Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43861   clinical trials with a EudraCT protocol, of which   7284   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

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

    Summary
    EudraCT number
    		 2019-003431-33
    Trial protocol
    		 CZ   GB   ES   PT   FI   DE   NL   AT   FR   HU   DK   BE   BG   PL   IT  
    Global end of trial date
    18 Feb 2022

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    BAY2433334/19766
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04304508
    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
    20 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the dose-response of 3 different doses of asundexian compared to placebo in reducing the composite of symptomatic ischemic strokes and covert brain infarcts detected by Magnetic resonance imaging (MRI) as well as other cerebro- and cardiovascular endpoints in participants with an acute noncardioembolic ischemic stroke and who are treated with 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
    		 Anti-platelet therapy
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 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
    Bulgaria: 177
    Country: Number of subjects enrolled
    Czechia: 68
    Country: Number of subjects enrolled
    Hungary: 29
    Country: Number of subjects enrolled
    Poland: 47
    Country: Number of subjects enrolled
    Russian Federation: 123
    Country: Number of subjects enrolled
    Slovakia: 80
    Country: Number of subjects enrolled
    United States: 23
    Country: Number of subjects enrolled
    Australia: 116
    Country: Number of subjects enrolled
    Austria: 40
    Country: Number of subjects enrolled
    Belgium: 51
    Country: Number of subjects enrolled
    Switzerland: 64
    Country: Number of subjects enrolled
    Germany: 73
    Country: Number of subjects enrolled
    Denmark: 79
    Country: Number of subjects enrolled
    Spain: 216
    Country: Number of subjects enrolled
    Finland: 36
    Country: Number of subjects enrolled
    France: 84
    Country: Number of subjects enrolled
    United Kingdom: 55
    Country: Number of subjects enrolled
    Italy: 87
    Country: Number of subjects enrolled
    Netherlands: 18
    Country: Number of subjects enrolled
    Portugal: 79
    Country: Number of subjects enrolled
    Sweden: 9
    Country: Number of subjects enrolled
    China: 81
    Country: Number of subjects enrolled
    Japan: 173
    Worldwide total number of subjects
    1808
    EEA total number of subjects
    1173
    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)
    709
    From 65 to 84 years
    1039
    85 years and over
    60

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Study was conducted at 197 centers in 23 countries or regions, between 15-Jun-2020 (first subject first visit) and 18-Feb-2022 (last subject last visit)

    Pre-assignment
    Screening details
    		 1880 subjects were screened. 72 subjects were screening failures. 1808 subjects were randomized in a 1:1:1:1 ratio to 4 treatment groups: 455, 450, and 447 subjects to asundexian 10 mg, 20 mg and 50 mg groups, 456 subjects to placebo group. 22 subjects (10, 4, 4 and 4 in the asundexian 10 mg, 20 mg and 50 mg, and placebo groups) never administered.

    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 for 26 weeks at least and up to 52 weeks
    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 for 26 weeks at least and up to 52 weeks
    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 for 26 weeks at least and up to 52 weeks
    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 Asundexian (BAY2433334) placebo for 26 weeks at least and up to 52 weeks
    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
    455
    450
    447
    456
    Treated
    445
    446
    443
    452
    Completed
    335
    329
    313
    314
    Not completed
    120
    121
    134
    142
         Physician decision
    3
    4
    9
    7
         Physician Decision: COVID-19 Pandemic Related
    1
    -
    -
    -
         Consent withdrawn by subject
    7
    5
    11
    6
         Subject Decision
    29
    39
    37
    48
         Logistical Difficulties
    2
    2
    3
    2
         Adverse event, non-fatal
    49
    50
    51
    56
         Subject Decision: COVID-19 Pandemic Related
    -
    1
    -
    2
         Other
    7
    6
    5
    4
         Non-compliance With Study Drug
    3
    1
    2
    -
         Death
    6
    1
    8
    5
         Missing Information
    1
    2
    1
    3
         Study drug never administered
    10
    4
    4
    4
         Lost to follow-up
    1
    5
    2
    3
         Switching To Other Therapy
    1
    1
    1
    2

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Asundexian 10 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 10 mg for 26 weeks at least and up to 52 weeks

    Reporting group title
    Asundexian 20 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 20 mg for 26 weeks at least and up to 52 weeks

