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    Clinical Trial Results:
    A 24-week, double-blind, randomised, parallel-group study evaluating the efficacy and safety of oral nintedanib co-administered with oral sildenafil, compared to treatment with nintedanib alone, in patients with idiopathic pulmonary fibrosis (IPF) and advanced lung function impairment.

    Summary
    EudraCT number
    		 2015-002619-14
    Trial protocol
    		 DE   ES   BE   GB   FR   IT  
    Global end of trial date
    13 Apr 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Dec 2021
    First version publication date
    20 Apr 2019
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1199.36
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02802345
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Scientific contact QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Scientific contact QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 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
    04 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the efficacy and safety of concomitant treatment with nintedanib and sildenafil in patients with idiopathic pulmonary fibrosis (IPF) with advanced lung function impairment.
    Protection of trial subjects
    Only patients that met all the study inclusion and none of the exclusion criteria were to be randomized in the study. All patients were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all patients was adhered to throughout the trial conduct.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jul 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 9
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Canada: 23
    Country: Number of subjects enrolled
    France: 42
    Country: Number of subjects enrolled
    Germany: 39
    Country: Number of subjects enrolled
    India: 28
    Country: Number of subjects enrolled
    Italy: 44
    Country: Number of subjects enrolled
    Japan: 29
    Country: Number of subjects enrolled
    Korea, Republic of: 42
    Country: Number of subjects enrolled
    Mexico: 34
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    United Kingdom: 22
    Country: Number of subjects enrolled
    United States: 52
    Worldwide total number of subjects
    406
    EEA total number of subjects
    167
    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)
    88
    From 65 to 84 years
    306
    85 years and over
    12

    Subject disposition

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    Recruitment
    Recruitment details
    		 Randomised, double-blind, parallel design comparison of nintedanib 150 milligram (mg) twice daily (bid) and sildenafil 20 mg three times a day (tid) to nintedanib 150 mg bid and placebo matching sildenafil tid administered orally over 24 weeks.

    Pre-assignment
    Screening details
    		 All patients were screened for eligibility to participate in the trial. Patients attended specialist sites to ensure that all patients met all inclusion/exclusion criteria. Patients were not to be randomized to trial if any one of the specific entry criteria were not met.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    It was a double-blind trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nintedanib+placebo
    Arm description
    		 Patients administered 150 milligram (mg) Nintedanib soft gelatine capsule orally twice daily (bid), with a possibility of dose reduction to 100 mg capsule bid along with placebo matching to Sildenafil for 24 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients administered 150 milligram (mg) Nintedanib soft gelatine capsule orally twice daily (bid), with a possibility of dose reduction to 100 mg capsule bid along with placebo matching to Sildenafil for 24 weeks.

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Patients administered 150 milligram (mg) Nintedanib soft gelatine capsule orally twice daily (bid), with a possibility of dose reduction to 100 mg capsule bid along with placebo matching to Sildenafil for 24 weeks.

    Arm title
    		 Nintedanib+sildenafil
    Arm description
    		 Patients administered 150 milligram (mg) Nintedanib soft gelatine capsule orally twice daily (bid), with a possibility of dose reduction to 100 mg capsule bid along with 20 mg thrice daily (tid) Sildenafil for 24 weeks.
    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
    Patients administered 150 milligram (mg) Nintedanib soft gelatine capsule orally twice daily (bid), with a possibility of dose reduction to 100 mg capsule bid along with 20 mg thrice daily (tid) Sildenafil for 24 weeks.

    Investigational medicinal product name
    Sildenafil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients administered 150 milligram (mg) Nintedanib soft gelatine capsule orally twice daily (bid), with a possibility of dose reduction to 100 mg capsule bid along with 20 mg thrice daily (tid) Sildenafil for 24 weeks.

    Number of subjects in period 1 [1]
    		Nintedanib+placebo Nintedanib+sildenafil
    Started
    136
    137
    Completed
    104
    108
    Not completed
    32
    29
         Adverse event, serious fatal
    8
    6
         Consent withdrawn by subject
    3
    3
         Adverse event, non-fatal
    20
    14
         Other than listed
    1
    5
         Protocol deviation
    -
    1
    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: 406 were enrolled worldwide whereof 273 were included in this trial.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nintedanib+placebo
    Reporting group description
    		 Patients administered 150 milligram (mg) Nintedanib soft gelatine capsule orally twice daily (bid), with a possibility of dose reduction to 100 mg capsule bid along with placebo matching to Sildenafil for 24 weeks.

