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    Clinical Trial Results:
    SENSCIS®: A double-blind, randomised, placebo-controlled trial evaluating efficacy and safety of oral nintedanib treatment for at least 52 weeks in patients with ‘Systemic Sclerosisassociated Interstitial Lung Disease’ (SSc-ILD)

    Summary
    EudraCT number
    		 2015-000392-28
    Trial protocol
    		 NL   DE   GB   PT   DK   BE   ES   GR   FR   PL   IE   FI   NO   SE   AT   HU   CZ   IT  
    Global end of trial date
    28 Nov 2018

    Results information
    Results version number
    		 v1
    This version publication date
    13 Nov 2019
    First version publication date
    13 Nov 2019
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1199.214
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02597933
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    173 Binger Strasse, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Nov 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy and safety of nintedanib 150 mg twice daily (bid) in patients with SSc-ILD
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Nov 2015
    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
    Argentina: 7
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 23
    Country: Number of subjects enrolled
    Brazil: 7
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Chile: 8
    Country: Number of subjects enrolled
    China: 39
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    Denmark: 15
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    France: 73
    Country: Number of subjects enrolled
    Germany: 63
    Country: Number of subjects enrolled
    Greece: 18
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    India: 54
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Israel: 15
    Country: Number of subjects enrolled
    Italy: 41
    Country: Number of subjects enrolled
    Japan: 92
    Country: Number of subjects enrolled
    Malaysia: 8
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Netherlands: 22
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Poland: 33
    Country: Number of subjects enrolled
    Portugal: 17
    Country: Number of subjects enrolled
    Spain: 27
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    Thailand: 9
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    United States: 181
    Worldwide total number of subjects
    819
    EEA total number of subjects
    373
    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)
    641
    From 65 to 84 years
    178
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a randomised, placebo-controlled, double-blind, parallel design trial. Abbreviaton used: treatment (trt) baseline (bl.) categorical (cat.) continuous (cont.) number (no.) patient (pt) Placebo (pl.) discontinued (disc.) primary analysis (PA)

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

    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
    Blinding implementation details
    This was a randomised, placebo-controlled, double-blind, parallel design trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events. Two subjects randomised to matching placebo were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.

    Arm title
    		 Nintedanib
    Arm description
    		 Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events. Two subjects randomised to Nintedanib were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started.
    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 were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events.

    Number of subjects in period 1 [1]
    		Placebo Nintedanib
    Started
    288
    288
    Completed
    252
    239
    Not completed
    36
    49
         Consent withdrawn by subject
    7
    5
         Adverse event, non-fatal
    20
    28
         Protocol deviation
    2
    2
         Other than stated above
    7
    14
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on the patients who were randomised after successfully completing the screening period and received at least one of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events. Two subjects randomised to matching placebo were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started.

    Reporting group title
    Nintedanib
    Reporting group description
    		 Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events. Two subjects randomised to Nintedanib were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started.

    Reporting group values
    		 Placebo Nintedanib Total
    Number of subjects
    		 288 288 576
    Age categorical
    Units: Subjects
    Age Continuous
    Treated set (TS): The treated set consisted of patients who were randomised to a treatment group and received at least 1 dose of trial medication.
    Units: years
        arithmetic mean (standard deviation)
    		 53.4 ( 12.6 ) 54.6 ( 11.8 ) -
    Sex: Female, Male
    TS
    Units: Subjects
        Female
    		 212 221 433
        Male
    		 76 67 143
    Race (NIH/OMB)
    TS
    Units: Subjects
        American Indian or Alaska Native
    		 3 2 5
        Asian
    		 81 62 143
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 16 20 36
        White
    		 186 201 387
        More than one race
    		 2 2 4
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    TS
    Units: Subjects
        Hispanic or Latino
    		 18 22 40
        Not Hispanic or Latino
    		 270 266 536
        Unknown or Not Reported
    		 0 0 0
    Baseline pulmonary efficacy variables - Forced Vital Capacity (FVC)
    TS
    Units: mL
        arithmetic mean (standard deviation)
    		 2541.0 ( 815.5 ) 2458.5 ( 735.9 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events. Two subjects randomised to matching placebo were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started.

    Reporting group title
    Nintedanib
    Reporting group description
    		 Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events. Two subjects randomised to Nintedanib were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started.