    Reporting group title
    Asundexian 50 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 50 mg for 26 weeks at least and up to 52 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) placebo for 26 weeks at least and up to 52 weeks

    Reporting group values
    		 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo Total
    Number of subjects
    		 455 450 447 456 1808
    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)
    		 186 154 174 195 709
        From 65-84 years
    		 255 279 258 247 1039
        85 years and over
    		 14 17 15 14 60
    Gender Categorical
    Units: Subjects
        Female
    		 161 150 154 150 615
        Male
    		 294 300 293 306 1193
    Race
    Units: Subjects
        Asian
    		 67 67 68 66 268
        Black or African American
    		 4 3 8 3 18
        Native Hawaiian or Other Pacific Islander
    		 0 1 1 1 3
        Not Reported
    		 3 2 3 6 14
        White
    		 381 377 367 380 1505
    Subject analysis sets

    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 a treatment group.

    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
    Total Asundexian
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    A subject was included in the Total Asundexian if he/she was randomized to Asundexian 10 mg group or Asundexian 20 mg group or Asundexian 50 mg group and had taken at least one dose of Asundexian.

    Subject analysis sets values
    		 Full analysis set (FAS) Safety analysis set (SAF) Total Asundexian
    Number of subjects
    1808
    1786
    1334
    Age Categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    709
    703
        From 65-84 years
    1039
    1024
        85 years and over
    60
    59
    Age Continuous
    Units:
        
    ±
    ±
    ±
    Gender Categorical
    Units: Subjects
        Female
    615
    608
        Male
    1193
    1178
    Race
    Units: Subjects
        Asian
    268
    263
        Black or African American
    18
    18
        Native Hawaiian or Other Pacific Islander
    3
    3
        Not Reported
    14
    13
        White
    1505
    1489

    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 for 26 weeks at least and up to 52 weeks

    Reporting group title
    Asundexian 20 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 20 mg for 26 weeks at least and up to 52 weeks

    Reporting group title
    Asundexian 50 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 50 mg for 26 weeks at least and up to 52 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) placebo for 26 weeks at least and up to 52 weeks

    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 a treatment group.

    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
    Total Asundexian
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    A subject was included in the Total Asundexian if he/she was randomized to Asundexian 10 mg group or Asundexian 20 mg group or Asundexian 50 mg group and had taken at least one dose of Asundexian.

    Primary: Efficacy-Number of subjects with composite of symptomatic ischemic stroke and covert brain infarcts detected by magnetic resonance imaging (MRI)

    		 Close Top of page
    End point title
    		 Efficacy-Number of subjects with composite of symptomatic ischemic stroke and covert brain infarcts detected by magnetic resonance imaging (MRI)
    End point description
    Ischemic stroke was defined as either of : 1) Rapid onset (or present on awakening) of a new focal neurological deficit with clinical (>24 hours symptoms/signs) or imaging evidence of infarction that was not attributable to a non-ischemic cause; 2) Acute worsening of an existing focal neurological deficit that was judged to be attributable to a new infarction or extension of the previous infarction in the same vascular territory, based on persisting symptoms/signs or imaging evidence of infarction and no evidence of a non-ischemic etiology. If imaging was inconclusive, persistent symptoms/signs must be significant (worsening of NIHSS score of 4 or more) and sustained (duration of ≥24 hours or until death). Covert brain infarcts were defined as incident infarcts detected by serial MRI in the absence of an adjudicated stroke consistent with the location of the infarct. MRI criteria for brain infarction were available in the MRI procedures manual.
    End point type
    Primary
    End point timeframe
    From baseline up to 26 weeks
    End point values
    		 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo
    Number of subjects analysed
    455
    450
    447
    456
    Units: Subjects
    86
    99
    90
    87
    Statistical analysis title
    		 Ratio of the incidence proportions
    Statistical analysis description
    Comparison of the Asundexian 10 mg group versus Placebo group
    Comparison groups
    Asundexian 10 mg v Placebo
    Number of subjects included in analysis
    911
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Crude incidence ratio
    Point estimate
    1.044
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8105
         upper limit
    		 1.3478
    Statistical analysis title
    		 Dose-response test
    Statistical analysis description
    Dose-response test by using multiple comparison procedures (MCP) Mod method
    Comparison groups
    Asundexian 10 mg v Asundexian 20 mg v Asundexian 50 mg v Placebo
    Number of subjects included in analysis
    1808
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7976
    Method
    		 MCP Mod
    Confidence interval
    Statistical analysis title
    		 Ratio of the incidence proportions
    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
    903
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Crude incidence ratio
    Point estimate
    1.0485
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.8082
         upper limit
    		 1.3619
    Statistical analysis title
    		 Ratio of the incidence proportions
    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
    906
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Crude incidence ratio
    Point estimate
    1.1963
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.9281
         upper limit
    		 1.5428

