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    Clinical Trial Results:
    A Randomized, Open-Label, Parallel-Group, Multi-Center Study of Adding Edoxaban or Clopidogrel to Aspirin to Maintain Patency in Subjects With Peripheral Arterial Disease Following Femoropopliteal Endovascular Intervention - Edoxaban in Peripheral Arterial Disease (ePAD)

    Summary
    EudraCT number
    2012-003009-88
    Trial protocol
    DE   BE   NL   AT  
    Global end of trial date
    03 Dec 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    07 Sep 2017
    First version publication date
    18 Aug 2016
    Other versions
    v1
    Version creation reason
    • Changes to summary attachments
    Taken out for editing in error - no summary needed, as a full data set was finalised.

    Trial information

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    Trial identification
    Sponsor protocol code
    DU176b-E-U210
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01802775
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo Pharma Development
    Sponsor organisation address
    399 THORNALL STREET, Edison, New Jersey, United States, 08837
    Public contact
    Clinical Trial Information, Daiichi Sankyo Development Ltd, +44 1753482800, info@dsd-eu.com
    Scientific contact
    Clinical Trial Information, Daiichi Sankyo Development Ltd, +44 1753482800, info@dsd-eu.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Dec 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate clinically relevant bleeding (that is, major or clinically relevant non-major bleeding) occurring during treatment or within 3 days of interrupting or stopping study drug and to evaluate re-stenosis/re-occlusion at the treated segment(s) measured at 1, 3 and 6 months after randomization using color coded duplex ultrasonography scanning (DUS).
    Protection of trial subjects
    The safety assessments included clinical laboratory tests, Physical examination, vital signs and ECG variables. Adverse events were monitored throughout the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Feb 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Switzerland: 25
    Country: Number of subjects enrolled
    United States: 89
    Country: Number of subjects enrolled
    Austria: 28
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Netherlands: 13
    Worldwide total number of subjects
    203
    EEA total number of subjects
    77
    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)
    63
    From 65 to 84 years
    133
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 275 subjects were screened, of these 203 subjects were randomized into the study, with 101 subjects in the edoxaban group and 102 subjects in the clopidogrel group.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Clopidogrel
    Arm description
    Subjects administered with a loading dose of clopidogrel 300 milligram (mg) (four 75-mg tablets) as first dose within 4 hours of hemostasis followed by 75 mg once daily (QD) (one 75 mg tablet) orally for a total of approximately 3 months on a background of aspirin 100 mg enteric coated tablets QD.
    Arm type
    Active comparator

    Investigational medicinal product name
    Clopidogrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects administered with a loading dose of clopidogrel 300 milligram (mg) (four 75-mg tablets) as first dose within 4 hours of hemostasis followed by 75 mg once daily (QD) (one 75 mg tablet) orally for a total of approximately 3 months.

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects administered with aspirin 100 mg enteric coated tablets QD orally as background treatment along with Clopidogrel for 3 months.

    Arm title
    Edoxaban
    Arm description
    Subjects administered with edoxaban 60 mg once daily (two 30 mg tablets) for approximately 3 months starting with the first dose given within 4 hours of hemostasis on a background of aspirin 100 mg tablets QD.
    Arm type
    Experimental

    Investigational medicinal product name
    Aspirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects administered with aspirin 100 mg enteric coated tablets QD orally as background treatment along with Edoxaban for 3 months.

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects administered with edoxaban 60 mg once daily (two 30 mg tablets) for approximately 3 months.

    Number of subjects in period 1
    Clopidogrel Edoxaban
    Started
    102
    101
    Completed
    96
    89
    Not completed
    6
    12
         Death
    -
    3
         Other
    -
    1
         Physician decision
    1
    -
         Adverse event, non-fatal
    1
    1
         Consent withdrawn by subject
    3
    5
         Lost to follow-up
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Clopidogrel
    Reporting group description
    Subjects administered with a loading dose of clopidogrel 300 milligram (mg) (four 75-mg tablets) as first dose within 4 hours of hemostasis followed by 75 mg once daily (QD) (one 75 mg tablet) orally for a total of approximately 3 months on a background of aspirin 100 mg enteric coated tablets QD.

    Reporting group title
    Edoxaban
    Reporting group description
    Subjects administered with edoxaban 60 mg once daily (two 30 mg tablets) for approximately 3 months starting with the first dose given within 4 hours of hemostasis on a background of aspirin 100 mg tablets QD.