    Primary: Annual rate of decline in Forced Vital Capacity (FVC) over 52 weeks

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    End point title
    		 Annual rate of decline in Forced Vital Capacity (FVC) over 52 weeks
    End point description
    Forced vital capacity (FVC) is the total amount of air exhaled during the lung function test. For this endpoint reported means represent the adjusted rate.
    End point type
    Primary
    End point timeframe
    up to week (wk) 52 after the start of administration
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    288 [1]
    288 [2]
    Units: millilitre (mL)/year (yr)
        arithmetic mean (standard error)
    -93.3 ( 13.5 )
    -52.4 ( 13.8 )
    Notes
    [1] - Treated Set
    [2] - Treated Set
    Statistical analysis title
    		 Statistical Analysis I
    Statistical analysis description
    The primary analysis is a restricted maximum likelihood (REML) based approach using a random slope & intercept model. The analysis included the fixed, categorical effects of treatment, ATA status & gender, fixed continuous effects of time & baseline FVC (mL), age and height as well as the treatment-by time & baseline-by-time interactions. Random effects was included for patient response for both time & intercept.Within-patient errors are modelled by an unstructured variance-covariance matrix
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.035
    Method
    		 random coefficient regression
    Parameter type
    		 Mean difference (final values)
    Point estimate
    40.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.88
         upper limit
    		 79.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    19.38
    Notes
    [3] - The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial.
    Statistical analysis title
    		 Statistical Analysis II
    Statistical analysis description
    This is a sensitivity analysis (SA) on primary endpoint including only on-trt measurements of FVC [mL]. The random coefficient model was used. The analysis included fixed, categorical effects of trt, ATA status & gender, fixed continuous effects of time & bl. FVC (mL), age, height, trt -by time & bl.-by-time interactions. Random effects included for patient response for both time & intercept. Within−patient errors were modelled by an Unstructured variance−covariance matrix.
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.0378
    Method
    		 random coefficient regression
    Parameter type
    		 Mean difference (final values)
    Point estimate
    43.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.44
         upper limit
    		 83.83
    Notes
    [4] - The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial.
    Statistical analysis title
    		 Statistical Analysis III
    Statistical analysis description
    In multiple imputation SA 1, missing FVC values at wk 52 in pts who were alive at wk 52 were imputed assuming similar rate of FVC decline as in pts from corresponding trt group who prematurely disc. trial drug but had wk 52 FVC value. Missing FVC values at wk 52 in pts who died before wk 52 were imputed assuming similar rate of FVC decline as in pl. pts with wk 52 FVC value who prematurely disc. trial drug with most severe declines.The imputation model was similar to statistical model of PA.
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1046
    Method
    		 random coefficient regression
    Parameter type
    		 Mean difference (final values)
    Point estimate
    30
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.22
         upper limit
    		 66.22
    Statistical analysis title
    		 Statistical Analysis IV
    Statistical analysis description
    In multiple imputation SA 2, missing FVC values at wk 52 in pts who were alive at wk 52 were imputed assuming similar rate of FVC decline as in pts from pl. group who prematurely disc. trial drug but had a wk 52 FVC value. Missing FVC values at wk 52 in pts who died before wk 52 were imputed assuming similar rate of FVC decline as in pl. pts with a wk 52 FVC value who prematurely disc. trial drug with most severe declines. The imputation model was similar to the statistical model of the PA
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.074
    Method
    		 random coefficient regression
    Parameter type
    		 Mean difference (final values)
    Point estimate
    32.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.19
         upper limit
    		 69.06
    Statistical analysis title
    		 Statistical Analysis V
    Statistical analysis description
    In multiple imputation SA 3, missing FVC values at wk 52 in pts who were alive at wk 52 were imputed assuming a similar rate of FVC decline as in all pts in the pl. group who were included in the PA. Missing FVC values at wk 52 in pts who died before wk 52 were imputed assuming a similar rate of FVC decline as in all placebo patients included in the primary analysis with the most severe declines. The imputation model was similar to the statistical model of the PA.
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0644
    Method
    		 random coefficient regression
    Parameter type
    		 Mean difference (final values)
    Point estimate
    33.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.03
         upper limit
    		 69.75
    Statistical analysis title
    		 Statistical Analysis VI
    Statistical analysis description
    This is sensitivity analysis using the model similar to the primary analysis but including a different set of covariates: the fixed, categorical effects of treatment, ATA status, the fixed continuous effects of time, baseline FVC (mL), and the treatment-by-time and baseline-by-time interactions.Random effects was included for patient response for both time and intercept.
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0351
    Method
    		 random coefficient regression
    Parameter type
    		 Mean difference (final values)
    Point estimate
    40.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.88
         upper limit
    		 79.01
    Statistical analysis title
    		 Statistical Analysis VII
    Statistical analysis description
    This is sensitivity analysis using the model similar to the primary analysis but including a different set of covariates: the fixed, categorical effects of treatment, ATA status (Positive / Negative), gender and mycophenolate mofetil /sodium background therapy use (Yes / No), fixed continuous effects of time, age , height and baseline FVC (mL), the treatment-by-time and baseline-by-time interactions. Random effects was included for patient response for both time and intercept
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0349
    Method
    		 random coefficient regression
    Parameter type
    		 Mean difference (final values)
    Point estimate
    40.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.92
         upper limit
    		 79.04