    Primary: Safety-Number of subjects with composite of International Society on Thrombosis and Hemostasis (ISTH) major bleeding and clinically relevant non-major (CRNM) bleeding

    		 Close Top of page
    End point title
    		 Safety-Number of subjects with composite of International Society on Thrombosis and Hemostasis (ISTH) major bleeding and clinically relevant non-major (CRNM) bleeding
    End point description
    ISTH Major Bleeding criteria: 1. Fatal bleeding, and/or 2. Symptomatic bleeding in a critical area or organ (intracranial, intraocular, intraspinal, pericardial, retroperitoneal, intraarticular, or intramuscular with compartment syndrome), and/or 3. Clinically overt bleeding associated with a recent decrease in the hemoglobin level of ≥ 2 g/dL (20 g/L; 1.24 mmol/L) compared to the most recent hemoglobin value available before the event, and/or 4. Clinically overt bleeding leading to transfusion of 2 or more units of packed red blood cells or whole blood. ISTH Clinically Relevant Non-Major Bleeding is considered any sign or symptom of hemorrhage that does not fit the criteria for the ISTH definition of major bleeding, but does meet at least one of the following criteria 1. requiring medical intervention by a healthcare professional. 2. leading to hospitalization or increased level of care. 3. prompting a face to face (i.e. not just a telephone or electronic communication) evaluation.
    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 Total Asundexian
    Number of subjects analysed
    445
    446
    443
    452
    1334
    Units: Subjects
    19
    14
    19
    11
    52
    Statistical analysis title
    		 Cause specific Hazard ratio (csHR)
    Statistical analysis description
    Comparison of the Asundexian 10 mg group versus Placebo group
    Comparison groups
    Asundexian 10 mg v Placebo
    Number of subjects included in analysis
    897
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.1507
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.724
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.924
         upper limit
    		 3.215
    Notes
    [1] - Cause specific HRs were only calculated if at least 3 events occurred in 1 of the compared groups and at least 1 event in each of the compared treatment groups.
    Statistical analysis title
    		 Cause-specific Hazard Ratio (csHR)
    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
    895
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.1401
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.749
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.938
         upper limit
    		 3.262
    Notes
    [2] - Cause specific HRs were only calculated if at least 3 events occurred in 1 of the compared groups and at least 1 event in each of the compared treatment groups.
    Statistical analysis title
    		 Cause specific Hazard ratio (csHR)
    Statistical analysis description
    Comparison of the Total Asundexian group versus Placebo group
    Comparison groups
    Placebo v Total Asundexian
    Number of subjects included in analysis
    1786
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.1653
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.585
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.918
         upper limit
    		 2.736
    Notes
    [3] - Cause specific HRs were only calculated if at least 3 events occurred in 1 of the compared groups and at least 1 event in each of the compared treatment groups.
    Statistical analysis title
    		 Cause-specific hazard ratio (csHR)
    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
    898
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.5339
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.285
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.662
         upper limit
    		 2.494
    Notes
    [4] - Cause specific HRs were only calculated if at least 3 events occurred in 1 of the compared groups and at least 1 event in each of the compared treatment groups.

    Secondary: Efficacy-Number of subjects with composite of symptomatic ischemic stroke and covert brain infarcts detected by MRI, cardiovascular (CV) death, Myocardial infarction (MI) and systemic embolism.

