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    Clinical Trial Results:
    A double blind, randomized, placebo-controlled trial evaluating the efficacy and safety of BI 1015550 over at least 52 weeks in patients with Idiopathic Pulmonary Fibrosis (IPF)

    Summary
    EudraCT number
    		 2022-001091-34
    Trial protocol
    		 IE   FR   ES   DE   NO   EE   FI   SI   PT   SE   NL   HU   BE   IT   GR   DK   HR  
    Global end of trial date
    17 Dec 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jan 2026
    First version publication date
    02 Jan 2026
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1305-0014
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05321069
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 018002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 018002430127, 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
    03 Feb 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Aug 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Dec 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall objective of the trial was to evaluate the efficacy and safety of nerandomilast 9 mg and 18 mg bid compared with placebo in patients with IPF in addition to the patient’s standard of care treatment.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all subjects as required.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Oct 2022
    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: 17
    Country: Number of subjects enrolled
    Australia: 61
    Country: Number of subjects enrolled
    Austria: 22
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Brazil: 23
    Country: Number of subjects enrolled
    Canada: 50
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    China: 97
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    France: 98
    Country: Number of subjects enrolled
    Germany: 80
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Italy: 48
    Country: Number of subjects enrolled
    Japan: 135
    Country: Number of subjects enrolled
    Malaysia: 6
    Country: Number of subjects enrolled
    Mexico: 7
    Country: Number of subjects enrolled
    Netherlands: 17
    Country: Number of subjects enrolled
    New Zealand: 14
    Country: Number of subjects enrolled
    Norway: 17
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Portugal: 3
    Country: Number of subjects enrolled
    Singapore: 5
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 83
    Country: Number of subjects enrolled
    Spain: 77
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Taiwan: 22
    Country: Number of subjects enrolled
    Thailand: 10
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    United States: 196
    Country: Number of subjects enrolled
    Estonia: 5
    Worldwide total number of subjects
    1177
    EEA total number of subjects
    421
    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)
    247
    From 65 to 84 years
    911
    85 years and over
    19

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a randomized, double-blind, placebo-controlled, Phase III trial evaluating nerandomilast 9 mg and 18 mg bid vs placebo in patients with IPF. Treatment Period A lasted up to 52 weeks post-randomisation, followed by Period B with continued blinded treatment beyond 52 weeks.

    Pre-assignment
    Screening details
    		 All participants were screened for eligibility prior to participation in the trial. Participants attended a specialist site which ensured that they (the participants) strictly met all inclusion and none of the exclusion criteria. Participants were not to be allocated to a treatment sequence if any of the entry criteria were 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, Carer, Data analyst, Assessor
    Blinding implementation details
    Patients, investigators, central reviewers, and everyone involved in trial conduct or analysis or with any other interest in this double-blind trial will remain blinded regarding the randomized treatment assignments until the database is declared ready for analysis.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo matching 9 mg or 18 mg nerandomilast film coated tablet orally twice daily, with doses given at least 12 hours apart and each taken with 250 mL of water.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo matching Nerandomilast
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo matching 9 mg or 18 mg Nerandomilast film coated tablet orally twice daily, with doses given at least 12 hours apart and each taken with 250 mL of water.

    Arm title
    		 Nerandomilast 9 mg BID
    Arm description
    		 Participants received 9 mg film-coated nerandomilast tablets orally twice daily, with doses administered at least 12 hours apart, each taken with 250 mL of water.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nerandomilast
    Investigational medicinal product code
    Other name
    BI 1015550
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 9 mg film-coated Nerandomilast tablets orally twice daily, with doses administered at least 12 hours apart, each taken with 250 mL of water.

    Arm title
    		 Nerandomilast 18 mg BID
    Arm description
    		 Participants received 18 mg film-coated nerandomilast tablets orally twice daily, with doses administered at least 12 hours apart, each taken with 250 mL of water.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nerandomilast
    Investigational medicinal product code
    Other name
    BI 1015550
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 18 mg film-coated Nerandomilast tablets orally twice daily, with doses administered at least 12 hours apart, each taken with 250 mL of water.

    Number of subjects in period 1
    		Placebo Nerandomilast 9 mg BID Nerandomilast 18 mg BID
    Started
    393
    392
    392
    Completed treatment period A (52 weeks)
    320
    324
    318
    Completed
    292
    298
    299
    Not completed
    101
    94
    93
         Consent withdrawn by subject
    23
    18
    12
         Adverse event, non-fatal
    52
    52
    64
         Lost to follow-up
    1
    -
    1
         No reason stated by the participants
    23
    22
    16
         Protocol deviation
    1
    1
    -
         Lack of efficacy
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matching 9 mg or 18 mg nerandomilast film coated tablet orally twice daily, with doses given at least 12 hours apart and each taken with 250 mL of water.

    Reporting group title
    Nerandomilast 9 mg BID
    Reporting group description
    		 Participants received 9 mg film-coated nerandomilast tablets orally twice daily, with doses administered at least 12 hours apart, each taken with 250 mL of water.

    Reporting group title
    Nerandomilast 18 mg BID
    Reporting group description
    		 Participants received 18 mg film-coated nerandomilast tablets orally twice daily, with doses administered at least 12 hours apart, each taken with 250 mL of water.