    Secondary: Absolute change from baseline in the Modified Rodnan Skin Score (mRSS) at Week 52

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    End point title
    		 Absolute change from baseline in the Modified Rodnan Skin Score (mRSS) at Week 52
    End point description
    This is the first key secondary endpoint. The modified Rodnan Skin Score (mRSS) is an evaluation of the patient’s skin thickness rated by clinical palpation using a 0 to 3 scale. The scale differentiates between 0 = normal skin, 1 = mild thickness, 2 = moderate thickness, and 3 = severe thickness with inability to pinch the skin into a fold. The palpation is done for each of the 17 surface anatomic areas of the body: face, anterior chest, abdomen, fingers (right and left separately), forearms, upper arms, thighs, lower legs, dorsum of hands and feet. The sum of these individual values is defined as the total skin score. The mRSS has a range from 0 (no thickening) to 51 (severe thickening in all 17 areas). A high score corresponds to worse skin thickness. Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).
    End point type
    Secondary
    End point timeframe
    Baseline and up to 52 weeks after the start of administration
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    288 [5]
    288 [6]
    Units: unit on scale
        least squares mean (standard error)
    -1.96 ( 0.26 )
    -2.17 ( 0.27 )
    Notes
    [5] - Treated Set
    [6] - Treated Set
    Statistical analysis title
    		 Statistical Analysis I
    Statistical analysis description
    The mixed model repeated measures (MMRM) approach was used. The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial.
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5785
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.94
         upper limit
    		 0.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.37

    Secondary: Absolute change from baseline in Saint George’s Respiratory Questionnaire (SGRQ) total score at Week 52.

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    End point title
    		 Absolute change from baseline in Saint George’s Respiratory Questionnaire (SGRQ) total score at Week 52.
    End point description
    This is the second key secondary endoint. The Saint George’s Respiratory Questionnaire measures the health status in patients with chronic airflow limitation. It consists of 2 parts that cover 3 domains: symptoms, activities, and impacts. The symptom domain relates to the effect, frequency and severity of respiratory symptoms. The activity domain relates to activities that cause or are limited by breathlessness. The impact domain evaluates a range of aspects concerned with social functioning and psychological disturbances resulting from airways disease. The scores of these domains range from 0 (no impairment) to 100 (worst possible). The calculated total score summarises the impact of the disease on overall health status. A high score corresponds to worse health. Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).
    End point type
    Secondary
    End point timeframe
    Baseline and up to 52 weeks after the start of administration
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    288 [7]
    288 [8]
    Units: unit on scale
        least squares mean (standard error)
    -0.88 ( 0.87 )
    0.81 ( 0.88 )
    Notes
    [7] - Treated Set
    [8] - Treated Set
    Statistical analysis title
    		 Statistical Analysis I
    Statistical analysis description
    The mixed model repeated measures (MMRM) approach was used, with fixed categorical effects of ATA status, visit, treatment-by visit interaction and baseline-by-visit interaction. Visit was the repeated measure. Within-patient errors were modelled by unstructured variance-covariance structure.
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.1711
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.73
         upper limit
    		 4.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.24
    Notes
    [9] - The MMRM model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial.