    		 Close Top of page
    End point title
    		 Efficacy-Number of subjects with composite of symptomatic ischemic stroke and covert brain infarcts detected by MRI, cardiovascular (CV) death, Myocardial infarction (MI) and systemic embolism.
    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. According to MI Universal Definition from 2018 the diagnosis of MI required the combination of: 1) Presence of acute myocardial injury, and 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. Systemic embolism was defined as abrupt vascular insufficiency associated with clinical or radiological evidence of arterial occlusion in the absence of other likely mechanisms (this did not include thromboembolism of the pulmonary vasculature or venous thrombosis).
    End point type
    Secondary
    End point timeframe
    From baseline up to 26 weeks
    End point values
    		 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo
    Number of subjects analysed
    455
    450
    447
    456
    Units: Subjects
    80
    87
    81
    79
    No statistical analyses for this end point

    Secondary: Efficacy-Number of subjects with symptomatic ischemic stroke

    		 Close Top of page
    End point title
    		 Efficacy-Number of subjects with symptomatic ischemic stroke
    End point description
    Definition of symptomatic ischemic stroke can be referred to first Primary endpoint.
    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
    455
    450
    447
    456
    Units: Subjects
    26
    26
    22
    28
    No statistical analyses for this end point

    Secondary: Efficacy-Number of subjects with symptomatic ischemic stroke, CV death, MI

    		 Close Top of page
    End point title
    		 Efficacy-Number of subjects with symptomatic ischemic stroke, CV death, MI
    End point description
    Definition of symptomatic ischemic stroke can be referred to first Primary endpoint. Definition of CV death and MI can be referred to first Second endpoint.
    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
    455
    450
    447
    456
    Units: Subjects
    33
    30
    33
    35
    No statistical analyses for this end point

    Secondary: Efficacy-Number of subjects with covert brain infarcts detected by MRI

    		 Close Top of page
    End point title
    		 Efficacy-Number of subjects with covert brain infarcts detected by MRI
    End point description
    Definition of covert brain infarcts can be referred to first Primary endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline up to 26 weeks
    End point values
    		 Asundexian 10 mg Asundexian 20 mg Asundexian 50 mg Placebo
    Number of subjects analysed
    455
    450
    447
    456
    Units: Subjects
    62
    68
    63
    60
    No statistical analyses for this end point

    Secondary: Efficacy-Number of subjects with symptomatic ischemic and hemorrhagic stroke

    		 Close Top of page
    End point title
    		 Efficacy-Number of subjects with symptomatic ischemic and hemorrhagic stroke
    End point description
    Definition of symptomatic ischemic can be referred to fourth secondary endpoint. Hemorrhagic stroke was defined as an acute, atraumatic extravasation of blood into the brain parenchyma, intraventricular or subarachnoid space with associated neurological symptoms. This did not include microbleeds or hemorrhagic transformation of an ischemic stroke.
    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
    455
    450
    447
    456
    Units: Subjects
    26
    26
    25
    30
    No statistical analyses for this end point

    Secondary: Efficacy-Number of subjects with Disabling stroke (mRS≥4)

    		 Close Top of page
    End point title
    		 Efficacy-Number of subjects with Disabling stroke (mRS≥4)
    End point description
    Modified ranking score (mRS): 0-No symptoms at all; 1-No significant disability despite symptoms; despite symptoms, able to carry out all usual duties and activities; 2-Slight disability; unable to carry out all previous activities but able to look after own affairs without assistance; 3-Moderate disability; requiring some help, but able to walk without assistance; 4-Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance; 5-Severe disability; bedridden, incontinent and requiring constant nursing care and attention; 6-Death.
    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
    455
    450
    447
    456
    Units: Subjects
    5
    5
    1
    3
    No statistical analyses for this end point

    Secondary: Efficacy-Number of subjects with All-cause mortality

    		 Close Top of page
    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
    Number of subjects analysed
    455
    450
    447
    456
    Units: Subjects
    10
    6
    17
    10
    No statistical analyses for this end point

    Secondary: Safety-Number of subjects with all bleeding

    		 Close Top of page
    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 Total Asundexian
    Number of subjects analysed
    445
    446
    443
    452
    1334
    Units: Subjects
    37
    48
    48
    44
    133
    No statistical analyses for this end point

    Secondary: Safety-Number of subjects with ISTH major bleeding

    		 Close Top of page
    End point title
    		 Safety-Number of subjects with ISTH major bleeding
    End point description
    Definition of ISTH major bleeding can be referred to second Primary endpoint.
    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
    445
    446
    443
    452
    Units: Subjects
    4
    3
    7
    4
    No statistical analyses for this end point

    Secondary: Safety-Number of subjects with ISTH CRNM bleeding

    		 Close Top of page
    End point title
    		 Safety-Number of subjects with ISTH CRNM bleeding
    End point description
    Definition of ISTH CRNM bleeding can be referred to second Primary endpoint.
    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
    445
    446
    443
    452
    Units: Subjects
    15
    12
    12
    7
    No statistical analyses for this end point