    Reporting group values
    Clopidogrel Edoxaban Total
    Number of subjects
    102 101 203
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    33 30 63
        From 65-84 years
    68 65 133
        85 years and over
    1 6 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    66.7 ± 8.55 68 ± 10.36 -
    Gender categorical
    Units: Subjects
        Female
    24 34 58
        Male
    78 67 145

    End points

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    End points reporting groups
    Reporting group title
    Clopidogrel
    Reporting group description
    Subjects administered with a loading dose of clopidogrel 300 milligram (mg) (four 75-mg tablets) as first dose within 4 hours of hemostasis followed by 75 mg once daily (QD) (one 75 mg tablet) orally for a total of approximately 3 months on a background of aspirin 100 mg enteric coated tablets QD.

    Reporting group title
    Edoxaban
    Reporting group description
    Subjects administered with edoxaban 60 mg once daily (two 30 mg tablets) for approximately 3 months starting with the first dose given within 4 hours of hemostasis on a background of aspirin 100 mg tablets QD.

    Primary: Percentage of Subjects with Re-stenosis/re-occlusion

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    End point title
    Percentage of Subjects with Re-stenosis/re-occlusion
    End point description
    Percentage of subjects with re-stenosis/re-occlusion, defined as Duplex ultrasonography scanning (DUS) Peak systolic velocity ratio (PSVR) greater than or equal to 2.4, at the treated segment(s) at 1, 3, and 6 months, as read at VasCore. Modified Intent-to-Treat (mITT) Set 2 population included all randomized subjects who received at least 1 dose of the study drug and had at least 1 post-dose duplex scanning. Here ‘n’ indicates the number of subjects analysed at specific time point.
    End point type
    Primary
    End point timeframe
    Months 1, 3 and 6
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    99
    96
    Units: percentage of subjects
    number (not applicable)
        Month 1 (n = 88, 90)
    5.7
    10
        Month 3 (n = 94, 93)
    13.8
    23.7
        Month 6 (n = 95, 94)
    34.7
    30.9
    Statistical analysis title
    Statistical analyses_Month 1
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    4.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.5
         upper limit
    12.2
    Statistical analysis title
    Statistical analyses_Month 3
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    9.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    20.9
    Statistical analysis title
    Statistical analyses_Month 6
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -3.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.3
         upper limit
    9.5

    Primary: Percentage of subjects with Adjudicated Bleeding Events in the On-Treatment Period Based on International Society of Thrombosis and Haemostasis (ISTH)

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    End point title
    Percentage of subjects with Adjudicated Bleeding Events in the On-Treatment Period Based on International Society of Thrombosis and Haemostasis (ISTH)
    End point description
    Clinically relevant bleeding Major or Clinically relevant non-major (CRNM) Bleeding, Major Bleeding, Life-threatening Bleeding, CRNM Bleeding, Minor Bleeding and Any Bleeding was assessed. Safety Analysis Set population included all subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    up to 3 months
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: percentage of subjects
    number (confidence interval 95%)
        Including Access Site Bleeding (IASB):Any Bleeding
    27.7 (19.3 to 37.5)
    30 (21.2 to 40)
        IASB: Major or CRNM Bleeding
    7.9 (3.5 to 15)
    11 (5.6 to 18.8)
        IASB : Major Bleeding
    5 (1.6 to 11.2)
    1 (0 to 5.4)
        IASB : Life-threatening Bleeding
    2 (0.2 to 7)
    1 (0 to 5.4)
        IASB : CRNM Bleeding
    4 (1.1 to 9.8)
    10 (4.9 to 17.6)
        IASB : Minor Bleeding
    20.8 (13.4 to 30)
    20 (12.7 to 29.2)
        Excluding Access Site Bleeding (EASB) Any Bleeding
    22.8 (15 to 32.2)
    25 (16.9 to 34.7)
        EASB : Major or CRNM Bleeding
    5.9 (2.2 to 12.5)
    6 (2.2 to 12.6)
        EASB : Major Bleeding
    4 (1.1 to 9.8)
    1 (0 to 5.4)
        EASB : Life-threatening Bleeding
    2 (0.2 to 7)
    1 (0 to 5.4)
        EASB : CRNM Bleeding
    3 (0.6 to 8.4)
    5 (1.6 to 11.3)
        EASB : Minor Bleeding
    17.8 (10.9 to 26.7)
    19 (11.8 to 28.1)
    Statistical analysis title
    Statistical analyses_ IASB: Major or CRNM Bleeding
    Statistical analysis description
    Statistical analysis was compared for Including Access Site Bleeding (IASB) Major or Clinically relevant non-major (CRNM) Bleeding.
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    3.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5
         upper limit
    11.2
    Statistical analysis title
    Statistical analyses_IASB: Major Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.6
         upper limit
    0.7
    Statistical analysis title
    SA_IASB: Life-threatening Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.3
         upper limit
    2.4
    Statistical analysis title
    Statistical analyses_IASB: CRNM Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    13
    Statistical analysis title
    Statistical analyses_IASB: Minor Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.9
         upper limit
    10.3
    Statistical analysis title
    Statistical analyses_IASB: Any Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    2.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.2
         upper limit
    14.8
    Statistical analysis title
    Statistical analyses_ EASB: Major or CRNM Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.5
         upper limit
    6.6
    Statistical analysis title
    Statistical analyses_EASB: Major Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.2
         upper limit
    1.3
    Statistical analysis title
    SA_EASB: Life-threatening Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.3
         upper limit
    2.4
    Statistical analysis title
    Statistical analyses_EASB: CRNM Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.4
         upper limit
    7.4
    Statistical analysis title
    Statistical analyses_EASB: Minor Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.5
         upper limit
    11.9
    Statistical analysis title
    Statistical analyses_EASB: Any Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    2.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.6
         upper limit
    14