    Reporting group title
    Nintedanib+sildenafil
    Reporting group description
    		 Patients administered 150 milligram (mg) Nintedanib soft gelatine capsule orally twice daily (bid), with a possibility of dose reduction to 100 mg capsule bid along with 20 mg thrice daily (tid) Sildenafil for 24 weeks.

    Reporting group values
    		 Nintedanib+placebo Nintedanib+sildenafil Total
    Number of subjects
    		 136 137 273
    Age categorical
    Units: Subjects
    Age Continuous
    Treated Set (TS): TS included all patients who were randomised to a treatment group and received at least one dose of randomised study medication.
    Units: years
        arithmetic mean (standard deviation)
    		 70.0 ± 7.9 70.3 ± 8.6 -
    Sex: Female, Male
    TS
    Units: Subjects
        Male
    		 106 110 216
        Female
    		 30 27 57
    Race (NIH/OMB)
    TS
    Units: Subjects
        American Indian or Alaska Native
    		 2 3 5
        Asian
    		 39 30 69
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 95 103 198
        More than one race
    		 0 1 1
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    TS
    Units: Subjects
        Hispanic or Latino
    		 15 23 38
        Not Hispanic or Latino
    		 121 114 235
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Nintedanib+placebo
    Reporting group description
    		 Patients administered 150 milligram (mg) Nintedanib soft gelatine capsule orally twice daily (bid), with a possibility of dose reduction to 100 mg capsule bid along with placebo matching to Sildenafil for 24 weeks.

    Reporting group title
    Nintedanib+sildenafil
    Reporting group description
    		 Patients administered 150 milligram (mg) Nintedanib soft gelatine capsule orally twice daily (bid), with a possibility of dose reduction to 100 mg capsule bid along with 20 mg thrice daily (tid) Sildenafil for 24 weeks.

    Primary: Change from baseline in St George’s Respiratory Questionnaire (SGRQ) total score at Week 12

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    End point title
    		 Change from baseline in St George’s Respiratory Questionnaire (SGRQ) total score at Week 12
    End point description
    The SGRQ is a 50-item questionnaire developed to measure health status (quality of life). Scores are calculated for three domains: Symptoms, Activity and Impacts (Psycho-social) as well as a total score. A minimum change in score of 4 units was established as clinically relevant after patient and clinician testing. Scores range from 0 to 100, with higher scores indicating more limitations. The mean and standard error presented are actually adjusted mean for change from baseline and its standard error. Treated Set (TS): TS included all patients who were randomised to a treatment group and received at least one dose of randomised study medication.
    End point type
    Primary
    End point timeframe
    Baseline and week 12
    End point values
    		 Nintedanib+placebo Nintedanib+sildenafil
    Number of subjects analysed
    133 [1]
    132 [2]
    Units: Unit on scale
        arithmetic mean (standard error)
    -0.77 ± 1.009
    -1.28 ± 1.013
    Notes
    [1] - TS
    [2] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Mixed Model for Repeated Measures (MMRM) included fixed effects for treatment, visit, presence of any echocardiographic signs, baseline SGRQ total score as covariate, treatment−by−visit and baseline SGRQ total score−by−visit interaction terms using an unstructured covariance matrix. No imputation was planned. Data collected after Visit 5 (planned 12 weeks after start of study treatment) were not used for analysis. Roger- Kenward approximation was used to estimate denominator degrees of freedom.
    Comparison groups
    Nintedanib+sildenafil v Nintedanib+placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.7191
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.33
         upper limit
    		 2.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.431
    Notes
    [3] - Adjusted mean is based on all analyzed patients in model (not only patients with a measurement at baseline and 12 weeks). H0: There is no difference in mean change from baseline in SGRQ total score at Week 12 between treatment with nintedanib co-administered with sildenafil and treatment with nintedanib alone. Ha: There is a difference in mean change from baseline in SGRQ total score at Week 12 between treatment with nintedanib coadministered with sildenafil and treatment with nintedanib alone.

    Secondary: Change from baseline in dyspnoea using the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) at Week 12