    Secondary: Safety-Number of subjects with ISTH minor bleeding

    		 Close Top of page
    End point title
    		 Safety-Number of subjects with ISTH minor bleeding
    End point description
    All other overt bleeding episodes not meeting the above criteria for ISTH major or CRNM bleeding were classified as minor bleeding (e.g. bleeding from a minor wound that does not prompt a face-to-face evaluation for a physical examination or laboratory testing).
    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
    445
    446
    443
    452
    Units: Subjects
    21
    39
    34
    34
    No statistical analyses for this end point

    Secondary: Safety-Number of subjects with Intracerebral hemorrhage (non-traumatic)

    		 Close Top of page
    End point title
    		 Safety-Number of subjects with Intracerebral hemorrhage (non-traumatic)
    End point description
    Non-traumatic intracerebral hemorrhage was defined as a hemorrhagic stroke on the “recurrent stroke” CRF page that is in addition classified as a bleeding with bleeding site intracranial (–subarachnoid, –intraparenchymal [excluding microbleeds], or –intraventricular) and spontaneous causality of bleeding, excluding all symptomatic and hemorrhagic transformation (defined by the PT “hemorrhagic transformation”).
    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
    445
    446
    443
    452
    Units: Subjects
    0
    0
    3
    1
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    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 for 26 weeks at least and up to 52 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) placebo for 26 weeks at least and up to 52 weeks

    Reporting group title
    Asundexian 50 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 50 mg for 26 weeks at least and up to 52 weeks

    Reporting group title
    Asundexian 20 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 20 mg for 26 weeks at least and up to 52 weeks

