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    Clinical Trial Results:
    Evaluation of Edoxaban in Anticoagulant Naïve Patients with Non-Valvular Atrial Fibrillation (NVAF) and high Creatinine Clearance

    Summary
    EudraCT number
    		 2016-001795-30
    Trial protocol
    		 LV   CZ   EE   LT   SK   DK   HU   ES   BE   PL   HR  
    Global end of trial date
    09 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Oct 2019
    First version publication date
    25 Oct 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    DU176b-C-E314
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02964949
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo, Inc.
    Sponsor organisation address
    211 Mount Airy Road, Basking Ridge, United States, 07920
    Public contact
    Clinical Trial Information Contact, Daiichi Sankyo, Inc., +1 908-992-6400, CTRinfo@dsi.com
    Scientific contact
    Clinical Trial Information Contact, Daiichi Sankyo, Inc., +1 908-992-6400, CTRinfo@dsi.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
    26 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to compare the exposure (based on average concentration at steady state (Cav), minimum concentration in plasma (Cmin), and anti-factor Xa [anti-FXa]) of edoxaban 75 mg once daily (QD) dose to edoxaban 60 mg QD dose in NVAF anticoagulant-naïve patients with CHADS2 score of ≥ 2 and CrCL > 100 mL/min (as calculated by the Cockcroft-Gault formula) treated for up to 12 months.
    Protection of trial subjects
    This study was conducted in compliance with the protocol, the ethical principles derived from the Declaration of Helsinki, the International Council for Harmonisation (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jan 2017
    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
    Poland: 46
    Country: Number of subjects enrolled
    Slovakia: 49
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Bulgaria: 91
    Country: Number of subjects enrolled
    Czech Republic: 36
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    Estonia: 13
    Country: Number of subjects enrolled
    Hungary: 43
    Country: Number of subjects enrolled
    Latvia: 41
    Country: Number of subjects enrolled
    Lithuania: 29
    Country: Number of subjects enrolled
    Russian Federation: 53
    Country: Number of subjects enrolled
    Serbia: 27
    Country: Number of subjects enrolled
    Ukraine: 170
    Worldwide total number of subjects
    607
    EEA total number of subjects
    357
    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)
    396
    From 65 to 84 years
    211
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 607 subjects who met the inclusion and none of the exclusion criteria were randomized; 606 subjects received the study drug.

    Pre-assignment
    Screening details
    		 Subjects were recruited after verification of inclusion and exclusion criteria including a diagnosis of non-valvular atrial fibrillation (NVAF) and anticoagulant-naive, and creatinine clearance (CrCL) >100 mL/min (calculated by Cockcroft-Gault formula).

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    This was a randomized, double-blind study. Blinding was applied to all personnel related to the study (subjects, investigators, and Sponsor).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Edoxaban 75 mg
    Arm description
    		 Subjects received Edoxaban 60 mg and Edoxaban 15 mg orally, once daily at the same time (preferably morning) up to 12 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 60 mg active tablet and one 15 mg active tablet taken orally once every day

    Arm title
    		 Edoxaban 60 mg
    Arm description
    		 Subjects received Edoxaban 60 mg and placebo 15 mg orally, once daily at the same time (preferably morning) up to 12 months.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 60 mg active tablet and one 15 mg placebo tablet taken orally once every day

    Number of subjects in period 1
    		Edoxaban 75 mg Edoxaban 60 mg
    Started
    304
    303
    Completed
    297
    299
    Not completed
    7
    4
         Consent withdrawn by subject
    -
    1
         Death
    7
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Edoxaban 75 mg
    Reporting group description
    		 Subjects received Edoxaban 60 mg and Edoxaban 15 mg orally, once daily at the same time (preferably morning) up to 12 months.

    Reporting group title
    Edoxaban 60 mg
    Reporting group description
    		 Subjects received Edoxaban 60 mg and placebo 15 mg orally, once daily at the same time (preferably morning) up to 12 months.