    Secondary: Annual rate of decline in FVC in percentage (%) predicted over 52 weeks

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    End point title
    		 Annual rate of decline in FVC in percentage (%) predicted over 52 weeks
    End point description
    Annual rate of decline in FVC in percentage (%) predicted over 52 weeks. For this endpoint reported means represent the adjusted rate.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks after the start of administration
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    288 [10]
    288 [11]
    Units: % predicted/yr
        arithmetic mean (standard error)
    -2.6 ( 0.4 )
    -1.4 ( 0.4 )
    Notes
    [10] - Treated set
    [11] - Treated set
    Statistical analysis title
    		 Statistical Analysis I
    Statistical analysis description
    Based on a random coefficient regression with fixed categorical effects of treatment, ATA status, fixed continuous effects of time, baseline FVC [% pred], & including treatment−by−time and baseline−by−time interactions. Random effect was included for patient specific intercept & time. Within−patient errors are modelled by an Unstructured variance−covariance matrix. Inter−individual variability is modelled by a Variance−Components variance−covariance matrix.
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.0331
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.15
    Confidence interval
         level
    		 1.15%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 2.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.54
    Notes
    [12] - The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial.

    Secondary: Absolute change from baseline in FVC in mL at Week 52

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    End point title
    		 Absolute change from baseline in FVC in mL at Week 52
    End point description
    Absolute change from baseline in FVC in mL at Week 52. Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).
    End point type
    Secondary
    End point timeframe
    Baseline and up to 52 weeks after the start of administration
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    288 [13]
    288 [14]
    Units: mL
        least squares mean (standard error)
    -101.03 ( 13.62 )
    -54.63 ( 13.94 )
    Notes
    [13] - Treated set
    [14] - Treated set
    Statistical analysis title
    		 Statistical Analysis I
    Statistical analysis description
    The mixed model repeated measures (MMRM) approach was used, with fixed categorical effects of ATA status, visit, treatment-byvisit interaction and baseline-by-visit interaction. Visit was the repeated measure. Within-patient errors were modelled by unstructured variance-covariance structure.
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.0177
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    46.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.09
         upper limit
    		 84.73
    Variability estimate
    Standard error of the mean
    Dispersion value
    19.51
    Notes
    [15] - The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial.

    Secondary: Relative change from baseline [%] of mRSS at Week 52

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    End point title
    		 Relative change from baseline [%] of mRSS at Week 52
    End point description
    Relative change from baseline [%] of mRSS at Week 52. Least square mean is actually the adjusted mean. Adjusted mean was based on all analysed patients in the model (not only patients with a baseline and measurement at Week 52).
    End point type
    Secondary
    End point timeframe
    Baseline and up to 52 weeks after the start of administration
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    288 [16]
    288 [17]
    Units: unit on scale
        least squares mean (standard error)
    -3.92 ( 5.89 )
    -10.20 ( 5.98 )
    Notes
    [16] - Treated set
    [17] - Treated set
    Statistical analysis title
    		 Statistical Analysis I
    Statistical analysis description
    The mixed model repeated measures (MMRM) approach was used, with fixed categorical effects of ATA status, visit, treatment-by-visit interaction and baseline-by-visit interaction. Visit was the repeated measure. Within-patient errors were modelled by unstructured variance-covariance structure.
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.4547
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -6.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.77
         upper limit
    		 10.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.39
    Notes
    [18] - The model assumed that data were missing at random & that patients who dropped out would have behaved similarly to those who remained in trial.

    Secondary: Time to death

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    End point title
    		 Time to death
    End point description
    Length of survival of patients treated with a placebo or Nintedanib 150 mg bid over the whole trial. The number of patients who observed an event are summarized below.
    End point type
    Secondary
    End point timeframe
    From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    288 [19]
    288 [20]
    Units: Participants
        number (not applicable)
    9
    10
    Notes
    [19] - Treated set
    [20] - Treated set
    Statistical analysis title
    		 Statistical Analysis I
    Statistical analysis description
    Based on Cox’s regression model (Wald test), stratified by ATA status.
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7535
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 2.84

    Secondary: The percentage (%) of responder based on Combined Response Index in Systemic Sclerosis (CRISS) at Week 52

