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    Clinical Trial Results:
    Multicenter, randomized, placebo controlled, double-blind, parallel group, dose-finding Phase 2 study to evaluate the efficacy and safety of BAY 2433334 in patients following an acute myocardial infarction

    Summary
    EudraCT number
    		 2019-003244-79
    Trial protocol
    		 CZ   BE   HU   NL   DE   AT   ES   SE   PL   GB   IT  
    Global end of trial date
    21 Feb 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Mar 2023
    First version publication date
    07 Mar 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BAY2433334/20603
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04304534
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    ​Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    11 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate whether the oral activated Factor XI (FXIa) inhibitor asundexian compared to placebo leads to a lower incidence of Cardiovascular (CV) death, Myocardial infarction (MI), stroke and stent thrombosis in participants with an acute myocardial infarction and who are treated with dual antiplatelet therapy
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 Asundexian or placebo was administered on top of standard of care treatment for post-MI patients, consisting of DAPT. The choice of P2Y12 inhibitor therapy (ticagrelor, clopidogrel or prasugrel) and duration of treatment with DAPT after hospital discharge for the index AMI, was left to the discretion of the treating physician and had to follow local standard of care guidelines. The use of the antiplatelet background therapy (ASA and P2Y12 inhibitors) was documented on the eCRF
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jun 2020
    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
    Czechia: 103
    Country: Number of subjects enrolled
    Hungary: 218
    Country: Number of subjects enrolled
    Poland: 122
    Country: Number of subjects enrolled
    Austria: 82
    Country: Number of subjects enrolled
    Belgium: 70
    Country: Number of subjects enrolled
    Germany: 73
    Country: Number of subjects enrolled
    Spain: 206
    Country: Number of subjects enrolled
    United Kingdom: 33
    Country: Number of subjects enrolled
    Italy: 139
    Country: Number of subjects enrolled
    Netherlands: 212
    Country: Number of subjects enrolled
    Sweden: 42
    Country: Number of subjects enrolled
    Japan: 194
    Country: Number of subjects enrolled
    United States: 59
    Country: Number of subjects enrolled
    Switzerland: 48
    Worldwide total number of subjects
    1601
    EEA total number of subjects
    1267
    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)
    499
    From 65 to 84 years
    1089
    85 years and over
    13

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 157 centers in 14 countries or regions, between 17-Jun-2020 (first subject first visit) and 21-Feb-2022 (last subject last visit)

    Pre-assignment
    Screening details
    		 1664 subjects were screened, 63 subjects were screening failures. 1601 subjects were randomized in a 1:1:1:1 ratio to 4 treatment groups: 397, 401, and 402 subjects to the asundexian 10 mg, 20 mg and 50 mg groups and 401 participants to the placebo group.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Asundexian 10 mg
    Arm description
    		 Subjects received Asundexian (BAY2433334) 10 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Asundexian
    Investigational medicinal product code
    BAY2433334
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Asundexian (BAY2433334) 10 mg (5 mg tablets) orally once daily in the morning

    Arm title
    		 Asundexian 20 mg
    Arm description
    		 Subjects received Asundexian (BAY2433334) 20 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Asundexian
    Investigational medicinal product code
    BAY2433334
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Asundexian (BAY2433334) 20 mg (5 mg and 15 mg tablets) orally once daily in the morning

    Arm title
    		 Asundexian 50 mg
    Arm description
    		 Subjects received Asundexian (BAY2433334) 50 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Asundexian
    Investigational medicinal product code
    BAY2433334
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Asundexian (BAY2433334) 50 mg (25 mg tablets) orally once daily in the morning

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo orally once daily in the morning.