    Reporting group values
    		 Edoxaban 75 mg Edoxaban 60 mg Total
    Number of subjects
    		 304 303 607
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 201 195 396
        From 65-84 years
    		 103 108 211
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.4 ( 8.39 ) 60.9 ( 8.06 ) -
    Gender categorical
    Units: Subjects
        Female
    		 82 88 170
        Male
    		 222 215 437

    End points

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    End points reporting groups
    Reporting group title
    Edoxaban 75 mg
    Reporting group description
    		 Subjects received Edoxaban 60 mg and Edoxaban 15 mg orally, once daily at the same time (preferably morning) up to 12 months.

    Reporting group title
    Edoxaban 60 mg
    Reporting group description
    		 Subjects received Edoxaban 60 mg and placebo 15 mg orally, once daily at the same time (preferably morning) up to 12 months.

    Primary: Analysis of Pharmacokinetic Parameter: Average Concentration of Edoxaban (Cav)

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    End point title
    		 Analysis of Pharmacokinetic Parameter: Average Concentration of Edoxaban (Cav)
    End point description
    Cav is the average concentration of Edoxaban in plasma.
    End point type
    Primary
    End point timeframe
    Days 30, 90, and 360 post-dose and at steady state (SS)
    End point values
    		 Edoxaban 75 mg Edoxaban 60 mg
    Number of subjects analysed
    297
    298
    Units: Mean concentration
    arithmetic mean (standard deviation)
        Day 30 (n=297, 297)
    93.25 ( 16.18 )
    75.09 ( 13.38 )
        Day 90 (n=288, 295)
    94.18 ( 17.42 )
    75.81 ( 14.49 )
        Day 360 (n=279, 286)
    94.72 ( 18.03 )
    76.60 ( 15.10 )
        Steady state (n=297, 298)
    93.24 ( 16.21 )
    74.84 ( 13.33 )
    Statistical analysis title
    		 Ratio of Means (Edoxaban 75 mg/Edoxaban 60 mg)-D30
    Statistical analysis description
    This statistical analysis assesses the ratio of means between Edoxaban 75 mg and Edoxaban 60 mg (Day 30).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    595
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.0001
    Method
    		 Based on log-transformed values
    Parameter type
    		 Ratio of means
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.21
         upper limit
    		 1.28
    Notes
    [1] - Ratio of means
    Statistical analysis title
    		 Ratio of Means (Edoxaban 75 mg/Edoxaban 60 mg)-D90
    Statistical analysis description
    This statistical analysis assesses the ratio of means between Edoxaban 75 mg (n=288) and Edoxaban 60 mg (n=295) (Day 90).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    595
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.0001
    Method
    		 Based on log-transformed values
    Parameter type
    		 Ratio of means
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.21
         upper limit
    		 1.28
    Notes
    [2] - Ratio of means
    Statistical analysis title
    		 Ratio of Means (Edoxaban 75mg/Edoxaban 60mg)-D360
    Statistical analysis description
    This statistical analysis assesses the ratio of means between Edoxaban 75 mg (n=279) and Edoxaban 60 mg (n=286) (Day 360).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    595
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.0001
    Method
    		 Based on log-transformed values
    Parameter type
    		 Ratio of means
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 1.28
    Notes
    [3] - Ratio of means
    Statistical analysis title
    		 Ratio of Means (Edoxaban 75mg/Edoxaban 60mg)-SS
    Statistical analysis description
    This statistical analysis assesses the ratio of means between Edoxaban 75 mg and Edoxaban 60 mg (steady state [SS]).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    595
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.0001
    Method
    		 Based on log-transformed values
    Parameter type
    		 Ratio of means
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.21
         upper limit
    		 1.28
    Notes
    [4] - Ratio of means

    Primary: Analysis of Pharmacokinetic Parameter: Maximum Concentration of Edoxaban (Cmax)