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    End point title
    		 The percentage (%) of responder based on Combined Response Index in Systemic Sclerosis (CRISS) at Week 52
    End point description
    The percentage (%) of responder based on Combined Response Index in Systemic Sclerosis (CRISS) at Week 52. This is a composite endpoint, based on the mRSS, FVC percent predicted, HAQ-DI, patient’s global impression of overall health VAS and physician’s global impression of patient’s overall health VAS, as well as the absence of significant worsening of interstitial lung disease, a new scleroderma renal crisis, left ventricular failure or pulmonary arterial hypertension. The CRISS index score represents a probability of improvement and ranges between 0 and 1. This is a 2 stage process to predict probability of improvement: Step 1 – absence of major organ progression (SRC etc.) – score “0” Step 2 – predicted probability of improvement – (score “0 – 1”).
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    288 [21]
    288 [22]
    Units: (%) of responder based on CRISS
        number (not applicable)
    11.8
    12.2
    Notes
    [21] - Treated set
    [22] - Treated set
    Statistical analysis title
    		 Statistical Analysis I
    Statistical analysis description
    The comparison between both treatment groups was performed using a Cochran-Mantel-Haenszel test. CRISS score at Week 52 was transformed into 100 binary responder endpoints using multiple imputation. These were analyzed using a Cochran-Mantel-Haenszel test, stratified by ATA status. OR and the 95% CI as obtained from all 100 imputations were combined using Rubin´s rule.
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9115
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.88

    Secondary: Absolute change from baseline in Carbon Monoxide Diffusion Capacity (DLco) in % predicted at Week 52

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    End point title
    		 Absolute change from baseline in Carbon Monoxide Diffusion Capacity (DLco) in % predicted at Week 52
    End point description
    Absolute change from baseline in Carbon Monoxide Diffusion Capacity (DLco) in % predicted at Week 52. Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).
    End point type
    Secondary
    End point timeframe
    Baseline and up to 52 weeks after the start of administration
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    288 [23]
    288 [24]
    Units: % predicted DLco
        least squares mean (standard error)
    -2.77 ( 0.54 )
    -3.21 ( 0.54 )
    Notes
    [23] - Treated set
    [24] - Treated set
    Statistical analysis title
    		 Statistical Analysis I
    Statistical analysis description
    The mixed model repeated measures (MMRM) approach was used, with fixed categorical effects of ATA status, visit, treatment-by-visit interaction and baseline-by-visit interaction. Visit was the repeated measure. Within-patient errors were modelled by unstructured variance-covariance structure.
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5668
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.94
         upper limit
    		 1.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.76

    Secondary: Absolute change from baseline in digital ulcer net burden at Week 52

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    End point title
    		 Absolute change from baseline in digital ulcer net burden at Week 52
    End point description
    Absolute change from baseline in digital ulcer net burden (defined as the number of new digital ulcers (DUs) plus the number of DUs that have been verified at any earlier assessment during the trial) at Week 52. It is calculated at a visit by counting the total number of fingertips with ulcers (i.e. number of fingers with presence of digital ulcer ticked “Yes”) at the corresponding visit Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).
    End point type
    Secondary
    End point timeframe
    Baseline and up to 52 weeks after the start of administration
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    288 [25]
    288 [26]
    Units: fingers
        least squares mean (standard error)
    0.06 ( 0.04 )
    0.03 ( 0.05 )
    Notes
    [25] - Treated set
    [26] - Treated set
    Statistical analysis title
    		 Statistical Analysis I
    Statistical analysis description
    The mixed model repeated measures (MMRM) approach was used, with fixed categorical effects of ATA status, visit, treatment-by-visit interaction and baseline-by-visit interaction. Visit was the repeated measure. Within-patient errors were modelled by unstructured variance-covariance structure.
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5914
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06

    Secondary: Absolute change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 52

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    End point title
    		 Absolute change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 52
    End point description
    Absolute change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) score at Week 52. The HAQ-DI score is calculated as follows: Each question is scored 0–3 (where 0= “without difficulty” & 3= “unable to do”). There are 8 categories (Dressing & Grooming, Arising, Eating, Walking, Hygiene, Reach, Grip, Activities), each including 2 or 3 questions. The score for each category corresponds to maximum question score within each category. Finally, HAQ-DI score corresponds to sum of the sub-scores of all 8 categories divided by number of categories completed. Please note that if there are fewer than 6 categories with responses, then a score cannot be calculated. The HAQ-DI score scale has 25 possible values (i.e., 0, 0.125, 0.250, 0.375 … 3). A high score corresponds to worse impairment. Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).
    End point type
    Secondary
    End point timeframe
    Baseline and up to 52 weeks after the start of administration
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    288 [27]
    288 [28]
    Units: unit on a scale
        least squares mean (standard error)
    0.022 ( 0.024 )
    0.054 ( 0.024 )
    Notes
    [27] - Treated set
    [28] - Treated set
    Statistical analysis title
    		 Statistical Analysis I
    Statistical analysis description
    Based on mixed model repeated measures (MMRM) approach was used, with fixed categorical effects of ATA status, visit, treatment-by-visit interaction and baseline-by-visit interaction. Visit was the repeated measure. Within-patient errors were modelled by unstructured variance-covariance structure.
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3447
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.032
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.035
         upper limit
    		 0.099
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.034