    Number of subjects in period 1
    		Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo
    Started
    397
    401
    402
    401
    Treated
    395
    397
    402
    399
    Completed
    303
    317
    309
    309
    Not completed
    94
    84
    93
    92
         Consent withdrawn by subject
    7
    2
    7
    4
         Physician decision
    4
    9
    9
    5
         Subject Decision
    34
    25
    25
    26
         Adverse event, non-fatal
    35
    40
    39
    44
         Other
    4
    2
    2
    2
         Death
    7
    2
    4
    3
         Technical Problems
    2
    2
    3
    4
         Subject decision COVID-19 pandemic related
    1
    -
    1
    -
         Non-Compliance with study drug
    -
    1
    1
    1
         Lost to follow-up
    -
    1
    2
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Asundexian 10 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 10 mg

    Reporting group title
    Asundexian 20 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 20 mg

    Reporting group title
    Asundexian 50 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 50 mg

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo

    Reporting group values
    		 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo Total
    Number of subjects
    		 397 401 402 401 1601
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 122 123 118 136 499
        From 65-84 years
    		 275 275 280 259 1089
        85 years and over
    		 0 3 4 6 13
    Gender Categorical
    Units: Subjects
        Female
    		 93 87 100 90 370
        Male
    		 304 314 302 311 1231
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 2 0 0 3
        Asian
    		 53 50 50 50 203
        Black or African American
    		 3 2 2 1 8
        Multiple
    		 1 0 2 2 5
        Not Reported
    		 5 2 1 9 17
        White
    		 334 345 347 339 1365

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Asundexian 10 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 10 mg

    Reporting group title
    Asundexian 20 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 20 mg

    Reporting group title
    Asundexian 50 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 50 mg

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A subject was included in the FAS if he/she was randomized to study intervention.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    A subject was included in the SAF if he/she was randomized to study intervention and had taken at least one dose of the study intervention.

    Subject analysis set title
    Asundexian 20+50 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Asundexian 20 mg group and Asundexian 50 mg group

    Subject analysis set title
    Pooled Asundexian
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Asundexian 10 mg group and Asundexian 20 mg group and Asundexian 50 mg group

    Primary: Efficacy - Number of subjects with composite of CV death, MI, stroke and stent thrombosis (ST)

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    End point title
    		 Efficacy - Number of subjects with composite of CV death, MI, stroke and stent thrombosis (ST)
    End point description
    CV death included death due to stroke, MI, heart failure or cardiogenic shock, sudden death or any other death due to other cardiovascular causes. Death due to non-traumatic hemorrhage was included. Acute MI was used when there was evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Stroke was defined as an acute episode of focal or global neurological dysfunction caused by an injury of the brain, spinal cord, or retina as a result of hemorrhage or infarction. ST was defined incorporating diagnostic certainty as well as timing: “Definite” ST: The highest level of certainty. Either angiographic or pathological confirmation of stent thrombosis. “Probable” ST: Regardless of the time after the index procedure, any MI that is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause
    End point type
    Primary
    End point timeframe
    From baseline up to 52 weeks
    End point values
    		 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo Asundexian 20+50 mg
    Number of subjects analysed
    397
    401
    402
    401
    803
    Units: Subjects
    27
    24
    22
    22
    46
    Statistical analysis title
    		 Hazard ratio (HR)
    Statistical analysis description
    Comparison of the Asundexian Asundexian 20+50 mg group versus Placebo group
    Comparison groups
    Placebo v Asundexian 20+50 mg
    Number of subjects included in analysis
    1204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.8439
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.052
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.687
         upper limit
    		 1.612
    Notes
    [1] - HRs were only calculated if at least three events occurred in one of the compared groups and at least one event in each of the compared treatment groups. The competing event was non-CV death for events that include CV death.
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison of the Asundexian 50 mg group versus Placebo group
    Comparison groups
    Placebo v Asundexian 50 mg
    Number of subjects included in analysis
    803
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.978
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.008
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.614
         upper limit
    		 1.656
    Notes
    [2] - HRs were only calculated if at least three events occurred in one of the compared groups and at least one event in each of the compared treatment groups. The competing event was non-CV death for events that include CV death.
    Statistical analysis title
    		 Hazard ratio (HR)
    Statistical analysis description
    Comparison of the Asundexian 20 mg group versus Placebo group
    Comparison groups
    Placebo v Asundexian 20 mg
    Number of subjects included in analysis
    802
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.7562
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.096
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.674
         upper limit
    		 1.781
    Notes
    [3] - HRs were only calculated if at least three events occurred in one of the compared groups and at least one event in each of the compared treatment groups. The competing event was non-CV death for events that include CV death.