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    End point title
    		 Analysis of Pharmacokinetic Parameter: Maximum Concentration of Edoxaban (Cmax)
    End point description
    Cmax is the maximum concentration of Edoxaban in plasma.
    End point type
    Primary
    End point timeframe
    Days 30, 90, and 360 post-dose and at steady state (SS)
    End point values
    		 Edoxaban 75 mg Edoxaban 60 mg
    Number of subjects analysed
    297
    298
    Units: Mean concentration
    arithmetic mean (standard deviation)
        Day 30 (n=297, 297)
    268.70 ( 62.59 )
    216.42 ( 51.67 )
        Day 90 (n=288, 295)
    266.99 ( 72.41 )
    215.97 ( 62.76 )
        Day 360 (n=279, 286)
    273.65 ( 65.66 )
    219.63 ( 53.36 )
        Steady state (n=297, 298)
    268.72 ( 62.36 )
    214.43 ( 51.09 )
    Statistical analysis title
    		 Ratio of Means (Edoxaban 75 mg/Edoxaban 60 mg)-D30
    Statistical analysis description
    This statistical analysis assesses the ratio of means between Edoxaban 75 mg and Edoxaban 60 mg (Day 30).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    595
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.0001
    Method
    		 Based on log-transformed values
    Parameter type
    		 Ratio of means
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 1.29
    Notes
    [5] - Ratio of means
    Statistical analysis title
    		 Ratio of Means (Edoxaban 75 mg/Edoxaban 60 mg)-D90
    Statistical analysis description
    This statistical analysis assesses the ratio of means between Edoxaban 75 mg (n=288) and Edoxaban 60 mg (n=295) (Day 90).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    595
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.0001
    Method
    		 Based on log-transformed values
    Parameter type
    		 Ratio of means
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.19
         upper limit
    		 1.3
    Notes
    [6] - Ratio of means
    Statistical analysis title
    		 Ratio of Means (Edoxaban 75mg/Edoxaban 60mg)-D360
    Statistical analysis description
    This statistical analysis assesses the ratio of means between Edoxaban 75 mg (n=279) and Edoxaban 60 mg (n=286) (Day 360).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    595
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 < 0.0001
    Method
    		 Based on log-transformed values
    Parameter type
    		 Ratio of means
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 1.3
    Notes
    [7] - Ratio of means
    Statistical analysis title
    		 Ratio of Means (Edoxaban 75mg/Edoxaban 60 mg)-SS
    Statistical analysis description
    This statistical analysis assesses the ratio of means between Edoxaban 75 mg and Edoxaban 60 mg (steady state [SS]).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    595
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 < 0.0001
    Method
    		 Based on log-transformed values
    Parameter type
    		 Ratio of means
    Point estimate
    1.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.21
         upper limit
    		 1.3
    Notes
    [8] - Ratio of means

    Primary: Analysis of Pharmacokinetic Parameter: Minimum Concentration of Exdoxaban (Cmin)

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    End point title
    		 Analysis of Pharmacokinetic Parameter: Minimum Concentration of Exdoxaban (Cmin)
    End point description
    Cmin is the minimum concentration of Edoxaban in plasma.
    End point type
    Primary
    End point timeframe
    Days 30, 90, and 360 post-dose and at steady state (SS)
    End point values
    		 Edoxaban 75 mg Edoxaban 60 mg
    Number of subjects analysed
    297
    298
    Units: Mean concentration
    arithmetic mean (standard deviation)
        Day 30 (n=297, 297)
    22.40 ( 6.48 )
    18.31 ( 5.33 )
        Day 90 (n=288, 295)
    22.79 ( 5.52 )
    18.44 ( 4.52 )
        Day 360 (n=279, 286)
    22.92 ( 7.77 )
    18.70 ( 6.19 )
        Steady state (n=297, 298)
    22.52 ( 6.49 )
    18.18 ( 5.20 )
    Statistical analysis title
    		 Ratio of Means (Edoxaban 75 mg/Edoxaban 60 mg)-D30
    Statistical analysis description
    This statistical analysis assesses the ratio of means between Edoxaban 75 mg and Edoxaban 60 mg (Day 30).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    595
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 < 0.0001
    Method
    		 Based on log-transformed values
    Parameter type
    		 Ratio of means
    Point estimate
    1.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.17
         upper limit
    		 1.29
    Notes
    [9] - Ratio of means
    Statistical analysis title
    		 Ratio of Means (Edoxaban 75 mg/Edoxaban 60 mg-D90
    Statistical analysis description
    This statistical analysis assesses the ratio of means between Edoxaban 75 mg (n=288) and Edoxaban 60 mg (n=295) (Day 90).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    595
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 < 0.0001
    Method
    		 Based on log-transformed values
    Parameter type
    		 Ratio of means
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.19
         upper limit
    		 1.29
    Notes
    [10] - Ratio of means
    Statistical analysis title
    		 Ratio of Means (Edoxaban 75mg/Edoxaban 60mg)-D360
    Statistical analysis description
    This statistical analysis assesses the ratio of means between Edoxaban 75 mg (n=279) and Edoxaban 60 mg (n=286) (Day 360).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    595
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 < 0.0001
    Method
    		 Based on log-transformed values
    Parameter type
    		 Ratio of means
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.16
         upper limit
    		 1.3
    Notes
    [11] - Ratio of means
    Statistical analysis title
    		 Ratio of Means (Edoxaban 75mg/Edoxaban 60 mg)-SS
    Statistical analysis description
    This statistical analysis assesses the ratio of means between Edoxaban 75 mg and Edoxaban 60 mg (steady state [SS]).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    595
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 < 0.0001
    Method
    		 Based on log-transformed values
    Parameter type
    		 Ratio of means
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.18
         upper limit
    		 1.3
    Notes
    [12] - Ratio of means