    Serious adverse events
    		 Asundexian 10 mg Placebo Asundexian 50 mg Asundexian 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    90 / 445 (20.22%)
    98 / 452 (21.68%)
    93 / 443 (20.99%)
    83 / 446 (18.61%)
         number of deaths (all causes)
    10
    10
    17
    6
         number of deaths resulting from adverse events
    5
    7
    12
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric cancer
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Glioblastoma multiforme
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Metastases to central nervous system
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 445 (0.22%)
    1 / 452 (0.22%)
    1 / 443 (0.23%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Rectal cancer
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Prostate cancer
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    1 / 443 (0.23%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Thymoma malignant
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Colorectal cancer
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Lung neoplasm
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Metastasis
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Invasive ductal breast carcinoma
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Hypertension
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    2 / 443 (0.45%)
    0 / 446 (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
    Aortic thrombosis
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Peripheral ischaemia
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Extremity necrosis
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Deep vein thrombosis
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    1 / 446 (0.22%)
         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
    Venous thrombosis
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Thrombophlebitis
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Atheroembolism
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Surgical and medical procedures
    Atrial septal defect repair
         subjects affected / exposed
    5 / 445 (1.12%)
    1 / 452 (0.22%)
    3 / 443 (0.68%)
    3 / 446 (0.67%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac pacemaker insertion
         subjects affected / exposed
    2 / 445 (0.45%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Carotid endarterectomy
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Hip arthroplasty
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Endarterectomy
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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 bypass
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Cholecystectomy
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Knee arthroplasty
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Stent placement
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal decompression
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Implantable defibrillator insertion
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Shoulder arthroplasty
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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 angioplasty
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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 arterial stent insertion
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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 bypass
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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 polypectomy
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Carotid artery stent insertion
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Bladder neoplasm surgery
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Transcatheter aortic valve implantation
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Vocal cord augmentation
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 445 (0.00%)
    2 / 452 (0.44%)
    1 / 443 (0.23%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
    Chest pain
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Sudden death
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Sudden cardiac death
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Fatigue
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Cystocele
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Prostatitis
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Intermenstrual bleeding
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 445 (0.22%)
    1 / 452 (0.22%)
    1 / 443 (0.23%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Pulmonary embolism
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    1 / 443 (0.23%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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 failure
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Hydrothorax
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcoholism
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Conversion disorder
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Depression
         subjects affected / exposed
    2 / 445 (0.45%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Investigations
    Angiogram cerebral
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Haemoglobin decreased
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Cardiovascular evaluation
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Sleep study
         subjects affected / exposed
    2 / 445 (0.45%)
    1 / 452 (0.22%)
    1 / 443 (0.23%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    2 / 445 (0.45%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Magnetic resonance imaging abnormal
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 445 (0.45%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carbon monoxide poisoning
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Femoral neck fracture
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Fibula fracture
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Femur fracture
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Hand fracture
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Hip fracture
         subjects affected / exposed
    2 / 445 (0.45%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Humerus fracture
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Subdural haematoma
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Rib fracture
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Subdural haemorrhage
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Traumatic fracture
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Tibia fracture
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Tendon rupture
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Contusion
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Lower limb fracture
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Foreign body in gastrointestinal tract
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    0 / 445 (0.00%)
    2 / 452 (0.44%)
    2 / 443 (0.45%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve stenosis
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Aortic valve incompetence
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Angina unstable
         subjects affected / exposed
    1 / 445 (0.22%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Angina pectoris
         subjects affected / exposed
    1 / 445 (0.22%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Atrial fibrillation
         subjects affected / exposed
    3 / 445 (0.67%)
    3 / 452 (0.66%)
    0 / 443 (0.00%)
    4 / 446 (0.90%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 445 (0.45%)
    1 / 452 (0.22%)
    2 / 443 (0.45%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Atrioventricular block complete
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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 arrest
         subjects affected / exposed
    1 / 445 (0.22%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Cardiac failure acute
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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 / 1
    Cardiac failure chronic
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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 failure congestive
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Chordae tendinae rupture
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Coronary artery disease
         subjects affected / exposed
    1 / 445 (0.22%)
    2 / 452 (0.44%)
    0 / 443 (0.00%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 445 (0.00%)
    2 / 452 (0.44%)
    3 / 443 (0.68%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Palpitations
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Pericardial effusion
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Intracardiac thrombus
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Acute coronary syndrome
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Sinus node dysfunction
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Brain stem infarction
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Carotid artery stenosis
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    1 / 443 (0.23%)
    0 / 446 (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
    Cerebral artery occlusion
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    2 / 443 (0.45%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 445 (0.00%)
    3 / 452 (0.66%)
    1 / 443 (0.23%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    9 / 445 (2.02%)
    7 / 452 (1.55%)
    9 / 443 (2.03%)
    8 / 446 (1.79%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 8
    0 / 10
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Epilepsy
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    4 / 446 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Headache