    Secondary: Absolute change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) dyspnoea score at Week 52

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    End point title
    		 Absolute change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) dyspnoea score at Week 52
    End point description
    Absolute change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT) dyspnoea score at Week 52. FACIT-Dyspnoea (Dyspnoea) 10 Item Short Form include a 4-point rating scale (no shortness of breath=0; mildly short of breath=1; moderately short of breath = 2; severely short of breath =3; or I did not do this in the past 7 days =4). Next, using the same 10 items, respondents are asked to rate the amount of difficulty they experienced when doing these tasks on a 4-point Likert scale (no difficulty=0; a little difficulty=1; some difficulty =2; much difficulty = 3). The FACIT-Dyspnea short forms are scored such that a high score represents high levels of dyspnea. Least square mean is actually the adjusted mean. Adjusted mean is based on all analysed patients in the model (not only patients with a baseline and measurement at week 52).
    End point type
    Secondary
    End point timeframe
    Baseline and up to 52 weeks after the start of administration
    End point values
    		 Placebo Nintedanib
    Number of subjects analysed
    288 [29]
    288 [30]
    Units: Unit on a scale
        least squares mean (standard error)
    0.34 ( 0.41 )
    0.99 ( 0.42 )
    Notes
    [29] - Treated set
    [30] - Treated set
    Statistical analysis title
    		 Statistical Analysis I
    Statistical analysis description
    The mixed model repeated measures (MMRM) approach was used, with fixed categorical effects of ATA status, visit, treatment-by-visit interaction and baseline-by-visit interaction. Visit was the repeated measure. Within-patient errors were modelled by unstructured variance-covariance structure.
    Comparison groups
    Placebo v Nintedanib
    Number of subjects included in analysis
    576
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2727
    Method
    		 MMRM
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 1.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.58

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of first trial drug intake up to date of death or last contact date (ie., up to 100 weeks)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients were administered orally placebo matching nintedanib 150 milligram (mg) soft gelatine capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events. Two subjects randomised to matching placebo were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started.

    Reporting group title
    Nintedanib
    Reporting group description
    		 Patients were administered orally 150 milligram (mg) soft gelatin capsules, twice daily with a possibility to interrupt treatment or to reduce to 100mg to manage adverse events. Two subjects randomised to Nintedanib were not treated. Although the actual number of randomised patients is 290, as two subjects were not treated, the number of patients that provided data for analyses (shown in “Started” column) is 288. To be consistent with the baseline section the number of subjects treated is shown as started.