    Primary: Analysis of Pharmacodynamics: Mean Exposure of Edoxaban Using Anti-Factor Xa Assay

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    End point title
    		 Analysis of Pharmacodynamics: Mean Exposure of Edoxaban Using Anti-Factor Xa Assay
    End point description
    The exposure of Edoxaban 75 mg was compared with Edoxaban 60 mg using a pharmacodynamic marker, anti-FXa.
    End point type
    Primary
    End point timeframe
    Day 0 (baseline) and at Days 30, 90, and 360 (at pre-dose [SS], 1-2 hours post-dose, and 4-8 hours post-dose)
    End point values
    		 Edoxaban 75 mg Edoxaban 60 mg
    Number of subjects analysed
    292
    291
    Units: Mean concentration
    arithmetic mean (standard deviation)
        Day 0 (n=292, 291)
    11.02 ( 37.18 )
    12.54 ( 41.83 )
        Day 30 pre-dose (n=284, 284)
    33.44 ( 58.22 )
    28.02 ( 58.12 )
        Day 30, 1-2 h post-dose (n=291, 280)
    233.37 ( 121.92 )
    201.24 ( 109.48 )
        Day 30, 4-8 h post-dose (n=292, 280)
    190.84 ( 73.36 )
    161.38 ( 63.46 )
        Day 90 pre-dose (n=273, 281)
    33.42 ( 59.23 )
    23.10 ( 47.12 )
        Day 90, 1-2 h post-dose (n=280, 281)
    229.32 ( 119.89 )
    179.69 ( 107.48 )
        Day 90, 4-8 h post-dose (n=277, 283)
    183.90 ( 78.65 )
    156.73 ( 67.12 )
        Day 360 pre-dose (n=269, 276)
    35.87 ( 59.23 )
    26.01 ( 55.48 )
        Day 360, 1-2 h post-dose (n=269, 277)
    214.73 ( 126.44 )
    181.13 ( 111.22 )
        Day 360, 4-8 h post-dose (n=267, 279)
    183.75 ( 94.73 )
    147.23 ( 76.63 )
    Statistical analysis title
    		 Difference of least square means (Day 30 pre-dose)
    Statistical analysis description
    This statistical analysis reports the difference in the least square means between Edoxaban 75 mg (n=284) and Edoxaban 60 mg (n=284) (Day 30 pre-dose).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 = 0.2644
    Method
    		 ANCOVA
    Parameter type
    		 Difference of least square means
    Point estimate
    5.464
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.14
         upper limit
    		 15.07
    Notes
    [13] - Difference in least square means
    Statistical analysis title
    		 Difference of least square means (Day 30, 1-2 h)
    Statistical analysis description
    This statistical analysis reports the difference in the least square means between Edoxaban 75 mg (n=291) and Edoxaban 60 mg (n=280) (Day 30, 1-2 h post-dose).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference of least square means
    Point estimate
    32.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.14
         upper limit
    		 51.39
    Notes
    [14] - Difference in least square means
    Statistical analysis title
    		 Difference of least square means (Day 30, 4-8 h)
    Statistical analysis description
    This statistical analysis reports the difference in the least square means between Edoxaban 75 mg (n=292) and Edoxaban 60 mg (n=280) (Day 30, 4-8 h post-dose).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference of least square means
    Point estimate
    29.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18.49
         upper limit
    		 41.08
    Notes
    [15] - Difference in least square means
    Statistical analysis title
    		 Difference of least square means (Day 90 pre-dose)
    Statistical analysis description
    This statistical analysis reports the difference in the least square means between Edoxaban 75 mg (n=273) and Edoxaban 60 mg (n=281) (Day 90 pre-dose).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.0228
    Method
    		 ANCOVA
    Parameter type
    		 Difference of least square means
    Point estimate
    10.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.45
         upper limit
    		 19.31
    Notes
    [16] - Difference in least square means
    Statistical analysis title
    		 Difference of least square means (Day 90, 1-2 h)
    Statistical analysis description
    This statistical analysis reports the difference in the least square means between Edoxaban 75 mg (n=280) and Edoxaban 60 mg (n=281) (Day 90, 1-2 h post-dose).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference of least square means
    Point estimate
    49.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 31.11
         upper limit
    		 68.88
    Notes
    [17] - Difference in least square means
    Statistical analysis title
    		 Difference of least square means; Day 360 pre-dose
    Statistical analysis description
    This statistical analysis reports the difference in the least square means between Edoxaban 75 mg (n=269) and Edoxaban 60 mg (n=276) (Day 360 pre-dose).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.0478
    Method
    		 ANCOVA
    Parameter type
    		 Difference of least square means
    Point estimate
    9.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 19.45
    Notes
    [18] - Difference in least square means
    Statistical analysis title
    		 Difference of least square means; Day 360, 1-2 h
    Statistical analysis description
    This statistical analysis reports the difference in the least square means between Edoxaban 75 mg (n=269) and Edoxaban 60 mg (n=277) (Day 360, 1-2 h post-dose).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.0011
    Method
    		 ANCOVA
    Parameter type
    		 Difference of least square means
    Point estimate
    33.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.54
         upper limit
    		 53.6
    Notes
    [19] - Difference in least square means
    Statistical analysis title
    		 Difference of least square means; Day 360, 4-8 h
    Statistical analysis description
    This statistical analysis reports the difference in the least square means between Edoxaban 75 mg (n=267) and Edoxaban 60 mg (n=279) (Day 360, 4-8 h post-dose).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference of least square means
    Point estimate
    36.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 22.41
         upper limit
    		 51.32
    Notes
    [20] - Difference in least square means
    Statistical analysis title
    		 Difference of least square means (Day 90, 4-8 h)
    Statistical analysis description
    This statistical analysis reports the difference in the least square means between Edoxaban 75 mg (n=277) and Edoxaban 60 mg (n=283) (Day 90, 4-8 h post-dose).
    Comparison groups
    Edoxaban 75 mg v Edoxaban 60 mg
    Number of subjects included in analysis
    583
    Analysis specification
    Pre-specified
    Analysis type
    		 other [21]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference of least square means
    Point estimate
    27.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 15.27
         upper limit
    		 39.5
    Notes
    [21] - Difference in least square means

    Secondary: Number of Subjects With Adjudicated Composite Endpoint: Composite of Stroke, Transient Ischemic Attack, and Systemic Embolic Events (On-Treatment Period)

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    End point title
    		 Number of Subjects With Adjudicated Composite Endpoint: Composite of Stroke, Transient Ischemic Attack, and Systemic Embolic Events (On-Treatment Period)
    End point description
    The composite endpoint included stroke, transient ischemic attack (TIA), and systemic embolic events (SEE).
    End point type
    Secondary
    End point timeframe
    Within 360 days post-dose
    End point values
    		 Edoxaban 75 mg Edoxaban 60 mg
    Number of subjects analysed
    303
    303
    Units: number of subjects
    number (not applicable)
        First of stroke, TIA, and SEE
    3
    2
    No statistical analyses for this end point

    Secondary: Analysis of Adjudicated Composite Endpoint: Composite of Stroke, Transient Ischemic Attack, Systemic Embolic Events, Myocardial Infarction, Cardiovascular Death, and Major Bleeding (On-Treatment Period)