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    1 / 443 (0.23%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Haemorrhagic cerebral infarction
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Facial paralysis
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Myasthenia gravis
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Presyncope
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Radiculopathy
         subjects affected / exposed
    1 / 445 (0.22%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Syncope
         subjects affected / exposed
    2 / 445 (0.45%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    3 / 446 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    4 / 445 (0.90%)
    4 / 452 (0.88%)
    2 / 443 (0.45%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Lacunar infarction
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Haemorrhagic transformation stroke
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    2 / 443 (0.45%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stroke in evolution
         subjects affected / exposed
    3 / 445 (0.67%)
    3 / 452 (0.66%)
    2 / 443 (0.45%)
    4 / 446 (0.90%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Ischaemic stroke
         subjects affected / exposed
    9 / 445 (2.02%)
    13 / 452 (2.88%)
    9 / 443 (2.03%)
    7 / 446 (1.57%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 14
    0 / 9
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Thrombotic cerebral infarction
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Carotid arteriosclerosis
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Brachial plexopathy
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Cerebral hypoperfusion
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Partial seizures
         subjects affected / exposed
    1 / 445 (0.22%)
    2 / 452 (0.44%)
    0 / 443 (0.00%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral amyloid angiopathy
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Neurological decompensation
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    1 / 443 (0.23%)
    0 / 446 (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
    Cerebral small vessel ischaemic disease
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Cerebellar microhaemorrhage
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Lacunar stroke
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Hemianaesthesia
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Blood loss anaemia
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Thrombocytopenia
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    3 / 446 (0.67%)
         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
    Eye disorders
    Macular oedema
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Diabetic retinopathy
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Cataract
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Angle closure glaucoma
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Retinal infarction
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Colitis ischaemic
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Dyspepsia
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Gastric ulcer haemorrhage
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Inguinal hernia
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Intussusception
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Melaena
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    1 / 443 (0.23%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Umbilical hernia
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Stomach mass
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Paraesthesia oral
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Large intestine polyp
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    1 / 443 (0.23%)
    0 / 446 (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
    Mechanical ileus
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    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 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Cholangitis acute
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Cholecystitis
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Hepatic failure
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Hepatitis acute
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Drug-induced liver injury
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Cholecystitis acute
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Cholelithiasis
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    1 / 443 (0.23%)
    0 / 446 (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
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Decubitus ulcer
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Skin toxicity
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Urticaria
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Skin ulcer
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Acute kidney injury
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Haematuria
         subjects affected / exposed
    1 / 445 (0.22%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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 failure
         subjects affected / exposed
    0 / 445 (0.00%)
    2 / 452 (0.44%)
    0 / 443 (0.00%)
    0 / 446 (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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 445 (0.00%)
    2 / 452 (0.44%)
    0 / 443 (0.00%)
    0 / 446 (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
    Spinal pain
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Pain in extremity
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Osteoporotic fracture
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    2 / 443 (0.45%)
    0 / 446 (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 / 1
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Cellulitis
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 445 (0.67%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    2 / 446 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 445 (0.22%)
    1 / 452 (0.22%)
    1 / 443 (0.23%)
    0 / 446 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Sepsis
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    1 / 443 (0.23%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Urosepsis
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    1 / 446 (0.22%)
         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
    Septic shock
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Abdominal abscess
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Joint abscess
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    0 / 445 (0.00%)
    1 / 452 (0.22%)
    0 / 443 (0.00%)
    0 / 446 (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
    Pneumonia bacterial
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
         subjects affected / exposed
    0 / 445 (0.00%)
    4 / 452 (0.88%)
    5 / 443 (1.13%)
    1 / 446 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    2 / 443 (0.45%)
    3 / 446 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 445 (0.22%)
    0 / 452 (0.00%)
    0 / 443 (0.00%)
    0 / 446 (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
    Hyponatraemia
         subjects affected / exposed
    0 / 445 (0.00%)
    0 / 452 (0.00%)
    1 / 443 (0.23%)
    0 / 446 (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
    Frequency threshold for reporting non-serious adverse events: 3%
    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
    126 / 445 (28.31%)
    136 / 452 (30.09%)
    136 / 443 (30.70%)
    127 / 446 (28.48%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    23 / 445 (5.17%)
    24 / 452 (5.31%)
    25 / 443 (5.64%)
    19 / 446 (4.26%)
         occurrences all number
    24
    25
    25
    19
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    18 / 445 (4.04%)
    22 / 452 (4.87%)
    16 / 443 (3.61%)
    21 / 446 (4.71%)
         occurrences all number
    18
    22
    16
    21
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 445 (1.57%)
    14 / 452 (3.10%)
    17 / 443 (3.84%)
    16 / 446 (3.59%)
         occurrences all number
    7
    14
    17
    18
    Headache
         subjects affected / exposed
    19 / 445 (4.27%)
    18 / 452 (3.98%)
    21 / 443 (4.74%)
    19 / 446 (4.26%)
         occurrences all number
    20
    19
    31
    38
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    28 / 445 (6.29%)
    34 / 452 (7.52%)
    28 / 443 (6.32%)
    18 / 446 (4.04%)
         occurrences all number
    29
    35
    29
    20
    Diarrhoea
         subjects affected / exposed
    12 / 445 (2.70%)
    12 / 452 (2.65%)
    15 / 443 (3.39%)
    14 / 446 (3.14%)
         occurrences all number
    12
    12
    18
    15
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 445 (1.35%)
    12 / 452 (2.65%)
    11 / 443 (2.48%)
    16 / 446 (3.59%)
         occurrences all number
    6
    13
    12
    16
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 445 (2.47%)
    12 / 452 (2.65%)
    16 / 443 (3.61%)
    11 / 446 (2.47%)
         occurrences all number
    11
    12
    16
    13
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    13 / 445 (2.92%)
    14 / 452 (3.10%)
    13 / 443 (2.93%)
    11 / 446 (2.47%)
         occurrences all number
    15
    18
    14
    11
    COVID-19
         subjects affected / exposed
    22 / 445 (4.94%)
    12 / 452 (2.65%)
    14 / 443 (3.16%)
    14 / 446 (3.14%)
         occurrences all number
    22
    12
    14
    14

    More information

    		 Close Top of page

    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/36063821
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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.

    European Medicines Agency © 1995-Thu Apr 25 14:19:23 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA