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    Clinical Trial Results:
    Multicenter, randomized, active comparator-controlled, double-blind, double-dummy, parallel group, dose-finding Phase 2 study to compare the safety of the oral FXIa inhibitor BAY 2433334 to apixaban in patients with atrial fibrillation

    Summary
    EudraCT number
    		 2019-002365-35
    Trial protocol
    		 CZ   SE   NL   FR   GB   HU   BE   LV   AT   ES   IT  
    Global end of trial date
    08 Oct 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Oct 2022
    First version publication date
    11 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY2433334/19765
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04218266
    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
    05 Nov 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Oct 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate that the oral FXIa inhibitor BAY 2433334 (asundexian) when compared to apixaban leads to a lower incidence of bleeding in participants with atrial fibrillation
    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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jan 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
    Japan: 119
    Country: Number of subjects enrolled
    Czechia: 64
    Country: Number of subjects enrolled
    Hungary: 105
    Country: Number of subjects enrolled
    Latvia: 95
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    Austria: 52
    Country: Number of subjects enrolled
    Belgium: 41
    Country: Number of subjects enrolled
    Switzerland: 20
    Country: Number of subjects enrolled
    Spain: 32
    Country: Number of subjects enrolled
    France: 49
    Country: Number of subjects enrolled
    United Kingdom: 37
    Country: Number of subjects enrolled
    Italy: 47
    Country: Number of subjects enrolled
    Netherlands: 49
    Country: Number of subjects enrolled
    Sweden: 24
    Worldwide total number of subjects
    755
    EEA total number of subjects
    558
    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)
    110
    From 65 to 84 years
    582
    85 years and over
    63

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 94 centers in 14 countries or regions, between 30-Jan-2020 (first subject first visit) and 08-Oct-2021 (last subject last visit)

    Pre-assignment
    Screening details
    		 862 subjects were enrolled. 107 subjects were screening failures. 755 subjects were randomized in a 1:1:1 ratio to 3 treatment groups: 251 subjects to the asundexian 20 mg group, 254 subjects to the asundexian 50 mg group and 250 subjects to the apixaban group. 2 subjects of asundexian 20 mg group never administered drug.

    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 20 mg
    Arm description
    		 Subjects received Asundexian (BAY2433334) 20 mg and Apixaban placebo for 12 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, and Apixaban placebo capsule orally twice daily for 12 weeks

    Arm title
    		 Asundexian 50 mg
    Arm description
    		 Subjects received Asundexian (BAY2433334) 50 mg and Apixaban placebo for 12 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 (two 25 mg tablets) orally once daily in the morning, and Apixaban placebo capsule orally twice daily for 12 weeks

    Arm title
    		 Apixaban
    Arm description
    		 Subjects received Asundexian (BAY2433334) placebo and Apixaban for 12 weeks
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Apixaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Asundexian (BAY2433334) placebo tablet orally once daily in the morning, and Apixaban 2.5 mg or 5 mg capsule orally twice daily for 12 weeks

    Number of subjects in period 1 [1]
    		Asundexian 20 mg Asundexian 50 mg Apixaban
    Started
    249
    254
    250
    Completed
    226
    227
    218
    Not completed
    23
    27
    32
         Consent withdrawn by subject
    1
    3
    1
         Physician decision
    1
    3
    2
         Adverse event, non-fatal
    13
    14
    11
         Death
    1
    2
    3
         Non-compliance with study drug
    -
    -
    1
         Unspecified
    7
    5
    14
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The worldwide number of subjects enrolled was 755, however, the baseline data is presented for the 753 subjects treated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Asundexian 20 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 20 mg and Apixaban placebo for 12 weeks

    Reporting group title
    Asundexian 50 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 50 mg and Apixaban placebo for 12 weeks

    Reporting group title
    Apixaban
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) placebo and Apixaban for 12 weeks

    Reporting group values
    		 Asundexian 20 mg Asundexian 50 mg Apixaban Total
    Number of subjects
    		 249 254 250 753
    Age Categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 33 43 34 110
        From 65-84 years
    		 198 191 191 580
        85 years and over
    		 18 20 25 63
    Gender Categorical
    Units: Subjects
        Female
    		 102 97 109 308
        Male
    		 147 157 141 445
    Race
    Units: Subjects
        Asian
    		 39 40 40 119
        Black or African American
    		 1 1 1 3
        White
    		 209 212 209 630
        Not reported
    		 0 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Asundexian 20 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 20 mg and Apixaban placebo for 12 weeks

    Reporting group title
    Asundexian 50 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 50 mg and Apixaban placebo for 12 weeks

    Reporting group title
    Apixaban
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) placebo and Apixaban for 12 weeks

    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 a treatment group and had taken at least one unit of the study medication.

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

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

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    End point title
    		 Number of subjects with composite of International Society on Thrombosis and Hemostasis (ISTH) major bleeding or 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
    After the first administration of study intervention with an average administration of 12 weeks (but not starting after more than 2 days after the last administration)
    End point values
    		 Asundexian 20 mg Asundexian 50 mg Apixaban Asundexian pooled
    Number of subjects analysed
    249
    254
    250
    503
    Units: Subjects
        ISTH major bleeding or CRNM bleeding
    3
    1
    6
    4
    Statistical analysis title
    		 Pooled ratio of the incidence proportions
    Statistical analysis description
    Comparison of the Asundexian pooled group versus Apixaban group in ISTH major bleeding or CRNM bleeding
    Comparison groups
    Apixaban v Asundexian pooled
    Number of subjects included in analysis
    753
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Crude incidence ratio
    Point estimate
    0.33
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.97

    Secondary: Number of subjects with all bleeding

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    End point title
    		 Number of subjects with all bleeding
    End point description
    Adjudication of all bleeding events was performed by members of the Clinical events committee (CEC) who reviewed events in a blinded fashion and adjudicated and classified the following events in a consistent and unbiased manner according to the following classifications: ISTH (major, clinically relevant non-major and minor); Thrombolysis in myocardial infarction (TIMI major, minor, requiring medical attention, minimal); Bleeding Academic Research Consortium (BARC type 1, 2, 3, 5).
    End point type
    Secondary
    End point timeframe
    After the first administration of study intervention with an average administration of 12 weeks (but not starting after more than 2 days after the last administration)
    End point values
    		 Asundexian 20 mg Asundexian 50 mg Apixaban Asundexian pooled
    Number of subjects analysed
    249
    254
    250
    503
    Units: Subjects
    12
    10
    26
    22
    Statistical analysis title
    		 Pooled ratio of the incidence proportions
    Statistical analysis description
    Comparison of the Asundexian pooled group versus Apixaban group in all bleeding
    Comparison groups
    Apixaban v Asundexian pooled
    Number of subjects included in analysis
    753
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Crude incidence ratio
    Point estimate
    0.42
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.26
         upper limit
    		 0.67

    Secondary: Number of subjects with ISTH major bleeding

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    End point title
    		 Number of subjects with ISTH major 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.
    End point type
    Secondary
    End point timeframe
    After the first administration of study intervention with an average administration of 12 weeks (but not starting after more than 2 days after the last administration)
    End point values
    		 Asundexian 20 mg Asundexian 50 mg Apixaban Asundexian pooled
    Number of subjects analysed
    249
    254
    250
    503
    Units: Subjects
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects of ISTH clinically relevant non-major (CRNM) bleeding

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    End point title
    		 Number of subjects of ISTH clinically relevant non-major (CRNM) bleeding
    End point description
    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
    Secondary
    End point timeframe
    After the first administration of study intervention with an average administration of 12 weeks (but not starting after more than 2 days after the last administration)
    End point values
    		 Asundexian 20 mg Asundexian 50 mg Apixaban Asundexian pooled
    Number of subjects analysed
    249
    254
    250
    503
    Units: Subjects
    3
    1
    6
    4
    Statistical analysis title
    		 Pooled ratio of the incidence proportions
    Statistical analysis description
    Comparison of the Asundexian pooled group versus Apixaban group in ISTH CRNM bleeding
    Comparison groups
    Apixaban v Asundexian pooled
    Number of subjects included in analysis
    753
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Crude incidence ratio
    Point estimate
    0.33
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.97

    Secondary: Number of subjects with ISTH minor bleeding

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    End point title
    		 Number of subjects with ISTH minor bleeding
    End point description
    All other overt bleeding episodes not meeting ISTH Major Bleeding criteria or clinically relevant non major bleeding were classified as minor bleeding.
    End point type
    Secondary
    End point timeframe
    After the first administration of study intervention with an average administration of 12 weeks (but not starting after more than 2 days after the last administration)
    End point values
    		 Asundexian 20 mg Asundexian 50 mg Apixaban Asundexian pooled
    Number of subjects analysed
    249
    254
    250
    503
    Units: Subjects
    10
    9
    20
    19
    Statistical analysis title
    		 Pooled ratio of the incidence proportions
    Statistical analysis description
    Comparison of the Asundexian pooled group versus Apixaban group in ISTH minor bleeding
    Comparison groups
    Apixaban v Asundexian pooled
    Number of subjects included in analysis
    753
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Crude incidence ratio
    Point estimate
    0.47
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 0.83

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After the first administration of study intervention with an average administration of 12 weeks (but not starting after more than 2 days after the last administration).
    Adverse event reporting additional description
    Adverse event reporting for the deaths (all causes) considers all deaths that occurred at any time during the study before the last contact, with an average of 14 weeks.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Asundexian 50 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 50 mg and Apixaban placebo for 12 weeks

    Reporting group title
    Asundexian 20 mg
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) 20 mg and Apixaban placebo for 12 weeks

    Reporting group title
    Apixaban
    Reporting group description
    		 Subjects received Asundexian (BAY2433334) placebo and Apixaban for 12 weeks

    Serious adverse events
    		 Asundexian 50 mg Asundexian 20 mg Apixaban
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 254 (7.87%)
    22 / 249 (8.84%)
    20 / 250 (8.00%)
         number of deaths (all causes)
    4
    2
    5
         number of deaths resulting from adverse events
    3
    1
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder neoplasm
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon neoplasm
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cardiac ablation
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Percutaneous coronary intervention
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Face oedema
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sudden cardiac death
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial haemorrhage
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 254 (1.18%)
    3 / 249 (1.20%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    4 / 254 (1.57%)
    3 / 249 (1.20%)
    3 / 250 (1.20%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus arrest
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 249 (0.80%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Asundexian 50 mg Asundexian 20 mg Apixaban
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    116 / 254 (45.67%)
    110 / 249 (44.18%)
    113 / 250 (45.20%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Prostate cancer
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Haematoma
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    3 / 250 (1.20%)
         occurrences all number
    0
    0
    3
    Hypertension
         subjects affected / exposed
    5 / 254 (1.97%)
    6 / 249 (2.41%)
    7 / 250 (2.80%)
         occurrences all number
    6
    6
    7
    Hypotension
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 249 (0.80%)
    3 / 250 (1.20%)
         occurrences all number
    1
    2
    3
    Orthostatic hypotension
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Peripheral coldness
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 249 (0.80%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    0
    Phlebitis superficial
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Subclavian artery thrombosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertensive urgency
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Hot flush
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Surgical and medical procedures
    Cardiac pacemaker insertion
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Cardioversion
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Tooth extraction
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Cataract operation
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 254 (0.39%)
    3 / 249 (1.20%)
    4 / 250 (1.60%)
         occurrences all number
    1
    3
    4
    Chest discomfort
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Discomfort
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Chest pain
         subjects affected / exposed
    2 / 254 (0.79%)
    3 / 249 (1.20%)
    0 / 250 (0.00%)
         occurrences all number
    2
    3
    0
    Fatigue
         subjects affected / exposed
    10 / 254 (3.94%)
    5 / 249 (2.01%)
    2 / 250 (0.80%)
         occurrences all number
    10
    5
    2
    Feeling abnormal
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    0
    Feeling cold
         subjects affected / exposed
    3 / 254 (1.18%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    3
    0
    0
    Malaise
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    1
    Feeling hot
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Oedema
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    0
    Oedema peripheral
         subjects affected / exposed
    3 / 254 (1.18%)
    2 / 249 (0.80%)
    3 / 250 (1.20%)
         occurrences all number
    3
    2
    3
    Pyrexia
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Pain
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    2
    0
    0
    Thirst
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    1
    Hernia pain
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    General physical health deterioration
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Inflammation
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Adverse drug reaction
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Vessel puncture site haematoma
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Medical device site inflammation
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Amyloidosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Cough
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 249 (0.80%)
    0 / 250 (0.00%)
         occurrences all number
    1
    2
    0
    Dyspnoea
         subjects affected / exposed
    5 / 254 (1.97%)
    3 / 249 (1.20%)
    3 / 250 (1.20%)
         occurrences all number
    6
    3
    3
    Dyspnoea exertional
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Emphysema
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Epistaxis
         subjects affected / exposed
    5 / 254 (1.97%)
    3 / 249 (1.20%)
    11 / 250 (4.40%)
         occurrences all number
    8
    3
    12
    Hiccups
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Productive cough
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    2
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Sputum discoloured
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Hydrothorax
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Pharyngeal paraesthesia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Pharyngeal swelling
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    1
    0
    1
    Confusional state
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Delirium
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Depression
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Insomnia
         subjects affected / exposed
    2 / 254 (0.79%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences all number
    3
    1
    1
    Nightmare
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Investigations
    Amylase increased
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Blood glucose increased
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    2
    0
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    1
    0
    1
    Blood urea increased
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    3 / 250 (1.20%)
         occurrences all number
    0
    1
    3
    Haemoglobin decreased
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Heart rate decreased
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Lipase increased
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    2
    Neutrophil count increased
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    2
    Reticulocyte count decreased
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 249 (0.80%)
    1 / 250 (0.40%)
         occurrences all number
    0
    2
    1
    Urinary occult blood positive
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    2 / 250 (0.80%)
         occurrences all number
    0
    0
    2
    Angiocardiogram
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    SARS-CoV-2 test positive
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Facial bones fracture
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Haematuria traumatic
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Humerus fracture
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    2
    Sunburn
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Wrist fracture
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Contusion
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    3 / 250 (1.20%)
         occurrences all number
    1
    1
    3
    Inflammation of wound
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Lip injury
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Joint injury
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth fracture
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Post-traumatic pain
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Craniocerebral injury
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Skin wound
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Congenital, familial and genetic disorders
    Accessory spleen
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 254 (0.79%)
    2 / 249 (0.80%)
    1 / 250 (0.40%)
         occurrences all number
    2
    2
    1
    Aortic valve stenosis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Arrhythmia supraventricular
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    8 / 254 (3.15%)
    7 / 249 (2.81%)
    7 / 250 (2.80%)
         occurrences all number
    9
    7
    7
    Atrial flutter
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    2
    Atrial tachycardia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Bradycardia
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    2 / 250 (0.80%)
         occurrences all number
    1
    1
    2
    Cardiac failure
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 249 (0.80%)
    5 / 250 (2.00%)
         occurrences all number
    0
    2
    5
    Cardiac failure acute
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    2 / 250 (0.80%)
         occurrences all number
    0
    1
    2
    Cardiomegaly
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Coronary artery disease
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    2
    Myocardial ischaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Palpitations
         subjects affected / exposed
    4 / 254 (1.57%)
    3 / 249 (1.20%)
    1 / 250 (0.40%)
         occurrences all number
    4
    3
    2
    Sinus bradycardia
         subjects affected / exposed
    3 / 254 (1.18%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    3
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 249 (0.00%)
    2 / 250 (0.80%)
         occurrences all number
    2
    0
    2
    Ventricular tachycardia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Dizziness
         subjects affected / exposed
    8 / 254 (3.15%)
    9 / 249 (3.61%)
    7 / 250 (2.80%)
         occurrences all number
    8
    9
    10
    Dysgeusia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    1
    Essential tremor
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Head discomfort
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    7 / 254 (2.76%)
    4 / 249 (1.61%)
    5 / 250 (2.00%)
         occurrences all number
    7
    4
    5
    Hypertonia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 249 (0.80%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    0
    Neuritis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    1 / 254 (0.39%)
    3 / 249 (1.20%)
    0 / 250 (0.00%)
         occurrences all number
    1
    3
    0
    Parkinsonism
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Presyncope
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Sciatica
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Syncope
         subjects affected / exposed
    2 / 254 (0.79%)
    2 / 249 (0.80%)
    0 / 250 (0.00%)
         occurrences all number
    2
    2
    0
    Orthostatic intolerance
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 249 (0.80%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    0
    Tremor
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 249 (0.80%)
    0 / 250 (0.00%)
         occurrences all number
    1
    2
    0
    Polycythaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Spontaneous haematoma
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    0
    Vertigo
         subjects affected / exposed
    4 / 254 (1.57%)
    2 / 249 (0.80%)
    3 / 250 (1.20%)
         occurrences all number
    4
    2
    3
    Vertigo labyrinthine
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 249 (0.80%)
    2 / 250 (0.80%)
         occurrences all number
    0
    2
    2
    Dry eye
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Myopia
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Eye irritation
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Photophobia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Swelling of eyelid
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    2 / 250 (0.80%)
         occurrences all number
    0
    1
    2
    Visual acuity reduced
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 249 (0.80%)
    0 / 250 (0.00%)
         occurrences all number
    1
    2
    0
    Abdominal distension
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    0
    Abdominal pain
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 254 (1.18%)
    2 / 249 (0.80%)
    6 / 250 (2.40%)
         occurrences all number
    3
    2
    6
    Change of bowel habit
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    2 / 254 (0.79%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    2
    1
    0
    Dental caries
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Dry mouth
         subjects affected / exposed
    3 / 254 (1.18%)
    3 / 249 (1.20%)
    1 / 250 (0.40%)
         occurrences all number
    3
    3
    1
    Diarrhoea
         subjects affected / exposed
    11 / 254 (4.33%)
    4 / 249 (1.61%)
    5 / 250 (2.00%)
         occurrences all number
    11
    5
    5
    Dyspepsia
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences all number
    1
    1
    1
    Eructation
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Food poisoning
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    0
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Gingival bleeding
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    1
    0
    1
    Haematochezia
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    8 / 254 (3.15%)
    6 / 249 (2.41%)
    9 / 250 (3.60%)
         occurrences all number
    8
    7
    10
    Melaena
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Oesophagitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Oral discomfort
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Saliva altered
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Stomatitis
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    0
    Vomiting
         subjects affected / exposed
    2 / 254 (0.79%)
    2 / 249 (0.80%)
    1 / 250 (0.40%)
         occurrences all number
    2
    2
    1
    Large intestinal haemorrhage
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Toothache
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences all number
    1
    1
    1
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal symptom
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Cholestasis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatic fibrosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatomegaly
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 249 (0.80%)
    1 / 250 (0.40%)
         occurrences all number
    0
    2
    1
    Blister
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis contact
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    1
    Intertrigo
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Papule
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    3 / 254 (1.18%)
    5 / 249 (2.01%)
    3 / 250 (1.20%)
         occurrences all number
    3
    5
    3
    Rash
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    2
    0
    0
    Rash papular
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Rash pruritic
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    0
    Skin disorder
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Skin fissures
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Skin ulcer
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Skin reaction
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Skin haemorrhage
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    1
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 249 (0.80%)
    6 / 250 (2.40%)
         occurrences all number
    0
    2
    6
    Hydronephrosis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Nocturia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 249 (0.80%)
    0 / 250 (0.00%)
         occurrences all number
    0
    2
    0
    Renal colic
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Renal cyst
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    1
    0
    1
    Renal failure
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    1
    0
    1
    Urinary retention
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Renal impairment
         subjects affected / exposed
    3 / 254 (1.18%)
    2 / 249 (0.80%)
    0 / 250 (0.00%)
         occurrences all number
    3
    2
    0
    Chronic kidney disease
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    2 / 250 (0.80%)
         occurrences all number
    0
    0
    2
    Acute kidney injury
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    2
    0
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    2 / 250 (0.80%)
         occurrences all number
    0
    1
    2
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 254 (1.57%)
    0 / 249 (0.00%)
    2 / 250 (0.80%)
         occurrences all number
    4
    0
    2
    Back pain
         subjects affected / exposed
    1 / 254 (0.39%)
    4 / 249 (1.61%)
    1 / 250 (0.40%)
         occurrences all number
    1
    5
    1
    Bursitis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Joint swelling
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    0
    Muscle spasms
         subjects affected / exposed
    2 / 254 (0.79%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    2
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 249 (0.80%)
    0 / 250 (0.00%)
         occurrences all number
    0
    3
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Myalgia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    1
    0
    1
    Pain in extremity
         subjects affected / exposed
    2 / 254 (0.79%)
    2 / 249 (0.80%)
    0 / 250 (0.00%)
         occurrences all number
    2
    2
    0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    1
    0
    1
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Limb discomfort
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Spinal stenosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    1
    Erysipelas
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Gingivitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Herpes zoster
         subjects affected / exposed
    0 / 254 (0.00%)
    3 / 249 (1.20%)
    0 / 250 (0.00%)
         occurrences all number
    0
    3
    0
    Localised infection
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 254 (1.18%)
    1 / 249 (0.40%)
    2 / 250 (0.80%)
         occurrences all number
    3
    1
    3
    Pharyngitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Periodontitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    2
    0
    0
    Pulpitis dental
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Tinea cruris
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 249 (0.80%)
    3 / 250 (1.20%)
         occurrences all number
    0
    2
    3
    Viral infection
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Gingival abscess
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0
    Oral fungal infection
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    COVID-19
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    2
    0
    0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Diabetes mellitus
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    2
    0
    0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Fluid overload
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Gout
         subjects affected / exposed
    1 / 254 (0.39%)
    4 / 249 (1.61%)
    1 / 250 (0.40%)
         occurrences all number
    1
    4
    1
    Folate deficiency
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    2 / 250 (0.80%)
         occurrences all number
    1
    1
    2
    Hyperkalaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences all number
    1
    1
    1
    Hyperuricaemia
         subjects affected / exposed
    2 / 254 (0.79%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences all number
    2
    1
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    1
    1
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    1 / 250 (0.40%)
         occurrences all number
    0
    1
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 249 (0.40%)
    0 / 250 (0.00%)
         occurrences all number
    0
    1
    0
    Decreased appetite
         subjects affected / exposed
    0 / 254 (0.00%)
    0 / 249 (0.00%)
    1 / 250 (0.40%)
         occurrences all number
    0
    0
    1
    Hyperlipidaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 249 (0.00%)
    0 / 250 (0.00%)
         occurrences all number
    1
    0
    0

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

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    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.

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