    Primary: Percentage of Subjects with Adjudicated Bleeding Events in the On-Treatment Period Based on Thrombolysis in Myocardial Infarction (TIMI)

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    End point title
    Percentage of Subjects with Adjudicated Bleeding Events in the On-Treatment Period Based on Thrombolysis in Myocardial Infarction (TIMI)
    End point description
    Clinically relevant bleeding Major or Clinically relevant non-major (CRNM) Bleeding, Major Bleeding, Life-threatening Bleeding, CRNM Bleeding, Minor Bleeding and Any Bleeding was assessed. Safety Analysis Set population included all subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 3 months
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: percentage of subjects
    number (confidence interval 95%)
        Including Access Site Bleeding(IASB):Any Bleeding
    8.9 (4.2 to 16.2)
    5 (1.6 to 11.3)
        IASB : Major Bleeding
    2 (0.2 to 7)
    0 (0 to 0)
        IASB : Life-threatening Bleeding
    2 (0.2 to 7)
    0 (0 to 0)
        IASB : Minor Bleeding
    2 (0.2 to 7)
    3 (0.6 to 8.5)
        IASB : Minimal Bleeding
    5 (1.6 to 11.2)
    2 (0.2 to 7)
        Excluding Access Site Bleeding (EASB):Any Bleeding
    6.9 (2.8 to 13.8)
    2 (0.2 to 7)
        EASB : Major Bleeding
    2 (0.2 to 7)
    0 (0 to 0)
        EASB : Life-threatening Bleeding
    2 (0.2 to 7)
    0 (0 to 0)
        EASB : Minor Bleeding
    1 (0 to 5.4)
    2 (0.2 to 7)
        EASB : Minimal Bleeding
    4 (1.1 to 9.8)
    0 (0 to 0)
    Statistical analysis title
    Statistical analyses_ IASB: Major Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.7
         upper limit
    0.7
    Statistical analysis title
    SA_ IASB:Life-threatening Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.7
         upper limit
    0.7
    Statistical analysis title
    Statistical analyses_ IASB: Minor Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.3
         upper limit
    5.3
    Statistical analysis title
    Statistical analyses_ IASB: Minimal Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8
         upper limit
    2.1
    Statistical analysis title
    Statistical analyses_ IASB: Any Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -3.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.9
         upper limit
    3.1
    Statistical analysis title
    Statistical analyses_ EASB: Major Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.7
         upper limit
    0.7
    Statistical analysis title
    SA_ EASB: Life-threatening Bleed
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.7
         upper limit
    0.7
    Statistical analysis title
    Statistical analyses_ EASB: Minor Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    4.4
    Statistical analysis title
    Statistical analyses_ EASB: Minimal Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.8
         upper limit
    -0.2
    Statistical analysis title
    Statistical analyses_ EASB: Any Bleeding
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -4.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.6
         upper limit
    0.7

    Secondary: Change in Peak Systolic Velocity Ratio (PSVR) in the Treated Segment(s) at 3 and 6 Months Compared to 1 Month

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    End point title
    Change in Peak Systolic Velocity Ratio (PSVR) in the Treated Segment(s) at 3 and 6 Months Compared to 1 Month
    End point description
    Change in Peak Systolic Velocity Ratio was evaluated. Modified Intent-to-Treat Set 1 population included all subjects who received at least 1 dose of the study drug. Here ‘n’ indicates the number of subjects analysed at specific time point.
    End point type
    Secondary
    End point timeframe
    Month 1, 3 and 6
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: ratio
    arithmetic mean (standard deviation)
        Month 1 (n= 72, 65)
    1.47 ± 0.721
    1.61 ± 1.175
        Change from Month 1 to Month 3 (n= 59, 50)
    0.23 ± 0.683
    0.36 ± 1.074
        Change from Month 1 to Month 6 (n= 49, 42)
    0.81 ± 1.159
    0.9 ± 1.37
    No statistical analyses for this end point

    Secondary: Change in Ankle-brachial index (ABI) at 3 and 6 months compared to 1 month

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    End point title
    Change in Ankle-brachial index (ABI) at 3 and 6 months compared to 1 month
    End point description
    Ratio between the systolic pressure measured at the ankle and the systolic pressure measured in the arm as follows: Ankle: The systolic pressure will be measured in the index limb at the arteria dorsalis pedis and/or the arteria tibialis posterior. If both pressures are measured, the highest pressures will be used for the ABI calculation. Brachial: The systolic pressure will be measured in both arms, and the highest of both pressures will be used for the ABI calculation. Here ‘n’ indicates the number of subjects analysed at specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 1, 3 and 6
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: ratio
    arithmetic mean (standard deviation)
        Baseline (n= 100, 93)
    0.69 ± 0.265
    0.67 ± 0.279
        Month 1 (n= 93, 93)
    0.97 ± 0.188
    0.93 ± 0.189
        Change from Month 1 to Month 3 (n= 88, 84)
    -0.05 ± 0.16
    -0.03 ± 0.148
        Change from Month 1 to Month 6 (n= 83, 73)
    -0.06 ± 0.213
    -0.03 ± 0.32
    No statistical analyses for this end point

    Secondary: Number of Subjects in Rutherford stage at 1, 3, and 6 months

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    End point title
    Number of Subjects in Rutherford stage at 1, 3, and 6 months
    End point description
    Modified Intent-to-Treat Set 1 population included all subjects who received at least 1 dose of the study drug. Here ‘n’ indicates the number of subjects analysed at specific time point.
    End point type
    Secondary
    End point timeframe
    Months 1, 3 and 6
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: subjects
    number (not applicable)
        Month 1 (n=95, 97): Stage 0 (Asymptomatic)
    59
    51
        Month 1 (n=95, 97): Stage 1 (Mild Claudication)
    24
    23
        Month 1 (n=95, 97):Stage 2 (Moderate Claudication)
    6
    10
        Month 1 (n=95, 97):Stage 3 (Severe Claudication)
    1
    7
        Month 1 (n=95, 97): Stage 4 (Ischemic rest pain)
    1
    3
        Month 1 (n=95, 97): Stage 5 (Minor tissue loss)
    4
    3
        Month 1(n=95, 97):Stage 6 (Ulceration or gangrene)
    0
    0
        Month 3 (n= 92, 88): Stage 0 (Asymptomatic)
    62
    55
        Month 3 (n= 92, 88): Stage 1 (Mild Claudication)
    14
    16
        Month 3 (n= 92, 88): Stage2(Moderate Claudication)
    11
    9
        Month 3 (n= 92, 88): Stage 3 (Severe Claudication)
    2
    5
        Month 3 (n= 92, 88): Stage 4 (Ischemic rest pain)
    0
    1
        Month 3 (n= 92, 88): Stage 5 (Minor tissue loss)
    2
    2
        Month 3 (n= 92,88):Stage 6(Ulceration or gangrene)
    1
    0
        Month 6 (n= 85, 78): Stage 0 (Asymptomatic)
    48
    40
        Month 6 (n= 85, 78):Stage 1 (Mild Claudication)
    19
    14
        Month 6 (n= 85, 78):Stage 2(Moderate Claudication)
    10
    13
        Month 6 (n= 85, 78):Stage 3 (Severe Claudication)
    6
    10
        Month 6 (n= 85, 78):Stage 4 (Ischemic rest pain)
    1
    1
        Month 6 (n= 85, 78):Stage 5 (Minor tissue loss)
    1
    0
        Month 6 (n= 85, 78):Stage6(Ulceration or gangrene)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Targeted Clinical Events Adjudicated by Clinical Events Committee

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    End point title
    Number of Subjects with Targeted Clinical Events Adjudicated by Clinical Events Committee
    End point description
    Targeted Clinical Events included Symptomatic Acute Thrombosis Event, Target Lesion Revascularization Event, Amputation, Major adverse cardiovascular events (MACEs) - Non-Fatal yocardial Infarction (MI), Non-Fatal Stroke, CV-Death and Systemic Embolism Event. Modified Intent-to-Treat Set 1 population included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Up to 6 months
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: subjects
    number (not applicable)
        Symptomatic Acute Thrombosis Event
    5
    7
        Target Lesion Revascularization Event
    10
    11
        Amputation
    4
    1
        MACEs - Non-Fatal MI, Non-Fatal Stroke, CV-Death
    1
    3
        Systemic Embolism Event : Fatal
    0
    0
        Systemic Embolism Event : Non-fatal
    0
    0
        Myocardial Infarction (MI) event
    1
    2
        Death
    0
    3
    Statistical analysis title
    Statistical analyses_Symptomatic Acute Thrombosis
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Relative Risk
    Point estimate
    1.41
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.46
         upper limit
    4.31
    Statistical analysis title
    SA_Target Lesion Revascularization Event
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Relative Risk
    Point estimate
    1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    2.5
    Statistical analysis title
    SA_Amputation
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Relative Risk
    Point estimate
    0.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.03
         upper limit
    2.22
    Statistical analysis title
    SA_Major Adverse Cardiovascular Events
    Comparison groups
    Edoxaban v Clopidogrel
    Number of subjects included in analysis
    201
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Relative Risk
    Point estimate
    3.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.32
         upper limit
    28.64

    Secondary: Number of Subjects with All-Cause Mortality Events During the Overall Study Period Adjudicated by Clinical Events Committee

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    End point title
    Number of Subjects with All-Cause Mortality Events During the Overall Study Period Adjudicated by Clinical Events Committee
    End point description
    Mortality was evaluated. Modified Intent-to-Treat Set 1 population included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    up to 7 weeks after last dose administration
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: subjects
        number (not applicable)
    0
    3
    No statistical analyses for this end point

    Secondary: Plasma concentrations of edoxaban (DU-176) and its metabolite D21-2393

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    End point title
    Plasma concentrations of edoxaban (DU-176) and its metabolite D21-2393 [1]
    End point description
    Safety Analysis Set population included all subjects who received at least 1 dose of edoxaban. Here ‘n’ indicates the number of subjects analysed at specific time point.
    End point type
    Secondary
    End point timeframe
    Day 30 and Day 90
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Clopidogrel was not included in this analysis.
    End point values
    Edoxaban
    Number of subjects analysed
    100
    Units: nanogram per milliliter
    arithmetic mean (standard deviation)
        DU-176, Day 30 (n= 81)
    132.066 ± 110.056
        DU-176, Day 90 (n= 76)
    129.053 ± 105.7143
        D21-2393, Day 30 (n= 81)
    12.3681 ± 15.45542
        D21-2393, Day 90 (n=75)
    11.2873 ± 11.63869
    No statistical analyses for this end point

    Secondary: Change From Day 1 to Day 90 in anti-Factor Xa low-molecular-weight heparin (LMWH)

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    End point title
    Change From Day 1 to Day 90 in anti-Factor Xa low-molecular-weight heparin (LMWH)
    End point description
    Change in anti-Factor Xa was assessed as a part of Pharmacodynamic analysis. Safety Analysis Set population included all subjects who received at least 1 dose of edoxaban. Here, 99999 indicates data was not evaluated at specific time point.
    End point type
    Secondary
    End point timeframe
    Day 1, 30 and 90
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: International units per millilitre
    arithmetic mean (standard deviation)
        Day 1 (n= 61, 60)
    0.912 ± 0.8447
    0.803 ± 0.5937
        Day 30 (n= 0, 86)
    99999 ± 99999
    1.323 ± 1.0705
        Day 90 (n= 0, 72)
    99999 ± 99999
    1.351 ± 1.0105
    No statistical analyses for this end point