    Reporting group values
    		 Placebo Nerandomilast 9 mg BID Nerandomilast 18 mg BID Total
    Number of subjects
    		 393 392 392 1177
    Age categorical
    Full Analysis Set (FAS): This patient set includes all randomized patients who received at least one dose of study drug.
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 86 78 83 247
        From 65-84 years
    		 304 306 301 911
        85 years and over
    		 3 8 8 19
    Age Continuous
    Full Analysis Set (FAS): This patient set includes all randomized patients who received at least one dose of study drug.
    Units: Years
        arithmetic mean (standard deviation)
    		 69.9 ( 7.5 ) 70.5 ( 7.8 ) 70.3 ( 7.8 ) -
    Sex: Female, Male
    Full Analysis Set (FAS): This patient set includes all randomized patients who received at least one dose of study drug.
    Units: Participants
        Female
    		 56 75 69 200
        Male
    		 337 317 323 977
    Race (NIH/OMB)
    Full Analysis Set (FAS): This patient set includes all randomized patients who received at least one dose of study drug.
    Units: Subjects
        American Indian or Alaska Native
    		 1 2 2 5
        Asian
    		 116 121 130 367
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 2 3 1 6
        White
    		 273 266 258 797
        More than one race
    		 1 0 1 2
        Unknown or Not Reported
    		 0 0 0 0
    Ethnicity (NIH/OMB)
    Full Analysis Set (FAS): This patient set includes all randomized patients who received at least one dose of study drug.
    Units: Subjects
        Hispanic or Latino
    		 28 23 44 95
        Not Hispanic or Latino
    		 365 369 348 1082
        Unknown or Not Reported
    		 0 0 0 0
    Forced Vital Capacity (FVC) at baseline
    Full Analysis Set (FAS): This patient set includes all randomized patients who received at least one dose of study drug.
    Units: Milliliters (mL)
        arithmetic mean (standard deviation)
    		 2863.9 ( 804.6 ) 2837.2 ( 781.4 ) 2827.3 ( 758.0 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matching 9 mg or 18 mg nerandomilast film coated tablet orally twice daily, with doses given at least 12 hours apart and each taken with 250 mL of water.

    Reporting group title
    Nerandomilast 9 mg BID
    Reporting group description
    		 Participants received 9 mg film-coated nerandomilast tablets orally twice daily, with doses administered at least 12 hours apart, each taken with 250 mL of water.

    Reporting group title
    Nerandomilast 18 mg BID
    Reporting group description
    		 Participants received 18 mg film-coated nerandomilast tablets orally twice daily, with doses administered at least 12 hours apart, each taken with 250 mL of water.

    Primary: Absolute change from baseline in Forced Vital Capacity (FVC) [mL] at Week 52

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    End point title
    		 Absolute change from baseline in Forced Vital Capacity (FVC) [mL] at Week 52
    End point description
    The absolute change from baseline in Forced Vital Capacity (FVC) [mL] at Week 52 is reported. The absolute change from baseline in forced vital capacity (FVC) at Week 52 was analyzed using a restricted maximum likelihood (REML)-based mixed model with repeated measures (MMRM). The model included fixed categorical effects of treatment and baseline antifibrotic use at each visit, as well as the continuous effect of baseline FVC. Visit was treated as a repeated measure, with an unstructured covariance structure for within-patient variability. Full Analysis Set (FAS): This patient set includes all randomized patients who received at least one dose of study drug. only patients with baseline measurement and at least one post−baseline measurement are included.
    End point type
    Primary
    End point timeframe
    The MMRM model is a longitudinal analysis, and it incorporated FVC measurements from baseline (Week -8 to Week -1) and Week 2, Week 6, Week 12, Week 18, Week 26, Week 36, Week 44 and Week 52. The data represent the Least Squares Mean at Week 52
    End point values
    		 Placebo Nerandomilast 9 mg BID Nerandomilast 18 mg BID
    Number of subjects analysed
    391
    390
    392
    Units: Milliliters (mL)
        least squares mean (confidence interval 95%)
    -183.48 (-210.86 to -156.10)
    -138.60 (-165.59 to -111.61)
    -114.65 (-141.81 to -87.50)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Based on a Mixed Model for Repeated Measures (MMRM), which included fixed, categorical effects of treatment at each visit, baseline use of antifibrotic therapy at each visit, and fixed continuous effects of baseline forced vital capacity (FVC) in milliliters at each visit. Patients were treated as a random effect. Visit was treated as the repeated measure, and an unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo v Nerandomilast 18 mg BID
    Number of subjects included in analysis
    783
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.0005
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    68.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 30.26
         upper limit
    		 107.39
    Notes
    [1] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Based on a Mixed Model for Repeated Measures (MMRM), which included fixed, categorical effects of treatment at each visit, baseline use of antifibrotic therapy at each visit, and fixed continuous effects of baseline forced vital capacity (FVC) in milliliters at each visit. Patients were treated as a random effect. Visit was treated as the repeated measure, and an unstructured covariance structure was used to model the within-patient measurements.
    Comparison groups
    Placebo v Nerandomilast 9 mg BID
    Number of subjects included in analysis
    781
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0222
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    44.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.44
         upper limit
    		 83.33
    Notes
    [2] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.

    Secondary: Time to first acute IPF exacerbation or death over the duration of the trial

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    End point title
    		 Time to first acute IPF exacerbation or death over the duration of the trial
    End point description
    The time to first acute IPF exacerbation or death during the trial is reported as the number of participants who experienced either event. Acute IPF is defined as an acute, clinically significant respiratory deterioration characterized by evidence of new, widespread alveolar abnormality, with all of the following: Acute worsening or development of dyspnea, typically of less than 1 month’s duration. Computed tomography showing new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with IPF. Deterioration not fully explained by cardiac failure or fluid overload. If more than one component occurred on the same day, the patient was counted under the first event according to the following hierarchy: acute IPF exacerbation followed by death. Full Analysis Set (FAS): This patient set includes all randomized patients who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From first administration of any trial drug (Nerandomilast or Placebo) up to 22.9 months.
    End point values
    		 Placebo Nerandomilast 9 mg BID Nerandomilast 18 mg BID
    Number of subjects analysed
    393
    392
    392
    Units: Participants
        Acute IPF exacerbation
    30
    31
    38
        Death
    19
    20
    12
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis was performed using a Cox proportional hazards regression model that included baseline use of antifibrotic therapy (antifibrotic group vs non-antifibrotic group), age, baseline forced vital capacity (FVC) percentage predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted (corrected for hemoglobin levels), and treatment group as covariates.
    Comparison groups
    Placebo v Nerandomilast 18 mg BID
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.5896
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.65
    Notes
    [3] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using a Cox proportional hazards regression model that included baseline use of antifibrotic therapy (antifibrotic group vs non-antifibrotic group), age, baseline forced vital capacity (FVC) percentage predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted (corrected for hemoglobin levels), and treatment group as covariates.
    Comparison groups
    Placebo v Nerandomilast 9 mg BID
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.5583
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.67
    Notes
    [4] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.