    Primary: Safety - Number of subjects with BARC bleeding definition type 2, 3 and 5

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    End point title
    		 Safety - Number of subjects with BARC bleeding definition type 2, 3 and 5
    End point description
    Type 2: any overt, actionable sign of hemorrhage that doesn’t fit the criteria for type 3 or 5 but meets at least one of the following criteria: 1) requires nonsurgical, med intervention by a HCP, 2) leads to hospital or rise in level of care, or 3) prompt eval. Type 3a: 1) overt bleed + Hg drop of 3 to <5 g/dl (provided Hg drop is related to bleed); 2 any transfusion with overt bleed. Type 3b: 1) overt bleed + Hg drop ≥5 g/dL (provided Hg drop is related to bleed); 2) cardiac tamponade; 3) bleed requiring surgical intervention for control (exclude dental/nasal /skin/hemorrhoid); 4) bleed requiring IV vasoactive agents. Type 3c: 1) ICH hemorrhage (doesn’t include microbleeds or HT, does include intraspinal); subcategories confirmed by autopsy or imaging or LP; 2) intraocular bleed compromising vision. Type 5: fatal bleed. Type 5a: probable fatal bleed; no autopsy or image confirmation but clinical suspicion. Type 5b: definite fatal bleed; overt bleed or autopsy or image confirmation.
    End point type
    Primary
    End point timeframe
    From baseline up to 52 weeks
    End point values
    		 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo Pooled Asundexian
    Number of subjects analysed
    395
    397
    402
    399
    1194
    Units: Subjects
    30
    32
    42
    36
    104
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison of the Pooled Asundexian group versus Placebo group
    Comparison groups
    Placebo v Pooled Asundexian
    Number of subjects included in analysis
    1593
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.9158
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.98
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.713
         upper limit
    		 1.347
    Notes
    [4] - HR was only calculated if at least three events occurred in one of the compared groups and at least one event in each of the compared treatment groups.
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison of the Asundexian 50 mg group versus Placebo group
    Comparison groups
    Placebo v Asundexian 50 mg
    Number of subjects included in analysis
    801
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.417
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.202
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.828
         upper limit
    		 1.747
    Notes
    [5] - HR was only calculated if at least three events occurred in one of the compared groups and at least one event in each of the compared treatment groups.
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison of the Asundexian 20 mg group versus Placebo group
    Comparison groups
    Placebo v Asundexian 20 mg
    Number of subjects included in analysis
    796
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.584
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.875
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.587
         upper limit
    		 1.306
    Notes
    [6] - HR was only calculated if at least three events occurred in one of the compared groups and at least one event in each of the compared treatment groups.
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison of the Asundexian 10 mg group versus Placebo group
    Comparison groups
    Placebo v Asundexian 10 mg
    Number of subjects included in analysis
    794
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.5633
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.867
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.577
         upper limit
    		 1.302
    Notes
    [7] - HR was only calculated if at least three events occurred in one of the compared groups and at least one event in each of the compared treatment groups.

    Secondary: Efficacy - Number of subjects with CV death

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    End point title
    		 Efficacy - Number of subjects with CV death
    End point description
    CV death included death due to stroke, MI, heart failure or cardiogenic shock, sudden death or any other death due to other cardiovascular causes. Death due to non-traumatic hemorrhage was included.
    End point type
    Secondary
    End point timeframe
    From baseline up to 52 weeks
    End point values
    		 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo Asundexian 20+50 mg
    Number of subjects analysed
    397
    401
    402
    401
    803
    Units: Subjects
    7
    4
    5
    2
    9
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison of the Asundexian 20+50 mg group versus Placebo group
    Comparison groups
    Placebo v Asundexian 20+50 mg
    Number of subjects included in analysis
    1204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.275
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.322
         upper limit
    		 5.05
    Notes
    [8] - HRs were only calculated if at least three events occurred in one of the compared groups and at least one event in each of the compared treatment groups. The competing event was non-CV death for events that include CV death.
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison of the Asundexian 50 mg group versus Placebo group
    Comparison groups
    Asundexian 50 mg v Placebo
    Number of subjects included in analysis
    803
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.991
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.479
         upper limit
    		 8.273
    Notes
    [9] - HRs were only calculated if at least three events occurred in one of the compared groups and at least one event in each of the compared treatment groups. The competing event was non-CV death for events that include CV death.

    Secondary: Efficacy - Number of subjects with MI

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    End point title
    		 Efficacy - Number of subjects with MI
    End point description
    Acute MI was used when there was evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. According to MI Universal Definition from 2018 the diagnosis of MI requires combination of: 1. Presence of acute myocardial injury. 2. Evidence of acute myocardial ischemia derived from the clinical presentation, electrocardiographic changes, or the results of myocardial or coronary artery imaging, or in case of post-mortem pathological findings irrespective of biomarker values.
    End point type
    Secondary
    End point timeframe
    From baseline up to 52 weeks
    End point values
    		 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo Asundexian 20+50 mg
    Number of subjects analysed
    397
    401
    402
    401
    803
    Units: Subjects
    18
    20
    18
    17
    38
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison of the Asundexian 20+50 mg group versus Placebo group
    Comparison groups
    Placebo v Asundexian 20+50 mg
    Number of subjects included in analysis
    1204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.125
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.696
         upper limit
    		 1.819
    Notes
    [10] - HRs were only calculated if at least three events occurred in one of the compared groups and at least one event in each of the compared treatment groups. The competing event was non-CV death for events that include CV death.
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison of the Asundexian 50 mg group versus Placebo group
    Comparison groups
    Asundexian 50 mg v Placebo
    Number of subjects included in analysis
    803
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.07
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.613
         upper limit
    		 1.866
    Notes
    [11] - HRs were only calculated if at least three events occurred in one of the compared groups and at least one event in each of the compared treatment groups. The competing event was non-CV death for events that include CV death.
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison of the Asundexian 20 mg group versus Placebo group
    Comparison groups
    Asundexian 20 mg v Placebo
    Number of subjects included in analysis
    802
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.181
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.686
         upper limit
    		 2.031

    Secondary: Efficacy - Number of subjects with stroke

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    End point title
    		 Efficacy - Number of subjects with stroke
    End point description
    Stroke was defined as an acute episode of focal or global neurological dysfunction caused by an injury of the brain, spinal cord, or retina as a result of hemorrhage or infarction.
    End point type
    Secondary
    End point timeframe
    From baseline up to 52 weeks
    End point values
    		 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo Asundexian 20+50 mg
    Number of subjects analysed
    397
    401
    402
    401
    803
    Units: Subjects
    4
    3
    0
    2
    3
    No statistical analyses for this end point

    Secondary: Efficacy - Number of subjects with stent thrombosis

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    End point title
    		 Efficacy - Number of subjects with stent thrombosis
    End point description
    ST was defined incorporating diagnostic certainty as well as timing: “Definite” ST: The highest level of certainty. Either angiographic or pathological confirmation of stent thrombosis. “Probable” ST: Regardless of the time after the index procedure, any MI that is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis and in the absence of any other obvious cause
    End point type
    Secondary
    End point timeframe
    From baseline up to 52 weeks
    End point values
    		 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo Asundexian 20+50 mg
    Number of subjects analysed
    397
    401
    402
    401
    803
    Units: Subjects
    4
    5
    4
    4
    9
    No statistical analyses for this end point

    Secondary: Efficacy - Number of subjects with all cause mortality

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    End point title
    		 Efficacy - Number of subjects with all cause mortality
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline up to 52 weeks
    End point values
    		 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo Asundexian 20+50 mg
    Number of subjects analysed
    397
    401
    402
    401
    803
    Units: Subjects
    10
    7
    10
    7
    17
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison of the Asundexian 20+50 mg group versus Placebo group
    Comparison groups
    Placebo v Asundexian 20+50 mg
    Number of subjects included in analysis
    1204
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.6016
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.266
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.603
         upper limit
    		 2.658
    Notes
    [12] - For all-cause mortality there is no competing event.
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison of the Asundexian 20 mg group versus Placebo group
    Comparison groups
    Asundexian 20 mg v Placebo
    Number of subjects included in analysis
    802
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9945
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.996
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.414
         upper limit
    		 2.401
    Statistical analysis title
    		 Hazard Ratio (HR)
    Statistical analysis description
    Comparison of the Asundexian 50 mg group versus Placebo group
    Comparison groups
    Asundexian 50 mg v Placebo
    Number of subjects included in analysis
    803
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4085
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.506
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.667
         upper limit
    		 3.405

