scleroderma
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Chronic tonsillitis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atypical mycobacterial pneumonia
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    4 / 434 (0.92%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    COVID-19
         subjects affected / exposed
    12 / 434 (2.76%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 4
    COVID-19 pneumonia
         subjects affected / exposed
    7 / 434 (1.61%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 5
    Coronavirus infection
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Device related infection
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 434 (0.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    36 / 434 (8.29%)
         occurrences causally related to treatment / all
    0 / 40
         deaths causally related to treatment / all
    0 / 4
    Pneumonia aspiration
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    4 / 434 (0.92%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Pneumonia pneumococcal
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    5 / 434 (1.15%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Sepsis
         subjects affected / exposed
    4 / 434 (0.92%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Cytomegalovirus viraemia
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 434 (0.92%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Abnormal loss of weight
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 434 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 434 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Nintedanib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    371 / 434 (85.48%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    43 / 434 (9.91%)
         occurrences all number
    56
    Weight decreased
         subjects affected / exposed
    69 / 434 (15.90%)
         occurrences all number
    75
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    31 / 434 (7.14%)
         occurrences all number
    35
    Aspartate aminotransferase increased
         subjects affected / exposed
    37 / 434 (8.53%)
         occurrences all number
    44
    Vascular disorders
    Hypertension
         subjects affected / exposed
    27 / 434 (6.22%)
         occurrences all number
    29
    Nervous system disorders
    Headache
         subjects affected / exposed
    31 / 434 (7.14%)
         occurrences all number
    32
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    22 / 434 (5.07%)
         occurrences all number
    22
    Abdominal pain
         subjects affected / exposed
    29 / 434 (6.68%)
         occurrences all number
    33
    Nausea
         subjects affected / exposed
    75 / 434 (17.28%)
         occurrences all number
    97
    Vomiting
         subjects affected / exposed
    54 / 434 (12.44%)
         occurrences all number
    76
    Diarrhoea
         subjects affected / exposed
    256 / 434 (58.99%)
         occurrences all number
    502
    Constipation
         subjects affected / exposed
    23 / 434 (5.30%)
         occurrences all number
    25
    Respiratory, thoracic and mediastinal disorders
    Productive cough
         subjects affected / exposed
    25 / 434 (5.76%)
         occurrences all number
    29
    Dyspnoea
         subjects affected / exposed
    61 / 434 (14.06%)
         occurrences all number
    69
    Cough
         subjects affected / exposed
    73 / 434 (16.82%)
         occurrences all number
    86
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    24 / 434 (5.53%)
         occurrences all number
    26
    Back pain
         subjects affected / exposed
    30 / 434 (6.91%)
         occurrences all number
    31
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    48 / 434 (11.06%)
         occurrences all number
    68
    COVID-19
         subjects affected / exposed
    22 / 434 (5.07%)
         occurrences all number
    22
    Nasopharyngitis
         subjects affected / exposed
    38 / 434 (8.76%)
         occurrences all number
    54
    Respiratory tract infection
         subjects affected / exposed
    25 / 434 (5.76%)
         occurrences all number
    30
    Urinary tract infection
         subjects affected / exposed
    28 / 434 (6.45%)
         occurrences all number
    36
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    45 / 434 (10.37%)
         occurrences all number
    50

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Sep 2020
    The following main changes were introduced by the amendment: A clarification was added that dose reduction was also possible at Visit 1, if required to manage AEs identified at the end of the parent trial. The wording regarding withdrawal and interruption of trial medication in the management of liver enzyme elevations was clarified. Furthermore it was added that trial medication could be resumed in the case that clear evidence for an alternative cause for the hepatic injury was identified and resolved and the conditions for this and monitoring requirements after reintroduction were specified. A clarification was added that blood pressure and pulse rate should ideally be taken prior to blood sampling. The requirement to report SAEs by fax was replaced with requirement to report SAEs according to the country-specific reporting process. A risk assessment due to the COVID-19 pandemic situation was added to the benefit/risk assessment. Specifications were added for modification of visits in exceptional circumstances in the context of the COVID-19 pandemic. Site visits could be replaced with home or remote visits; as a minimum, at least AEs, concomitant treatments, and details on interruption of trial medication were to be collected. Instead of the planned central laboratory assessments, local laboratory assessments could be performed. If dose reduction was required for management of liver enzyme elevations but patients could not come to site and/or patient safety and follow-up safety laboratory testing could not be guaranteed, treatment had to be interrupted. Shipping of trial medication from site/depot to patients was permitted instead of dispensation on site.

    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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