    Serious adverse events
    		 Placebo Nintedanib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    79 / 288 (27.43%)
    88 / 288 (30.56%)
         number of deaths (all causes)
    9
    10
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign mesothelioma
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (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 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant melanoma
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mesothelioma malignant
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nasopharyngeal cancer
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 288 (0.35%)
    2 / 288 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sweat gland tumour
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 288 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Raynaud's phenomenon
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         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
    Brain death
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyp
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anti-neutrophil cytoplasmic antibody positive vasculitis
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 288 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 288 (0.00%)
    3 / 288 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulvovaginal swelling
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute lung injury
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Acute respiratory failure
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    8 / 288 (2.78%)
    5 / 288 (1.74%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    6 / 288 (2.08%)
    10 / 288 (3.47%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 10
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Painful respiration
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 288 (0.35%)
    2 / 288 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 288 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    4 / 288 (1.39%)
    4 / 288 (1.39%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    4 / 288 (1.39%)
    4 / 288 (1.39%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    4 / 288 (1.39%)
    5 / 288 (1.74%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic sclerosis pulmonary
         subjects affected / exposed
    5 / 288 (1.74%)
    3 / 288 (1.04%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Cell marker increased
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Forced vital capacity decreased
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative ileus
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hypertrophic cardiomyopathy
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    3 / 288 (1.04%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuropericarditis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Restrictive cardiomyopathy
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery aneurysm
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral amyloid angiopathy
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral microhaemorrhage
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Immune thrombocytopenic purpura
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Macular oedema
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhegmatogenous retinal detachment
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 288 (0.69%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal mass
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal pseudo-obstruction
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         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 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Digital pitting scar
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Petechiae
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sclerema
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    2 / 288 (0.69%)
    2 / 288 (0.69%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 288 (0.35%)
    3 / 288 (1.04%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder perforation
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scleroderma renal crisis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary incontinence
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drooping shoulder syndrome
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    3 / 288 (1.04%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scleroderma
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic scleroderma
         subjects affected / exposed
    2 / 288 (0.69%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (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
    1 / 288 (0.35%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 288 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 288 (0.00%)
    2 / 288 (0.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         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
    1 / 288 (0.35%)
    2 / 288 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 288 (0.69%)
    10 / 288 (3.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumonia bacterial
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 288 (0.00%)
    3 / 288 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 288 (0.35%)
    2 / 288 (0.69%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic candida
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 288 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 288 (0.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Nintedanib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    239 / 288 (82.99%)
    270 / 288 (93.75%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 288 (1.39%)
    22 / 288 (7.64%)
         occurrences all number
    4
    30
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 288 (0.35%)
    16 / 288 (5.56%)
         occurrences all number
    1
    20
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    4 / 288 (1.39%)
    19 / 288 (6.60%)
         occurrences all number
    4
    22
    Weight decreased
         subjects affected / exposed
    15 / 288 (5.21%)
    39 / 288 (13.54%)
         occurrences all number
    15
    41
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    15 / 288 (5.21%)
    19 / 288 (6.60%)
         occurrences all number
    15
    22
    Headache
         subjects affected / exposed
    28 / 288 (9.72%)
    34 / 288 (11.81%)
         occurrences all number
    40
    49
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    21 / 288 (7.29%)
    33 / 288 (11.46%)
         occurrences all number
    26
    37
    Pyrexia
         subjects affected / exposed
    13 / 288 (4.51%)
    20 / 288 (6.94%)
         occurrences all number
    18
    22
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    21 / 288 (7.29%)
    36 / 288 (12.50%)
         occurrences all number
    29
    56
    Abdominal pain upper
         subjects affected / exposed
    15 / 288 (5.21%)
    21 / 288 (7.29%)
         occurrences all number
    22
    41
    Constipation
         subjects affected / exposed
    19 / 288 (6.60%)
    15 / 288 (5.21%)
         occurrences all number
    19
    15
    Diarrhoea
         subjects affected / exposed
    92 / 288 (31.94%)
    218 / 288 (75.69%)
         occurrences all number
    211
    647
    Gastrooesophageal reflux disease
         subjects affected / exposed
    26 / 288 (9.03%)
    20 / 288 (6.94%)
         occurrences all number
    30
    25
    Nausea
         subjects affected / exposed
    41 / 288 (14.24%)
    96 / 288 (33.33%)
         occurrences all number
    49
    213
    Vomiting
         subjects affected / exposed
    31 / 288 (10.76%)
    78 / 288 (27.08%)
         occurrences all number
    39
    165
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    62 / 288 (21.53%)
    41 / 288 (14.24%)
         occurrences all number
    80
    46
    Dyspnoea
         subjects affected / exposed
    27 / 288 (9.38%)
    23 / 288 (7.99%)
         occurrences all number
    29
    27
    Epistaxis
         subjects affected / exposed
    16 / 288 (5.56%)
    8 / 288 (2.78%)
         occurrences all number
    17
    18
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    54 / 288 (18.75%)
    56 / 288 (19.44%)
         occurrences all number
    87
    94
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    23 / 288 (7.99%)
    23 / 288 (7.99%)
         occurrences all number
    28
    31
    Back pain
         subjects affected / exposed
    15 / 288 (5.21%)
    20 / 288 (6.94%)
         occurrences all number
    15
    22
    Myalgia
         subjects affected / exposed
    11 / 288 (3.82%)
    16 / 288 (5.56%)
         occurrences all number
    11
    17
    Pain in extremity
         subjects affected / exposed
    14 / 288 (4.86%)
    15 / 288 (5.21%)
         occurrences all number
    15
    17
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    27 / 288 (9.38%)
    22 / 288 (7.64%)
         occurrences all number
    32
    32
    Influenza
         subjects affected / exposed
    15 / 288 (5.21%)
    16 / 288 (5.56%)
         occurrences all number
    15
    16
    Nasopharyngitis
         subjects affected / exposed
    56 / 288 (19.44%)
    43 / 288 (14.93%)
         occurrences all number
    77
    61
    Respiratory tract infection
         subjects affected / exposed
    16 / 288 (5.56%)
    10 / 288 (3.47%)
         occurrences all number
    19
    14
    Upper respiratory tract infection
         subjects affected / exposed
    43 / 288 (14.93%)
    39 / 288 (13.54%)
         occurrences all number
    63
    53
    Urinary tract infection
         subjects affected / exposed
    28 / 288 (9.72%)
    28 / 288 (9.72%)
         occurrences all number
    41
    42
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    14 / 288 (4.86%)
    28 / 288 (9.72%)
         occurrences all number
    15
    33

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Mar 2016
    The following main changes in the conduct of the trial were introduced by the amendment: 1) To ensure regular pregnancy testing as requested by health authorities, information was added that women of childbearing potential had to perform a pregnancy test every 4 to 6 weeks. Once intervals between site visits were >6 weeks, home urine dipstick pregnancy tests were centrally provided and had to be performed at home. 2)For Inclusion Criterion No. 5, the reference time point for the historical HRCT, which had to be performed within 12 months, was changed from Visit 2 to Visit 1, as Visit 1 represented the better predictable time point 3) Exclusion Criterion No. 8 was updated to clarify that not only digital ulcers but also severe other ulcers could have led to the exclusion of a patient at the discretion of the investigator 4) Exclusion Criterion No. 12 was updated to clarify that also severe gastrointestinal symptoms due to SSc could have led to the exclusion of a patient 5) Exclusion Criterion No. 25 was added based on advice from regulatory agencies: patients with underlying chronic liver disease (Child Pugh A, B, C hepatic impairment) 6) The restrictions regarding concomitant treatment with corticosteroids were modified. 7) Patients on low dose corticosteroid therapy were eligible for the trial even if the dose of the corticosteroid medication was not stable 8) The description of the method of measuring DLco was harmonised within the CTP, by removal of the adjustments for altitude and carboxyhaemoglobin incorrectly mentioned in one section of the CTP 9) Addition of mycophenolate sodium to clarify that for ‘mycophenolate’ 2 possible salt forms are available.
    26 Jan 2017
    1)For selection of trial population, it was added that recruitment of pts who were on stable dose of mycophenolate or methotrexate background medications could have been restricted, although enrolment was generally competitive 2)Numbers of sites & countries contributing pts worldwide were updated from approximately 170sites to about 230sites & from about 20 to 33 countries 3)Inclusion Criterion No. 4 was revised &requested SSc disease onset (defined by first non-Raynaud symptom) had to occur within 7 years instead of 5 years of Visit 1.This change was introduced to facilitate recruitment into trial, without compromising characterisation of trial population.4)For Exclusion Criterion No.4, reference time point to assess eligibility regarding airway obstruction (pre-bronchodilator FEV1/FVC <0.7) was changed from Visit1 to Visit2 to ensure consistency with all other lung function criteria 5)To Exclusion Criterion No. 18 & restrictions of concomitant trt required washout period of at least 8 weeks before Visit 2 was added for mycophenolate mofetil/sodium or methotrexate 6)In Exclusion Criterion No. 22 tubal occlusion was removed as an example for method of permanent sterilization, since according to Clinical Trial Facilitation Group recommendations (2014),woman who underwent tubal ligation is still to be considered ‘of childbearing potential’ 7)Exclusion Criterion No.26 was added: pts with history of SSc renal crisis 8)For AE collection & reporting it was clarified that independent adjudication committee reviewed all fatal cases for primary causes of death.Data protection measures for committee & adjudication process were clarified too. 9)Absolute change from bl. at wk 52 in CRISS index score was added as secondary endpoint & removed from list of further endpoints; however, TSAP defined to analyse proportion of responders instead of absolute change from bl.10)ATA status & bl. FVC% predicted were included as covariates in analysis of rate of decline in FVC in % predicted.
    15 Feb 2018
    The following main changes in the conduct of the trial were introduced by the amendment: 1) The end of trial for patients on-treatment as well as for patients who prematurely discontinued trial medication and attended visits as planned was clarified. Details regarding the time point of the EOT Visit and requirements for Follow-up Visits were added. 2) The restrictions regarding concomitant treatment were modified. The definition of clinically significant deterioration was extended to other clinical parameters than mRSS and FVC 3) Clarification that based on the half-life of the trial drug, a safety analysis restricted to AEs that occurred between the start of treatment and up to 7 days after the date of the last dose of trial medication were analysed in addition

    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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