    Secondary: Time to hospitalization for respiratory cause or death over the duration of the trial

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    End point title
    		 Time to hospitalization for respiratory cause or death over the duration of the trial
    End point description
    Time to hospitalization for respiratory cause or death over the duration of the trial is reported as the number of participants who experienced either event. Hospitalizations due to respiratory causes were recorded on a specific non-elective hospitalization CRF page. This page captured the hospitalization date, confirmation of a respiratory cause, and the primary admission diagnosis. If more than one component occurred on the same day, the patient was counted under the first event according to the hierarchy: hospitalization for respiratory cause, followed by death. Full Analysis Set (FAS): This patient set includes all randomized patients who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From first administration of any trial drug (Nerandomilast or Placebo) up to 22.9 months.
    End point values
    		 Placebo Nerandomilast 9 mg BID Nerandomilast 18 mg BID
    Number of subjects analysed
    393
    392
    392
    Units: Participants
        Hospitalization for respiratory cause
    59
    57
    68
        Death
    14
    11
    7
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using a Cox proportional hazards regression model that included baseline use of antifibrotic therapy (antifibrotic group vs non-antifibrotic group), age, baseline forced vital capacity (FVC) percentage predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted (corrected for hemoglobin levels), and treatment group as covariates.
    Comparison groups
    Placebo v Nerandomilast 9 mg BID
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.9038
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 1.36
    Notes
    [5] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis was performed using a Cox proportional hazards regression model that included baseline use of antifibrotic therapy (antifibrotic group vs non-antifibrotic group), age, baseline forced vital capacity (FVC) percentage predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted (corrected for hemoglobin levels), and treatment group as covariates.
    Comparison groups
    Placebo v Nerandomilast 18 mg BID
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.4687
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.56
    Notes
    [6] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.

    Secondary: Time to death over the duration of the trial

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    End point title
    		 Time to death over the duration of the trial
    End point description
    Time to death over the duration of the trial is reported as the number of participants who died. Time to death will be based either on the date of death on the AE report for patients with AEs leading to death or will be based on the information from the vital status assessment. Full Analysis Set (FAS): This patient set includes all randomized patients who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From first administration of any trial drug (Nerandomilast or Placebo) up to 22.9 months.
    End point values
    		 Placebo Nerandomilast 9 mg BID Nerandomilast 18 mg BID
    Number of subjects analysed
    393
    392
    392
    Units: Participants
    28
    26
    21
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis was performed using a Cox proportional hazards regression model that included baseline use of antifibrotic therapy (antifibrotic group vs non-antifibrotic group), age, baseline forced vital capacity (FVC) percentage predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted (corrected for hemoglobin levels), and treatment group as covariates.
    Comparison groups
    Placebo v Nerandomilast 18 mg BID
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.4682
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.43
    Notes
    [7] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using a Cox proportional hazards regression model that included baseline use of antifibrotic therapy (antifibrotic group vs non-antifibrotic group), age, baseline forced vital capacity (FVC) percentage predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted (corrected for hemoglobin levels), and treatment group as covariates.
    Comparison groups
    Placebo v Nerandomilast 9 mg BID
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.9084
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 1.76
    Notes
    [8] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.

    Secondary: Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms Cough domain score at Week 52

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    End point title
    		 Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms Cough domain score at Week 52
    End point description
    The absolute change from baseline in the L-PF Cough domain score at Week 52 is reported. This endpoint was analyzed using a Mixed Model for Repeated Measures (MMRM). The model included fixed effects for treatment, baseline antifibrotic therapy, and baseline L-PF Cough score at each visit, with an unstructured covariance matrix for repeated measures. The Living with Pulmonary Fibrosis (L-PF) questionnaire is a 44-item tool consisting of two modules: Symptoms (23 items) and Impacts (21 items). The Symptoms module yields three domain scores: Dyspnea, Cough, and Fatigue, as well as a Total Symptoms score. Scoring is based on the mean of item ratings within each domain, multiplied by 100. Scores range from 0 to 100, with higher scores indicating greater impairment. Full Analysis Set (FAS): This patient set includes all randomized patients who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    The MMRM model is a longitudinal analysis and it incorporated L-PF measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, Week 36, Week 44 and Week 52. The data represent the Least Squares Mean at Week 52.
    End point values
    		 Placebo Nerandomilast 9 mg BID Nerandomilast 18 mg BID
    Number of subjects analysed
    379
    373
    385
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    4.54 (2.49 to 6.59)
    4.44 (2.42 to 6.46)
    3.95 (1.93 to 5.97)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The analysis was based on a Mixed Model for Repeated Measures (MMRM), which included fixed categorical effects for treatment group at each visit, baseline use of antifibrotic therapy at each visit, and fixed continuous effects of the baseline Living with Pulmonary Fibrosis (L-PF) Cough domain score at each visit. An unstructured covariance structure modeled repeated measures. Baseline antifibrotic use, recorded in the concomitant medication case report form (CRF), was included as a covariate.
    Comparison groups
    Placebo v Nerandomilast 18 mg BID
    Number of subjects included in analysis
    764
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.6862
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.47
         upper limit
    		 2.28
    Notes
    [9] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The analysis was based on a Mixed Model for Repeated Measures (MMRM), which included fixed categorical effects for treatment group at each visit, baseline use of antifibrotic therapy at each visit, and fixed continuous effects of the baseline Living with Pulmonary Fibrosis (L-PF) Cough domain score at each visit. An unstructured covariance structure modeled repeated measures. Baseline antifibrotic use, recorded in the concomitant medication case report form (CRF), was included as a covariate.
    Comparison groups
    Placebo v Nerandomilast 9 mg BID
    Number of subjects included in analysis
    752
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.9442
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.98
         upper limit
    		 2.77
    Notes
    [10] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.

    Secondary: Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms Dyspnea domain score at Week 52

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    End point title
    		 Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms Dyspnea domain score at Week 52
    End point description
    The absolute change from baseline in the Living with Pulmonary Fibrosis (L-PF) Symptoms Dyspnea domain score at Week 52 is reported. This endpoint was analyzed using a Mixed Model for Repeated Measures (MMRM). The model included fixed effects for treatment, baseline use of antifibrotic therapy, and baseline dyspnea score at each visit, with an unstructured covariance structure to model repeated measures. The L-PF questionnaire is a 44-item tool consisting of two modules: Symptoms (23 items) and Impacts (21 items). The Symptoms module yields three domain scores: Dyspnea, Cough, and Fatigue, as well as a Total Symptoms score. Scoring is based on the mean of item ratings within each domain, multiplied by 100. Scores range from 0 to 100, with higher scores indicating greater impairment. Full Analysis Set (FAS): this set includes all randomized patients who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    The MMRM model is a longitudinal analysis and it incorporated L-PF measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, Week 36, Week 44 and Week 52. The data represent the Least Squares Mean at Week 52.
    End point values
    		 Placebo Nerandomilast 9 mg BID Nerandomilast 18 mg BID
    Number of subjects analysed
    380
    375
    385
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    7.26 (5.70 to 8.82)
    6.26 (4.71 to 7.80)
    6.63 (5.09 to 8.17)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The analysis used a Mixed Model for Repeated Measures (MMRM) with fixed categorical effects for treatment group and baseline antifibrotic therapy at each visit, and fixed continuous effects of baseline Living with Pulmonary Fibrosis (L-PF) Dyspnea domain score. An unstructured covariance structure accounted for within-patient correlations. Baseline antifibrotic use, as recorded in the concomitant medication case report form (CRF), was included as a covariate.
    Comparison groups
    Placebo v Nerandomilast 18 mg BID
    Number of subjects included in analysis
    765
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.5734
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.83
         upper limit
    		 1.57
    Notes
    [11] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The analysis used a Mixed Model for Repeated Measures (MMRM) with fixed categorical effects for treatment group and baseline antifibrotic therapy at each visit, and fixed continuous effects of baseline Living with Pulmonary Fibrosis (L-PF) Dyspnea domain score. An unstructured covariance structure accounted for within-patient correlations. Baseline antifibrotic use, as recorded in the concomitant medication case report form (CRF), was included as a covariate.
    Comparison groups
    Placebo v Nerandomilast 9 mg BID
    Number of subjects included in analysis
    755
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.3697
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 1.19
    Notes
    [12] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.

    Secondary: Absolute change from baseline in Forced Vital Capacity percent predicted at Week 52

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    End point title
    		 Absolute change from baseline in Forced Vital Capacity percent predicted at Week 52
    End point description
    The absolute change from baseline in Forced Vital Capacity percent predicted at Week 52 is reported. Analysis was based on a Mixed Model for Repeated Measures (MMRM), which included fixed, categorical effects of treatment at each visit, baseline use of antifibrotic therapy at each visit, and the fixed continuous effects of baseline forced vital capacity (FVC) percentage predicted at each visit. An unstructured covariance structure was used to model repeated measures within patients. Baseline use of antifibrotic therapy, as recorded in the concomitant medication case report form (CRF) page, was included as a covariate. Full Analysis Set (FAS): This patient set includes all randomized patients who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    The MMRM model is a longitudinal analysis, and it incorporated FVC measurements from baseline (Week -8 to Week -1) and Week 1, Week 2, Week 6, Week 12, Week 18, Week 26, Week 36, Week 44 and Week 52. The data represent the Least Squares Mean at Week 52.
    End point values
    		 Placebo Nerandomilast 9 mg BID Nerandomilast 18 mg BID
    Number of subjects analysed
    391
    390
    392
    Units: FVC percent predicted
        least squares mean (confidence interval 95%)
    -4.92 (-5.67 to -4.18)
    -3.75 (-4.48 to -3.01)
    -3.19 (-3.93 to -2.45)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis was based on a Mixed Model for Repeated Measures (MMRM), which included fixed, categorical effects of treatment, baseline use of antifibrotic therapy, and the fixed continuous effects of baseline forced vital capacity (FVC) percentage predicted at each visit. An unstructured covariance structure was used to model repeated measures within patients. Baseline use of antifibrotic therapy, as recorded in the concomitant medication case report form (CRF) page, was included as a covariate.
    Comparison groups
    Placebo v Nerandomilast 18 mg BID
    Number of subjects included in analysis
    783
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.0013
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 2.78
    Notes
    [13] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was based on a Mixed Model for Repeated Measures (MMRM), which included fixed, categorical effects of treatment, baseline use of antifibrotic therapy, and the fixed continuous effects of baseline forced vital capacity (FVC) percentage predicted at each visit. An unstructured covariance structure was used to model repeated measures within patients. Baseline use of antifibrotic therapy, as recorded in the concomitant medication case report form (CRF) page, was included as a covariate.
    Comparison groups
    Placebo v Nerandomilast 9 mg BID
    Number of subjects included in analysis
    781
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.028
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.13
         upper limit
    		 2.22
    Notes
    [14] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.

    Secondary: Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms Fatigue domain score at Week 52

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    End point title
    		 Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms Fatigue domain score at Week 52
    End point description
    The absolute change from baseline in the Living with Pulmonary Fibrosis (L-PF) Fatigue domain score at Week 52 is reported. The analysis used a mixed model for repeated measures (MMRM) with fixed categorical effects for treatment and baseline antifibrotic (AF) therapy, and the fixed continuous effect of baseline L-PF score; covariance was unstructured. Baseline AF therapy was a covariate. The L-PF questionnaire (44 items) consists of two modules: Symptoms (23 items) and Impacts (21 items). The Symptoms module yields three domain scores (Dyspnea, Cough, Fatigue) and a Total Symptoms score. Scoring is based on the mean of item ratings within each domain, multiplied by 100. Scores range from 0 to 100, with higher scores indicating greater impairment. The Full Analysis Set (FAS) includes all randomized patients who received at least one dose of study drug, with baseline measurement and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    The MMRM model is a longitudinal analysis and it incorporated L-PF measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, Week 36, Week 44 and Week 52. The data represent the Least Squares Mean at Week 52.
    End point values
    		 Placebo Nerandomilast 9 mg BID Nerandomilast 18 mg BID
    Number of subjects analysed
    380
    375
    386
    Units: Score on a scale
        least squares mean (confidence interval 95%)
    5.40 (3.66 to 7.14)
    5.59 (3.88 to 7.30)
    5.82 (4.11 to 7.54)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    The analysis was based on a Mixed Model for Repeated Measures (MMRM), which included fixed categorical effects for treatment group at each visit, baseline use of antifibrotic therapy at each visit, and fixed continuous effects of the baseline Living with Pulmonary Fibrosis (L-PF) Fatigue domain score at each visit. An unstructured covariance structure modeled repeated measures. Baseline antifibrotic use, recorded in the concomitant medication case report form (CRF), was included as a covariate.
    Comparison groups
    Placebo v Nerandomilast 18 mg BID
    Number of subjects included in analysis
    766
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.732
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.02
         upper limit
    		 2.87
    Notes
    [15] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The analysis was based on a Mixed Model for Repeated Measures (MMRM), which included fixed categorical effects for treatment group at each visit, baseline use of antifibrotic therapy at each visit, and fixed continuous effects of the baseline Living with Pulmonary Fibrosis (L-PF) Fatigue domain score at each visit. An unstructured covariance structure modeled repeated measures. Baseline antifibrotic use, recorded in the concomitant medication case report form (CRF), was included as a covariate.
    Comparison groups
    Placebo v Nerandomilast 9 mg BID
    Number of subjects included in analysis
    755
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 = 0.8759
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.25
         upper limit
    		 2.63
    Notes
    [16] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.

    Secondary: Key Secondary Endpoint: Time to the first occurrence of any of the components of the composite endpoint: time to first acute IPF exacerbation, first hospitalization for respiratory cause, or death (whichever occurs first) over the duration of the trial

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    End point title
    		 Key Secondary Endpoint: Time to the first occurrence of any of the components of the composite endpoint: time to first acute IPF exacerbation, first hospitalization for respiratory cause, or death (whichever occurs first) over the duration of the trial
    End point description
    Time to first occurrence of any component of the composite endpoint—acute IPF exacerbation, hospitalization for a respiratory cause, or death (whichever occurred first)—is reported as the number of participants experiencing one or more events. Acute IPF is defined as an acute, clinically significant respiratory deterioration with: (1) dyspnea <1 month; (2) CT showing new bilateral ground-glass opacity and/or consolidation on IPF background; (3) deterioration not fully explained by cardiac failure or fluid overload. If >1 component occurred on the same day, the first event was counted in the hierarchy: acute IPF exacerbation, hospitalization, death. The Full Analysis Set (FAS) includes all randomized patients who received ≥1 dose of study drug
    End point type
    Secondary
    End point timeframe
    From first administration of any trial drug (Nerandomilast or Placebo) up to 22.9 months.
    End point values
    		 Placebo Nerandomilast 9 mg BID Nerandomilast 18 mg BID
    Number of subjects analysed
    393
    392
    392
    Units: Participants
        Acute IPF exacerbation as the first event
    38
    32
    38
        Hospitalisation for respiratory cause as 1st event
    49
    45
    47
        Death as the first event
    16
    13
    8
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Based on Cox proportional hazards model including treatment, baseline antifibrotic therapy, age, baseline Forced Vital Capacity (FVC) percent predicted, and baseline Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) percent predicted (corrected for haemoglobin) as covariates. p-values not adjusted for multiplicity.
    Comparison groups
    Placebo v Nerandomilast 18 mg BID
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.9512
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.75
         upper limit
    		 1.31
    Notes
    [17] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The hazard ratio (HR) was estimated using a Cox proportional hazards model with treatment group, baseline antifibrotic therapy use, age (continuous), baseline FVC % predicted, and baseline DLCO % predicted (hemoglobin-corrected) as covariates. Breslow’s method was applied for tied event times. A two-sided p-value from the Wald test assessed the treatment effect. P-values were not adjusted for multiplicity.
    Comparison groups
    Placebo v Nerandomilast 9 mg BID
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.5443
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.22
    Notes
    [18] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.

    Secondary: Absolute change from baseline in Diffusing Capacity of the Lungs for Carbon Monoxide percent predicted at Week 52

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    End point title
    		 Absolute change from baseline in Diffusing Capacity of the Lungs for Carbon Monoxide percent predicted at Week 52
    End point description
    The absolute change from baseline in Diffusing Capacity of the Lungs for Carbon Monoxide percent predicted at Week 52 is reported. The analysis was based on a Mixed Model for Repeated Measures (MMRM), which included fixed, categorical effects of treatment at each visit, baseline use of antifibrotic therapy at each visit, and the fixed continuous effects of baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted at each visit. An unstructured covariance structure was used to model repeated measures within patients. Baseline use of antifibrotic therapy, as recorded in the concomitant medication case report form (CRF) page, was included as a covariate. Full Analysis Set (FAS): This patient set includes all randomized patients who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    The MMRM model is a longitudinal analysis and it incorporated DLCO measurements from baseline (Week -8 to Week -1) and Week 12, Week 26, and Week 52. The data represent the Least Squares Mean at Week 52.
    End point values
    		 Placebo Nerandomilast 9 mg BID Nerandomilast 18 mg BID
    Number of subjects analysed
    380
    378
    384
    Units: DLCO percent predicted
        least squares mean (confidence interval 95%)
    -6.14 (-7.35 to -4.94)
    -3.66 (-4.85 to -2.46)
    -4.47 (-5.66 to -3.27)
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Based on a Mixed Model for Repeated Measures (MMRM), which included fixed, categorical effects of treatment, baseline use of antifibrotic therapy, and the fixed continuous effects of baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted at each visit. An unstructured covariance structure was used to model repeated measures within patients. Baseline use of antifibrotic therapy, as recorded in the concomitant medication CRF page, was included as a covariate.
    Comparison groups
    Placebo v Nerandomilast 18 mg BID
    Number of subjects included in analysis
    764
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.053
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.02
         upper limit
    		 3.37
    Notes
    [19] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Based on a Mixed Model for Repeated Measures (MMRM), which included fixed, categorical effects of treatment, baseline use of antifibrotic therapy, and the fixed continuous effects of baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted at each visit. An unstructured covariance structure was used to model repeated measures within patients. Baseline use of antifibrotic therapy, as recorded in the concomitant medication CRF page, was included as a covariate.
    Comparison groups
    Placebo v Nerandomilast 9 mg BID
    Number of subjects included in analysis
    758
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.0042
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 4.19
    Notes
    [20] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.