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    End point title
    		 Analysis of Adjudicated Composite Endpoint: Composite of Stroke, Transient Ischemic Attack, Systemic Embolic Events, Myocardial Infarction, Cardiovascular Death, and Major Bleeding (On-Treatment Period)
    End point description
    The composite endpoint included Stroke, Transient Ischemic Attack (TIA), Systemic Embolic Events (SEE), Myocardial Infarction (MI), Cardiovascular Death, and Major Bleeding events.
    End point type
    Secondary
    End point timeframe
    Within 360 days post-dose
    End point values
    		 Edoxaban 75 mg Edoxaban 60 mg
    Number of subjects analysed
    303
    303
    Units: Number of subjects
    number (not applicable)
        First stroke, TIA, SEE, MI, death, and bleeding
    8
    5
        First adjudicated stroke
    3
    2
        First adjudicated TIA
    0
    0
        First adjudicated SEE
    0
    0
        First adjudicated MI
    0
    0
        First adjudicated death
    5
    1
        First adjudicated major bleeding
    3
    2
    No statistical analyses for this end point

    Secondary: Analysis of Adjudicated Bleeding Events: Major Bleeding and/or Clinically Relevant Non-Major Bleeding (On-Treatment Period)

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    End point title
    		 Analysis of Adjudicated Bleeding Events: Major Bleeding and/or Clinically Relevant Non-Major Bleeding (On-Treatment Period)
    End point description
    Adjudicated bleeding events (major bleeding and clinically relevant non-major [CRNM] bleeding events) were assessed.
    End point type
    Secondary
    End point timeframe
    Within 360 days post-dose
    End point values
    		 Edoxaban 75 mg Edoxaban 60 mg
    Number of subjects analysed
    303
    303
    Units: Number of subjects
    number (not applicable)
        Major bleeding or CRNM bleeding
    10
    11
        First adjudicated major bleeding
    3
    2
        First adjudicated CRNM bleeding
    7
    9
        All bleeding
    20
    19
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adjudicated Composite Endpoint: Composite of Ischemic Stroke, Transient Ischemic Attack, and Systemic Embolic Events (On-Treatment Period)

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    End point title
    		 Number of Subjects With Adjudicated Composite Endpoint: Composite of Ischemic Stroke, Transient Ischemic Attack, and Systemic Embolic Events (On-Treatment Period)
    End point description
    The composite endpoint included ischemic stroke, transient ischemic attack (TIA), and systemic embolic events (SEE).
    End point type
    Secondary
    End point timeframe
    Within 360 days post-dose
    End point values
    		 Edoxaban 75 mg Edoxaban 60 mg
    Number of subjects analysed
    303
    303
    Units: Number of subjects
    number (not applicable)
        First of ischemic stroke, TIA, and SEE
    1
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data were collected and reported from the time of signing the informed consent form to the end of study assessment and follow-up period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Edoxaban 75 mg
    Reporting group description
    		 Subjects received Edoxaban 60 mg and Edoxaban 15 mg orally, once daily at the same time (preferably morning) up to 12 months.

    Reporting group title
    Edoxaban 60 mg
    Reporting group description
    		 Subjects received Edoxaban 60 mg and placebo 15 mg orally, once daily at the same time (preferably morning) up to 12 months.