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    End point title
    		 Change from baseline in dyspnoea using the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) at Week 12
    End point description
    The UCSD SOBQ is a 24-item questionnaire developed to measure breathlessness on a scale between zero and five where 0 is not at all breathless and 5 is maximally breathless or too breathless to do the activity. The mean and standard error presented for descriptive statistics are actually adjusted mean for change from baseline and its standard error. TS.
    End point type
    Secondary
    End point timeframe
    Baseline and week 12
    End point values
    		 Nintedanib+placebo Nintedanib+sildenafil
    Number of subjects analysed
    122 [4]
    120 [5]
    Units: Unit on scale
        arithmetic mean (standard error)
    4.40 ± 1.529
    1.46 ± 1.575
    Notes
    [4] - TS
    [5] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    MMRM included fixed effects for treatment, visit, presence of any echocardiographic signs, baseline UCSD SOBQ total score as covariate, treatment−by−visit and baseline UCSD SOBQ total score−by−visit interaction terms using an unstructured covariance matrix. No imputation was planned. Data collected after Visit 5 (planned 12 weeks after start of study treatment) were not used for analysis. Roger- Kenward approximation was used to estimate denominator degrees of freedom.
    Comparison groups
    Nintedanib+placebo v Nintedanib+sildenafil
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.1823
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -2.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.27
         upper limit
    		 1.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.198
    Notes
    [6] - Adjusted mean is based on all analyzed patients in the model (not only patients with a measurement at baseline and at 12 weeks).

    Secondary: Change from baseline in SGRQ total score at Week 24

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    End point title
    		 Change from baseline in SGRQ total score at Week 24
    End point description
    The SGRQ is a 50-item questionnaire developed to measure health status (quality of life). Scores are calculated for three domains: Symptoms, Activity and Impacts (Psycho-social) as well as a total score. A minimum change in score of 4 units was established as clinically relevant after patient and clinician testing. The mean and standard error presented for descriptive statistics are actually adjusted mean for change from baseline and its standard error. TS
    End point type
    Secondary
    End point timeframe
    Baseline and week 24
    End point values
    		 Nintedanib+placebo Nintedanib+sildenafil
    Number of subjects analysed
    133 [7]
    132 [8]
    Units: Unit on scale
        arithmetic mean (standard error)
    2.42 ± 1.158
    0.23 ± 1.148
    Notes
    [7] - TS
    [8] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Mixed Model for Repeated Measures (MMRM) included fixed effects for treatment, visit, presence of any echocardiographic signs, baseline SGRQ total score as covariate, treatment−by−visit and baseline SGRQ total score−by−visit interaction terms using an unstructured covariance matrix. No imputation was planned. Roger- Kenward approximation was used to estimate denominator degrees of freedom.
    Comparison groups
    Nintedanib+placebo v Nintedanib+sildenafil
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.1809
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -2.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.4
         upper limit
    		 1.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.631
    Notes
    [9] - Adjusted mean is based on all analyzed patients in the model (not only patients with a measurement at baseline and at 12 weeks).

    Secondary: Change from baseline in dyspnoea using UCSD SOBQ at Week 24

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    End point title
    		 Change from baseline in dyspnoea using UCSD SOBQ at Week 24
    End point description
    The UCSD SOBQ is a 24-item questionnaire developed to to measure breathlessness on a scale between zero and five where 0 is not at all breathless and 5 is maximally breathless or too breathless to do the activity. The mean and standard error presented for descriptive statistics are actually adjusted mean for change from baseline and its standard error. TS
    End point type
    Secondary
    End point timeframe
    Baseline and week 24
    End point values
    		 Nintedanib+placebo Nintedanib+sildenafil
    Number of subjects analysed
    124 [10]
    123 [11]
    Units: Unit on scale
        arithmetic mean (standard error)
    6.85 ± 1.791
    4.44 ± 1.779
    Notes
    [10] - TS
    [11] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Mixed Model for Repeated Measures (MMRM) included fixed effects for treatment, visit, presence of any echocardiographic signs, baseline UCSD SOBQ total score as covariate, treatment−by−visit and baseline UCSD SOBQ total score−by−visit interaction terms using an unstructured covariance matrix. No imputation was planned. The Roger- Kenward approximation was used to estimate denominator degrees of freedom.
    Comparison groups
    Nintedanib+placebo v Nintedanib+sildenafil
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.3421
    Method
    		 Mixed Model for Repeated Measures (MMRM)
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -2.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.39
         upper limit
    		 2.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.529
    Notes
    [12] - Adjusted mean is based on all analyzed patients in the model (not only patients with a measurement at baseline and at 12 weeks).

    Secondary: Percentage of patients with on-treatment serious adverse events (SAE) from baseline to Week 24

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    End point title
    		 Percentage of patients with on-treatment serious adverse events (SAE) from baseline to Week 24
    End point description
    Percentage of patients with on-treatment serious adverse events (SAE) from baseline to Week 24 is presented. TS
    End point type
    Secondary
    End point timeframe
    Baseline and week 24
    End point values
    		 Nintedanib+placebo Nintedanib+sildenafil
    Number of subjects analysed
    136 [13]
    137 [14]
    Units: Percentage of participants (%)
        number (not applicable)
    32.4
    27.0
    Notes
    [13] - TS
    [14] - TS
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Relative risk, Comparison of treatment groups is calculated by Cochran−Mantel−Haenszel test adjusting for the categorical covariate presence of any echocardiographic signs indicative of right heart dysfunction (yes/no), adjusted Mantel−Haenszel type risk ratios and risk differences with 95% confidence are presented.
    Comparison groups
    Nintedanib+placebo v Nintedanib+sildenafil
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    Method
    Parameter type
    		 Percentage ratio (%)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 1.2
    Notes
    [15] - Within strata confidence limits are calculated according to Wald. Percentage ratio = (% of Nintedanib+sildenafil) / (% of Nintedanib+placebo).
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Risk difference, Comparison of treatment groups is calculated by Cochran−Mantel−Haenszel test adjusting for the categorical covariate presence of any echocardiographic signs indicative of right heart dysfunction (yes/no), adjusted Mantel−Haenszel type risk ratios and risk differences with 95% confidence are presented.
    Comparison groups
    Nintedanib+placebo v Nintedanib+sildenafil
    Number of subjects included in analysis
    273
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.334
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage difference (%)
    Point estimate
    -5.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.25
         upper limit
    		 5.52
    Notes
    [16] - Within strata confidence limits are calculated according to Wald. Percentage difference = (% of Nintedanib+sildenafil) - (% of Nintedanib+placebo).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration until 28 days after the last drug administration.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Nintedanib+sildenafil
    Reporting group description
    		 Patients administered 150 milligram (mg) Nintedanib soft gelatine capsule orally twice daily (bid), with a possibility of dose reduction to 100 mg capsule bid along with 20 mg thrice daily (tid) Sildenafil for 24 weeks.

    Reporting group title
    Nintedanib+placebo
    Reporting group description
    		 Patients administered 150 milligram (mg) Nintedanib soft gelatine capsule orally twice daily (bid), with a possibility of dose reduction to 100 mg capsule bid along with placebo matching to Sildenafil for 24 weeks.

    Serious adverse events
    		 Nintedanib+sildenafil Nintedanib+placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 137 (27.01%)
    44 / 136 (32.35%)
         number of deaths (all causes)
    12
    12
         number of deaths resulting from adverse events
    12
    12
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neuroendocrine carcinoma of the skin
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 137 (0.73%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 137 (0.73%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 137 (0.73%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 137 (3.65%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    8 / 137 (5.84%)
    9 / 136 (6.62%)
         occurrences causally related to treatment / all
    2 / 9
    0 / 10
         deaths causally related to treatment / all
    1 / 3
    0 / 3
    Lung disorder
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 137 (1.46%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 137 (0.00%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 137 (0.73%)
    4 / 136 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 137 (1.46%)
    3 / 136 (2.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eosinophil percentage increased
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eosinophil count increased
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Pelvic fracture
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 137 (0.00%)
    3 / 136 (2.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemianopia homonymous
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 137 (0.73%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 137 (0.73%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    2 / 137 (1.46%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 137 (0.00%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 137 (3.65%)
    8 / 136 (5.88%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 8
         deaths causally related to treatment / all
    0 / 1
    1 / 3
    Respiratory tract infection
         subjects affected / exposed
    0 / 137 (0.00%)
    2 / 136 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 137 (1.46%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 2
    1 / 1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 137 (0.73%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    2 / 137 (1.46%)
    0 / 136 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    0 / 137 (0.00%)
    1 / 136 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Nintedanib+sildenafil Nintedanib+placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    118 / 137 (86.13%)
    113 / 136 (83.09%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 137 (5.84%)
    8 / 136 (5.88%)
         occurrences all number
    9
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 137 (3.65%)
    7 / 136 (5.15%)
         occurrences all number
    6
    10
    C-reactive protein increased
         subjects affected / exposed
    6 / 137 (4.38%)
    7 / 136 (5.15%)
         occurrences all number
    6
    9
    Weight decreased
         subjects affected / exposed
    7 / 137 (5.11%)
    12 / 136 (8.82%)
         occurrences all number
    7
    13
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    7 / 137 (5.11%)
    7 / 136 (5.15%)
         occurrences all number
    7
    9
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 137 (4.38%)
    8 / 136 (5.88%)
         occurrences all number
    6
    8
    Headache
         subjects affected / exposed
    21 / 137 (15.33%)
    10 / 136 (7.35%)
         occurrences all number
    24
    12
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 137 (4.38%)
    7 / 136 (5.15%)
         occurrences all number
    6
    8
    Fatigue
         subjects affected / exposed
    7 / 137 (5.11%)
    6 / 136 (4.41%)
         occurrences all number
    7
    6
    Oedema peripheral
         subjects affected / exposed
    7 / 137 (5.11%)
    6 / 136 (4.41%)
         occurrences all number
    8
    6
    Pyrexia
         subjects affected / exposed
    6 / 137 (4.38%)
    9 / 136 (6.62%)
         occurrences all number
    9
    10
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 137 (2.92%)
    9 / 136 (6.62%)
         occurrences all number
    4
    10
    Abdominal pain upper
         subjects affected / exposed
    6 / 137 (4.38%)
    7 / 136 (5.15%)
         occurrences all number
    8
    8
    Constipation
         subjects affected / exposed
    3 / 137 (2.19%)
    8 / 136 (5.88%)
         occurrences all number
    3
    10
    Diarrhoea
         subjects affected / exposed
    79 / 137 (57.66%)
    66 / 136 (48.53%)
         occurrences all number
    152
    110
    Dyspepsia
         subjects affected / exposed
    9 / 137 (6.57%)
    4 / 136 (2.94%)
         occurrences all number
    9
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    7 / 137 (5.11%)
    5 / 136 (3.68%)
         occurrences all number
    7
    9
    Nausea
         subjects affected / exposed
    22 / 137 (16.06%)
    14 / 136 (10.29%)
         occurrences all number
    30
    15
    Vomiting
         subjects affected / exposed
    19 / 137 (13.87%)
    9 / 136 (6.62%)
         occurrences all number
    32
    12
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 137 (14.60%)
    13 / 136 (9.56%)
         occurrences all number
    24
    13
    Dyspnoea
         subjects affected / exposed
    13 / 137 (9.49%)
    11 / 136 (8.09%)
         occurrences all number
    14
    11
    Epistaxis
         subjects affected / exposed
    11 / 137 (8.03%)
    6 / 136 (4.41%)
         occurrences all number
    15
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    7 / 137 (5.11%)
    2 / 136 (1.47%)
         occurrences all number
    8
    2
    Myalgia
         subjects affected / exposed
    7 / 137 (5.11%)
    3 / 136 (2.21%)
         occurrences all number
    8
    3
    Infections and infestations
    Influenza
         subjects affected / exposed
    4 / 137 (2.92%)
    7 / 136 (5.15%)
         occurrences all number
    4
    7
    Bronchitis
         subjects affected / exposed
    12 / 137 (8.76%)
    4 / 136 (2.94%)
         occurrences all number
    13
    5
    Nasopharyngitis
         subjects affected / exposed
    9 / 137 (6.57%)
    8 / 136 (5.88%)
         occurrences all number
    9
    8
    Respiratory tract infection
         subjects affected / exposed
    8 / 137 (5.84%)
    4 / 136 (2.94%)
         occurrences all number
    9
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    19 / 137 (13.87%)
    23 / 136 (16.91%)
         occurrences all number
    20
    24

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2016
    The text describing potential risks of sildenafil treatment was updated. The number of participating sites and the number of patients per site were modified based on a site feasibility assessment. In the exclusion criteria 6, ‘partial thromboplastin time’ was replaced by ‘activated thromboplastin time’. Exclusion criteria 34, concerning patients with chronic liver disease, was added. Measurements of nintedanib metabolites were removed from the planned pharmacokinetic (PK) assessments. The amount of blood needed for biomarker assessments was increased.
    18 Aug 2016
    A trade name (INSTAGETM) was assigned to the trial. Pancreatitis and thrombocytopenia were added as risks of nintedanib treatment. major cardiovascular events (MACE) was added to the list of events to be adjudicated. The inclusion and exclusion criteria were modified to allow retesting, within a defined time frame, for the parameters mentioned in the inclusion criterion 5 and the exclusion criteria 4, 9 and 15, in case values at Visit 1 were abnormal. Footnote 1 of the inclusion and exclusion criteria was modified to also allow retesting of blood pressure and lung function tests, in addition to the laboratory parameters. In the exclusion criterion 15, ‘systolic blood pressure (SBP) >180 millimeter of mercury (mmHg); diastolic blood pressure (DBP) >100 mmHg’ was changed to (SBP >180 mmHg or DBP >100 mmHg). In the exclusion criterion 23 ‘treatment for pulmonary hypertension’ was changed to ‘treatment’. Clarifications were added regarding restrictions in concomitant medication use. The method of measuring oxygen saturation was corrected. The definition of acute IPF exacerbation was modified according to the new definition by an international working group. It was clarified that biobanking is an optional procedure, requiring local approval. Details of analyses of further endpoints were added in the statistical methods.

    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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