    Secondary: Time to absolute decline in Forced Vital Capacity (FVC) % predicted of >10% from baseline or death over the duration of the trial

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    End point title
    		 Time to absolute decline in Forced Vital Capacity (FVC) % predicted of >10% from baseline or death over the duration of the trial
    End point description
    The time to absolute decline of more than 10% from baseline in forced vital capacity (FVC) percent predicted, or death, over the duration of the trial is reported as the number of participants who experienced either event. If more than one component occurred on the same day, the patient was counted under the first event according to the hierarchy; Absolute decline in FVC % predicted of > 10% followed by death. Full Analysis Set (FAS): This patient set includes all randomized patients who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From first administration of any trial drug (Nerandomilast or Placebo) up to 22.9 months.
    End point values
    		 Placebo Nerandomilast 9 mg BID Nerandomilast 18 mg BID
    Number of subjects analysed
    393
    392
    392
    Units: Participants
        Absolute decline in FVC % predicted of > 10%
    91
    89
    80
        Death
    20
    18
    14
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis was performed using a Cox proportional hazards regression model that included baseline use of antifibrotic therapy (antifibrotic group vs non-antifibrotic group), age, baseline forced vital capacity (FVC) percentage predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted (corrected for hemoglobin levels), and treatment group as covariates.
    Comparison groups
    Placebo v Nerandomilast 18 mg BID
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.2068
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 1.1
    Notes
    [21] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using a Cox proportional hazards regression model that included baseline use of antifibrotic therapy (antifibrotic group vs non-antifibrotic group), age, baseline forced vital capacity (FVC) percentage predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted (corrected for hemoglobin levels), and treatment group as covariates.
    Comparison groups
    Placebo v Nerandomilast 9 mg BID
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 = 0.7695
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.25
    Notes
    [22] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.

    Secondary: Time to absolute decline in diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted by more than 15% from baseline or death, measured over the duration of the trial

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    End point title
    		 Time to absolute decline in diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted by more than 15% from baseline or death, measured over the duration of the trial
    End point description
    The time to absolute decline of more than 15% from baseline in diffusing capacity of the lungs for carbon monoxide (DLCO) percent predicted, or death, over the duration of the trial is reported as the number of participants who experienced either event. Predicted DLCO value was corrected for hemoglobin (Hb). If more than one component occurred on the same day, the patient was counted under the first event according to the hierarchy: Absolute decline in DLCO % predicted of > 15%, followed by Death. Full Analysis Set (FAS): This patient set includes all randomized patients who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    From first administration of any trial drug (Nerandomilast or Placebo) up to 22.9 months.
    End point values
    		 Placebo Nerandomilast 9 mg BID Nerandomilast 18 mg BID
    Number of subjects analysed
    393
    392
    392
    Units: Participants
        Absolute decline in DLCO % predicted of > 15%
    38
    35
    43
        Death
    28
    24
    16
    Statistical analysis title
    		 Statistical Analysis 2
    Statistical analysis description
    Analysis was performed using a Cox proportional hazards regression model that included baseline use of antifibrotic therapy (antifibrotic group vs non-antifibrotic group), age, baseline forced vital capacity (FVC) percentage predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted (corrected for hemoglobin levels), and treatment group as covariates.
    Comparison groups
    Placebo v Nerandomilast 18 mg BID
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.4988
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.26
    Notes
    [23] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Analysis was performed using a Cox proportional hazards regression model that included baseline use of antifibrotic therapy (antifibrotic group vs non-antifibrotic group), age, baseline forced vital capacity (FVC) percentage predicted, baseline diffusing capacity of the lungs for carbon monoxide (DLCO) percentage predicted (corrected for hemoglobin levels), and treatment group as covariates.
    Comparison groups
    Placebo v Nerandomilast 9 mg BID
    Number of subjects included in analysis
    785
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.9251
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.41
    Notes
    [24] - The Kenward-Roger method estimated denominator degrees of freedom and adjusted standard errors; tests used two-sided α per multiple testing strategy.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE collection and All-cause mortality From first trial drug administration (Placebo or Nerandomilast) up to 22.9 months.
    Adverse event reporting additional description
    Treated Set (TS): This patient set includes all randomized patients who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matching 9 mg or 18 mg Nerandomilast film coated tablet orally twice daily, with doses given at least 12 hours apart and each taken with 250 mL of water.

    Reporting group title
    Nerandomilast 9 mg BID
    Reporting group description
    		 Participants received 9 mg film-coated Nerandomilast tablets orally twice daily, with doses administered at least 12 hours apart, each taken with 250 mL of water.

    Reporting group title
    Nera 18 mg BID
    Reporting group description
    		 Participants received 18 mg film-coated Nerandomilast tablets orally twice daily, with doses administered at least 12 hours apart, each taken with 250 mL of water.