    Secondary: Safety - Number of subjects with all bleeding

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    End point title
    		 Safety - Number of subjects with all bleeding
    End point description
    All bleeding events occurred from first intake of study intervention until 2 days after the last intake of study intervention
    End point type
    Secondary
    End point timeframe
    From baseline up to 52 weeks
    End point values
    		 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo
    Number of subjects analysed
    395
    397
    402
    399
    Units: Subjects
    70
    75
    82
    85
    No statistical analyses for this end point

    Secondary: Safety - Number of subjects with BARC bleeding definition type 3, 5

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    End point title
    		 Safety - Number of subjects with BARC bleeding definition type 3, 5
    End point description
    BARC bleeding Type 3,5 definition, please refer to primary endpoint "Number of subjects with BARC bleeding definition type 2, 3 and 5".
    End point type
    Secondary
    End point timeframe
    From baseline up to 52 weeks
    End point values
    		 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo
    Number of subjects analysed
    395
    397
    402
    399
    Units: Subjects
    5
    3
    3
    5
    No statistical analyses for this end point

    Secondary: Safety - Number of subjects with BARC bleeding definition type 1,2,3,5

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    End point title
    		 Safety - Number of subjects with BARC bleeding definition type 1,2,3,5
    End point description
    Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled performance of studies, hospitalization, or treatment by a healthcare professional; may include episodes leading to self-discontinuation of medical therapy by the patient without consulting a healthcare professional. BARC bleeding Type 2,3,5 definition, please refer to primary endpoint "Number of subjects with BARC bleeding definition type 2, 3 and 5".
    End point type
    Secondary
    End point timeframe
    From baseline up to 52 weeks
    End point values
    		 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo
    Number of subjects analysed
    395
    397
    402
    399
    Units: Subjects
    70
    75
    82
    85
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After the first administration of study intervention for up to 52 weeks (but not starting after more than 2 days after the last administration).
    Adverse event reporting additional description
    Reporting for the deaths (all causes) considers all deaths that occurred at any time during the study before the last contact, for up to 54 weeks.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Asundexian 10 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 10 mg

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo

    Reporting group title
    Asundexian 50 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 50 mg

    Reporting group title
    Asundexian 20 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 20 mg