    Serious adverse events
    		 Edoxaban 75 mg Edoxaban 60 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 303 (14.52%)
    33 / 303 (10.89%)
         number of deaths (all causes)
    7
    3
         number of deaths resulting from adverse events
    5
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer metastatic
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lymph nodes
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Knee arthroplasty
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 303 (0.66%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Investigations
    Prostatic specific antigen increased
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scrotal haematoma
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    10 / 303 (3.30%)
    8 / 303 (2.64%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 303 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    4 / 303 (1.32%)
    6 / 303 (1.98%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Cardiac failure acute
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 303 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinoatrial block
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachyarrhythmia
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 303 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic neuropathy
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye haemorrhage
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis erosive
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 303 (0.66%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle mass
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 303 (0.00%)
    2 / 303 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteochondritis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Chronic sinusitis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 303 (0.66%)
    1 / 303 (0.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 303 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Edoxaban 75 mg Edoxaban 60 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    132 / 303 (43.56%)
    115 / 303 (37.95%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 303 (2.64%)
    8 / 303 (2.64%)
         occurrences all number
    8
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 303 (1.65%)
    1 / 303 (0.33%)
         occurrences all number
    5
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 303 (0.33%)
    3 / 303 (0.99%)
         occurrences all number
    1
    3
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 303 (0.66%)
    3 / 303 (0.99%)
         occurrences all number
    2
    3
    Epistaxis
         subjects affected / exposed
    3 / 303 (0.99%)
    2 / 303 (0.66%)
         occurrences all number
    3
    2
    Investigations
    Blood pressure increased
         subjects affected / exposed
    3 / 303 (0.99%)
    2 / 303 (0.66%)
         occurrences all number
    3
    2
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    14 / 303 (4.62%)
    12 / 303 (3.96%)
         occurrences all number
    14
    12
    Cardiac failure
         subjects affected / exposed
    5 / 303 (1.65%)
    7 / 303 (2.31%)
         occurrences all number
    5
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 303 (1.98%)
    7 / 303 (2.31%)
         occurrences all number
    6
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 303 (0.00%)
    3 / 303 (0.99%)
         occurrences all number
    0
    3
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 303 (0.00%)
    3 / 303 (0.99%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Anal haemorrhage
         subjects affected / exposed
    3 / 303 (0.99%)
    0 / 303 (0.00%)
         occurrences all number
    3
    0
    Diarrhea
         subjects affected / exposed
    4 / 303 (1.32%)
    2 / 303 (0.66%)
         occurrences all number
    4
    2
    Gingival bleeding
         subjects affected / exposed
    0 / 303 (0.00%)
    3 / 303 (0.99%)
         occurrences all number
    0
    3
    Haemorrhoids
         subjects affected / exposed
    4 / 303 (1.32%)
    1 / 303 (0.33%)
         occurrences all number
    4
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 303 (0.00%)
    3 / 303 (0.99%)
         occurrences all number
    0
    3
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    4 / 303 (1.32%)
    4 / 303 (1.32%)
         occurrences all number
    4
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 303 (0.99%)
    2 / 303 (0.66%)
         occurrences all number
    3
    2
    Back pain
         subjects affected / exposed
    5 / 303 (1.65%)
    0 / 303 (0.00%)
         occurrences all number
    5
    0
    Osteoarthritis
         subjects affected / exposed
    3 / 303 (0.99%)
    2 / 303 (0.66%)
         occurrences all number
    3
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    7 / 303 (2.31%)
    4 / 303 (1.32%)
         occurrences all number
    7
    4
    Influenza
         subjects affected / exposed
    6 / 303 (1.98%)
    5 / 303 (1.65%)
         occurrences all number
    6
    5
    Nasopharyngitis
         subjects affected / exposed
    4 / 303 (1.32%)
    4 / 303 (1.32%)
         occurrences all number
    4
    4
    Pneumonia
         subjects affected / exposed
    3 / 303 (0.99%)
    2 / 303 (0.66%)
         occurrences all number
    3
    2
    Respiratory tract infection viral
         subjects affected / exposed
    6 / 303 (1.98%)
    1 / 303 (0.33%)
         occurrences all number
    6
    1
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 303 (1.98%)
    3 / 303 (0.99%)
         occurrences all number
    6
    3
    Urinary tract infection
         subjects affected / exposed
    3 / 303 (0.99%)
    1 / 303 (0.33%)
         occurrences all number
    3
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    4 / 303 (1.32%)
    1 / 303 (0.33%)
         occurrences all number
    4
    1
    Hyperuricaemia
         subjects affected / exposed
    2 / 303 (0.66%)
    3 / 303 (0.99%)
         occurrences all number
    2
    3
    Type 2 diabetes mellitus
         subjects affected / exposed
    3 / 303 (0.99%)
    3 / 303 (0.99%)
         occurrences all number
    3
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Mar 2017
    Clarified inclusion and exclusion criteria, updated the list of participating countries, updated screening, randomization, and baseline procedures, clarified adverse event collection and reporting procedures, confirmed appropriate reporting procedures for prior and concomitant medications, updated the PK/PD procedures, and modified study period and bleeding definitions.

    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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    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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