    Serious adverse events
    		 Placebo Nerandomilast 9 mg BID Nera 18 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    181 / 393 (46.06%)
    159 / 392 (40.56%)
    165 / 392 (42.09%)
         number of deaths (all causes)
    42
    36
    26
         number of deaths resulting from adverse events
    42
    36
    25
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 393 (0.25%)
    5 / 392 (1.28%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Atypical fibroxanthoma
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute leukaemia
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Colon cancer
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer stage 0, with cancer in situ
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder papilloma
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bowen's disease
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ductal adenocarcinoma of pancreas
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Extranodal marginal zone B-cell lymphoma (MALT type)
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hodgkin's disease
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Laryngeal neoplasm
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lip squamous cell carcinoma
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Lung neoplasm malignant
         subjects affected / exposed
    3 / 393 (0.76%)
    4 / 392 (1.02%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neuroendocrine carcinoma of the skin
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal neoplasm
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 393 (0.51%)
    3 / 392 (0.77%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Queyrat erythroplasia
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Sarcomatoid carcinoma
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin cancer
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    3 / 393 (0.76%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of lung
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    4 / 393 (1.02%)
    4 / 392 (1.02%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sweat gland tumour
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic dilatation
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aneurysm
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Vasculitis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Microscopic polyangiitis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iliac artery stenosis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Granulomatosis with polyangiitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Assisted suicide
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 392 (0.00%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    5 / 393 (1.27%)
    4 / 392 (1.02%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 5
    0 / 4
    0 / 2
    Condition aggravated
         subjects affected / exposed
    34 / 393 (8.65%)
    28 / 392 (7.14%)
    32 / 392 (8.16%)
         occurrences causally related to treatment / all
    3 / 49
    2 / 35
    1 / 43
         deaths causally related to treatment / all
    0 / 13
    1 / 6
    0 / 6
    Illness
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Asthenia
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 393 (0.51%)
    3 / 392 (0.77%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular stent stenosis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic shock
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Genital prolapse
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatomegaly
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypersensitivity pneumonitis
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Hepatopulmonary syndrome
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    7 / 393 (1.78%)
    7 / 392 (1.79%)
    6 / 392 (1.53%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 7
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    3 / 393 (0.76%)
    4 / 392 (1.02%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 392 (0.26%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    7 / 393 (1.78%)
    5 / 392 (1.28%)
    5 / 392 (1.28%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    12 / 393 (3.05%)
    13 / 392 (3.32%)
    11 / 392 (2.81%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 20
    0 / 16
         deaths causally related to treatment / all
    0 / 1
    0 / 4
    0 / 3
    Interstitial lung disease
         subjects affected / exposed
    2 / 393 (0.51%)
    2 / 392 (0.51%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    Painful respiration
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 393 (0.51%)
    4 / 392 (1.02%)
    8 / 392 (2.04%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    3 / 393 (0.76%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary artery dilatation
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pulmonary hypertension
         subjects affected / exposed
    12 / 393 (3.05%)
    9 / 392 (2.30%)
    12 / 392 (3.06%)
         occurrences causally related to treatment / all
    1 / 12
    0 / 9
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vocal cord leukoplakia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    9 / 393 (2.29%)
    4 / 392 (1.02%)
    4 / 392 (1.02%)
         occurrences causally related to treatment / all
    2 / 9
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    Respiratory distress
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary venous hypertension
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depressive symptom
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alcohol abuse
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hallucinations, mixed
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tobacco abuse
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    2 / 393 (0.51%)
    3 / 392 (0.77%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 4
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Amylase increased
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza A virus test positive
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heart rate irregular
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    False positive investigation result
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium test positive
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interferon gamma release assay positive
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Coronary artery restenosis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Compression fracture
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venomous bite
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pneumothorax
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Retinopathy congenital
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertrophic cardiomyopathy
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 393 (0.51%)
    3 / 392 (0.77%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Acute right ventricular failure
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bundle branch block right
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 393 (0.51%)
    3 / 392 (0.77%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    0 / 1
    Cardiac failure
         subjects affected / exposed
    3 / 393 (0.76%)
    1 / 392 (0.26%)
    5 / 392 (1.28%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 393 (0.25%)
    2 / 392 (0.51%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery dissection
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 392 (0.26%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cor pulmonale chronic
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac valve disease
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 392 (0.51%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    Heart failure with reduced ejection fraction
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Heart failure with preserved ejection fraction
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Ventricular hypertrophy
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    3 / 393 (0.76%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery dissection
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central nervous system haemorrhage
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental impairment
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Monoplegia
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 393 (0.25%)
    2 / 392 (0.51%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 392 (0.26%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Middle cerebral artery stroke
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Focal dyscognitive seizures
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 393 (0.51%)
    2 / 392 (0.51%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    3 / 393 (0.76%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural hygroma
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal claudication
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelopathy
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Acquired factor VIII deficiency
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood loss anaemia
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presbyacusis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Amaurosis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 392 (0.00%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal tear
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal infarction
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotony of eye
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glaucoma
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dry age-related macular degeneration
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retinal vein occlusion
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal mass
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tongue ulceration
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oronasal fistula
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal rupture
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    3 / 393 (0.76%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 393 (0.00%)
    2 / 392 (0.51%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary obstruction
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary dilatation
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suspected drug-induced liver injury
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urethral stenosis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephritis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    3 / 393 (0.76%)
    5 / 392 (1.28%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism primary
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chondropathy
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 393 (0.25%)
    2 / 392 (0.51%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal stenosis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Systemic scleroderma
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polymyositis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    1 / 393 (0.25%)
    2 / 392 (0.51%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Aspergillus infection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendiceal abscess
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical mycobacterial infection
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 392 (0.26%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    2 / 393 (0.51%)
    4 / 392 (1.02%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleurisy bacterial
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Norovirus infection
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Latent tuberculosis
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    3 / 393 (0.76%)
    3 / 392 (0.77%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HCoV-OC43 infection
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal bacterial infection
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia pseudomonal
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 393 (0.51%)
    1 / 392 (0.26%)
    4 / 392 (1.02%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    22 / 393 (5.60%)
    18 / 392 (4.59%)
    17 / 392 (4.34%)
         occurrences causally related to treatment / all
    4 / 26
    0 / 19
    0 / 18
         deaths causally related to treatment / all
    1 / 2
    0 / 4
    0 / 2
    Pneumonia aspiration
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 393 (0.25%)
    6 / 392 (1.53%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 7
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 393 (0.76%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    3 / 392 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 393 (0.25%)
    2 / 392 (0.51%)
    2 / 392 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Sinusitis
         subjects affected / exposed
    0 / 393 (0.00%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 393 (0.25%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    0 / 393 (0.00%)
    1 / 392 (0.26%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    1 / 392 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 393 (0.51%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 393 (0.25%)
    0 / 392 (0.00%)
    0 / 392 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Nerandomilast 9 mg BID Nera 18 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    316 / 393 (80.41%)
    319 / 392 (81.38%)
    337 / 392 (85.97%)
    Investigations
    Weight decreased
         subjects affected / exposed
    39 / 393 (9.92%)
    45 / 392 (11.48%)
    54 / 392 (13.78%)
         occurrences all number
    42
    59
    68
    Nervous system disorders
    Headache
         subjects affected / exposed
    23 / 393 (5.85%)
    27 / 392 (6.89%)
    28 / 392 (7.14%)
         occurrences all number
    26
    33
    37
    Dizziness
         subjects affected / exposed
    21 / 393 (5.34%)
    28 / 392 (7.14%)
    19 / 392 (4.85%)
         occurrences all number
    27
    29
    22
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    23 / 393 (5.85%)
    35 / 392 (8.93%)
    30 / 392 (7.65%)
         occurrences all number
    28
    39
    31
    Condition aggravated
         subjects affected / exposed
    27 / 393 (6.87%)
    19 / 392 (4.85%)
    27 / 392 (6.89%)
         occurrences all number
    30
    21
    38
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    75 / 393 (19.08%)
    130 / 392 (33.16%)
    166 / 392 (42.35%)
         occurrences all number
    110
    189
    250
    Vomiting
         subjects affected / exposed
    19 / 393 (4.83%)
    19 / 392 (4.85%)
    21 / 392 (5.36%)
         occurrences all number
    33
    22
    42
    Nausea
         subjects affected / exposed
    28 / 393 (7.12%)
    39 / 392 (9.95%)
    33 / 392 (8.42%)
         occurrences all number
    39
    44
    41
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    79 / 393 (20.10%)
    74 / 392 (18.88%)
    73 / 392 (18.62%)
         occurrences all number
    91
    84
    84
    Dyspnoea
         subjects affected / exposed
    58 / 393 (14.76%)
    50 / 392 (12.76%)
    44 / 392 (11.22%)
         occurrences all number
    66
    53
    54
    Psychiatric disorders
    Depression
         subjects affected / exposed
    38 / 393 (9.67%)
    42 / 392 (10.71%)
    42 / 392 (10.71%)
         occurrences all number
    45
    49
    47
    Anxiety
         subjects affected / exposed
    40 / 393 (10.18%)
    35 / 392 (8.93%)
    44 / 392 (11.22%)
         occurrences all number
    49
    44
    48
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    17 / 393 (4.33%)
    25 / 392 (6.38%)
    31 / 392 (7.91%)
         occurrences all number
    19
    33
    33
    Arthralgia
         subjects affected / exposed
    26 / 393 (6.62%)
    23 / 392 (5.87%)
    16 / 392 (4.08%)
         occurrences all number
    29
    25
    22
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    12 / 393 (3.05%)
    15 / 392 (3.83%)
    23 / 392 (5.87%)
         occurrences all number
    25
    18
    35
    Pneumonia
         subjects affected / exposed
    17 / 393 (4.33%)
    21 / 392 (5.36%)
    18 / 392 (4.59%)
         occurrences all number
    21
    27
    21
    Nasopharyngitis
         subjects affected / exposed
    53 / 393 (13.49%)
    46 / 392 (11.73%)
    49 / 392 (12.50%)
         occurrences all number
    69
    58
    59
    COVID-19
         subjects affected / exposed
    61 / 393 (15.52%)
    74 / 392 (18.88%)
    59 / 392 (15.05%)
         occurrences all number
    61
    77
    60
    Bronchitis
         subjects affected / exposed
    37 / 393 (9.41%)
    35 / 392 (8.93%)
    37 / 392 (9.44%)
         occurrences all number
    46
    46
    45
    Upper respiratory tract infection
         subjects affected / exposed
    47 / 393 (11.96%)
    49 / 392 (12.50%)
    56 / 392 (14.29%)
         occurrences all number
    62
    57
    72
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    28 / 393 (7.12%)
    39 / 392 (9.95%)
    41 / 392 (10.46%)
         occurrences all number
    30
    41
    48