    Serious adverse events
    		 Asundexian 10 mg Placebo Asundexian 50 mg Asundexian 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    74 / 395 (18.73%)
    82 / 399 (20.55%)
    67 / 402 (16.67%)
    82 / 397 (20.65%)
         number of deaths (all causes)
    10
    7
    10
    7
         number of deaths resulting from adverse events
    7
    5
    7
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder neoplasm
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial carcinoma
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic neoplasm
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urethral cancer
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Shock
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular stenosis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Giant cell arteritis
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial rupture
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Percutaneous coronary intervention
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac resynchronisation therapy
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sigmoidectomy
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polypectomy
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transurethral bladder resection
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary arterial stent insertion
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Revascularisation procedure
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    4 / 395 (1.01%)
    4 / 399 (1.00%)
    4 / 402 (1.00%)
    5 / 397 (1.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 4
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular stent stenosis
         subjects affected / exposed
    2 / 395 (0.51%)
    2 / 399 (0.50%)
    1 / 402 (0.25%)
    2 / 397 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular stent thrombosis
         subjects affected / exposed
    1 / 395 (0.25%)
    2 / 399 (0.50%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 399 (0.50%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperventilation
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 395 (0.25%)
    3 / 399 (0.75%)
    1 / 402 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    2 / 397 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 399 (0.50%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coagulation factor VIII level increased
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Von Willebrand's factor antigen increased
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Von Willebrand's factor activity increased
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial bruit
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periprocedural myocardial infarction
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention postoperative
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vaccination complication
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    9 / 395 (2.28%)
    8 / 399 (2.01%)
    10 / 402 (2.49%)
    9 / 397 (2.27%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 8
    0 / 11
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    5 / 395 (1.27%)
    1 / 399 (0.25%)
    6 / 402 (1.49%)
    4 / 397 (1.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    4 / 395 (1.01%)
    4 / 399 (1.00%)
    2 / 402 (0.50%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 395 (0.25%)
    2 / 399 (0.50%)
    1 / 402 (0.25%)
    2 / 397 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    2 / 397 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    3 / 395 (0.76%)
    5 / 399 (1.25%)
    2 / 402 (0.50%)
    4 / 397 (1.01%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    3 / 395 (0.76%)
    1 / 399 (0.25%)
    1 / 402 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Cardiac tamponade
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery embolism
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interventricular septum rupture
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dressler's syndrome
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery thrombosis
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 395 (0.51%)
    3 / 399 (0.75%)
    3 / 402 (0.75%)
    2 / 397 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    2 / 397 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 395 (0.00%)
    2 / 399 (0.50%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Coronary artery dissection
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery perforation
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 395 (0.00%)
    3 / 399 (0.75%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    2 / 395 (0.51%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 399 (0.25%)
    1 / 402 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness postural
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myelitis transverse
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 399 (0.00%)
    2 / 402 (0.50%)
    2 / 397 (0.50%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal epidural haematoma
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal ulcer haemorrhage
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric antral vascular ectasia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic hepatitis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis toxic
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Portal hypertension
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Henoch-Schonlein purpura
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal artery stenosis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 399 (0.00%)
    2 / 402 (0.50%)
    2 / 397 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    2 / 402 (0.50%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    2 / 397 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tenosynovitis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    3 / 395 (0.76%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    2 / 397 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    2 / 402 (0.50%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis intestinal haemorrhagic
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 395 (0.51%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 395 (0.25%)
    4 / 399 (1.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 395 (0.25%)
    5 / 399 (1.25%)
    7 / 402 (1.74%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    0 / 0
    Acarodermatitis
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    1 / 402 (0.25%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 395 (0.25%)
    1 / 399 (0.25%)
    1 / 402 (0.25%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 395 (0.25%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 395 (0.00%)
    1 / 399 (0.25%)
    0 / 402 (0.00%)
    0 / 397 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 395 (0.00%)
    0 / 399 (0.00%)
    0 / 402 (0.00%)
    1 / 397 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Asundexian 10 mg Placebo Asundexian 50 mg Asundexian 20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    89 / 395 (22.53%)
    107 / 399 (26.82%)
    94 / 402 (23.38%)
    118 / 397 (29.72%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    22 / 395 (5.57%)
    30 / 399 (7.52%)
    15 / 402 (3.73%)
    27 / 397 (6.80%)
         occurrences all number
    23
    30
    15
    29
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    18 / 395 (4.56%)
    19 / 399 (4.76%)
    21 / 402 (5.22%)
    19 / 397 (4.79%)
         occurrences all number
    19
    22
    22
    22
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    13 / 395 (3.29%)
    17 / 399 (4.26%)
    15 / 402 (3.73%)
    29 / 397 (7.30%)
         occurrences all number
    15
    20
    15
    32
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    22 / 395 (5.57%)
    18 / 399 (4.51%)
    22 / 402 (5.47%)
    21 / 397 (5.29%)
         occurrences all number
    23
    19
    25
    22
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    21 / 395 (5.32%)
    23 / 399 (5.76%)
    21 / 402 (5.22%)
    27 / 397 (6.80%)
         occurrences all number
    21
    25
    23
    28
    Epistaxis
         subjects affected / exposed
    17 / 395 (4.30%)
    20 / 399 (5.01%)
    21 / 402 (5.22%)
    19 / 397 (4.79%)
         occurrences all number
    25
    26
    29
    45

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/36030390
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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