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 May 2023
    In this revision of the CTP, major changes were made to address several aspects. Eligibility criteria were updated to include patients with an “alternative diagnosis” HRCT finding, and the upper DLCO limit was removed as it was not a relevant exclusion criterion. Inclusion criterion IC7 was revised to allow oral contraceptives as a highly effective method of contraception in WOCBP when combined with a barrier method, based on a drug-drug interaction trial with midazolam. A FEV/FVC ratio <0.7 was to be avoided due to the high risk of emphysema and obstruction impacting efficacy endpoints. Exclusion criterion EC10 was clarified to specify that Child Pugh refers only to liver cirrhosis, not chronic liver disease. EC23 was revised to indicate that nerandomilast was not expected to negatively affect latent TB, based on preclinical data, and TB diagnosis was simplified. A new exclusion criterion, EC27, was added for patients with a history of stem cell therapy for pulmonary fibrosis due to unknown long-term effects; such therapy was also not permitted as concomitant treatment. Guidance on managing patients and data if the 9 mg bid dose was deemed futile was clarified, considering blinding, randomisation, and interim analysis details. Restrictions on prior prednisone use were relaxed to permit historical use and use during exacerbations. Patients were to be analysed as randomised for efficacy and as treated for safety, with the PPS removed in favour of estimands per ICH E9 addendum; the FAS became the primary efficacy analysis population and the TS the primary safety population. Lastly, for time-to-event endpoints, the start date was changed from the randomisation date to the first drug intake date to accurately reflect the actual time at risk.
    20 Sep 2023
    In this revision of the CTP, major updates were introduced. The efficacy interim analysis was removed, and only the main and final analyses were specified. This decision, made by the sponsor before the futility analysis, was based on Health Authority feedback and rapid recruitment, which reduced the time benefit of conducting an interim analysis. The overall trial design section was updated accordingly to reflect these analyses. Sponsor unblinding at the main analysis (DBL1) was clarified, along with the use of unblinded PK data before DBL1 by personnel involved in PK analyses to support early preparation. It was also clarified that hypothesis testing of the key secondary endpoint would occur at the main analysis, and a high-level overview of endpoints to be assessed at both the main and final analyses was provided. Regarding concomitant treatments, restrictions on PDE inhibitors were narrowed to those specifically interfering with PDE4. Additionally, AE reporting procedures based on HADS were clarified.

    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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