    Secondary: Pharmacokinetic or Pharmacodynamic Parameter: DDimer

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    End point title
    Pharmacokinetic or Pharmacodynamic Parameter: DDimer
    End point description
    Safety Analysis Set population included all subjects who received at least 1 dose of study drug. Units for Change From Day 1 to Day 90 in DDimer is milligram per litre (mg/L fibrinogen-equivalent units(FEU)).
    End point type
    Secondary
    End point timeframe
    Day 1, 30 and 90
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: milligram per litre (mg/L (FEU))
    arithmetic mean (standard deviation)
        Day 1 (n=95, 90)
    1.149 ± 1.3628
    1.283 ± 1.7241
        Day 30 (n= 86, 93)
    1.022 ± 1.358
    0.837 ± 1.8743
        Day 90 (n= 84, 85)
    0.912 ± 1.0351
    0.932 ± 2.5883
    No statistical analyses for this end point

    Secondary: Pharmacokinetic or Pharmacodynamic Parameter: Factor Xa

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    End point title
    Pharmacokinetic or Pharmacodynamic Parameter: Factor Xa
    End point description
    Change in Factor Xa was assessed as a part of Pharmacodynamic analysis. Safety Analysis Set population included all subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Days 1, 30 and 90
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: percentage
    arithmetic mean (standard deviation)
        Day 1 (n= 95, 92)
    102.5 ± 21.989
    101.24 ± 17.665
        Day 30 (n= 86, 94)
    116.25 ± 25.404
    73.09 ± 28.79
        Day 90 (n= 85, 88)
    114.7 ± 23.752
    75.47 ± 29.86
    No statistical analyses for this end point

    Secondary: Pharmacokinetic or Pharmacodynamic Parameter: hs-C-Reactive Protein

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    End point title
    Pharmacokinetic or Pharmacodynamic Parameter: hs-C-Reactive Protein
    End point description
    Change in hs-C-Reactive Protein was assessed as a part of Pharmacodynamic analysis. Safety Analysis Set population included all subjects who received at least 1 dose of stud drug. ‘n’ indicates number of subjects evaluated at specific time point.
    End point type
    Secondary
    End point timeframe
    Day 1, 30 and 90
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: milligram per litre
    arithmetic mean (standard deviation)
        Day 1 (n= 99, 99)
    6.34 ± 10.75
    4.75 ± 7.88
        Day 30 (n= 95, 96)
    5.3 ± 6.602
    5.67 ± 8.254
        Day 90 (n= 92, 88)
    5.73 ± 13.127
    4.74 ± 8.657
    No statistical analyses for this end point

    Secondary: Pharmacokinetic or Pharmacodynamic Parameter: International Normalized Ratio

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    End point title
    Pharmacokinetic or Pharmacodynamic Parameter: International Normalized Ratio
    End point description
    Change in International Normalized Ratio was evaluated as a part of Pharmacodynamic analysis. Safety Analysis Set population included all subjects who received at least 1 dose of study drug. ‘n’ indicates number of subjects evaluated at specific time point.
    End point type
    Secondary
    End point timeframe
    Day 1, 30 and 90
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: ratio
    arithmetic mean (standard deviation)
        Day 1 (n= 95, 91)
    1.22 ± 0.482
    1.18 ± 0.548
        Day 30 (n= 87, 89)
    1 ± 0.229
    1.37 ± 0.367
        Day 90 (n= 85, 85)
    0.99 ± 0.185
    1.37 ± 0.512
    No statistical analyses for this end point

    Secondary: Pharmacokinetic or Pharmacodynamic Parameter: P-Selectin

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    End point title
    Pharmacokinetic or Pharmacodynamic Parameter: P-Selectin
    End point description
    P-Selectin was evaluated as a part of Pharmacodynamic parameters. Safety Analysis Set population included all subjects who received at least 1 dose of study drug. ‘n’ indicates number of subjects evaluated at specific time point.
    End point type
    Secondary
    End point timeframe
    Day 1, 30 and 90
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: nanogram per millilitre
    arithmetic mean (standard deviation)
        Day 1 (n= 101, 95)
    43.16 ± 20.96
    45.4 ± 28.921
        Day 30 (n= 93, 93)
    41.19 ± 18.989
    43.48 ± 22.403
        Day 90 (n= 87, 89)
    41.91 ± 30.932
    43.45 ± 24.406
    No statistical analyses for this end point

    Secondary: Pharmacokinetic or Pharmacodynamic Parameter: Partial Thromboplastin Time

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    End point title
    Pharmacokinetic or Pharmacodynamic Parameter: Partial Thromboplastin Time
    End point description
    Safety Analysis Set population included all subjects who received at least 1 dose of study drug. ‘n’ indicates number of subjects evaluated at specific time point.
    End point type
    Secondary
    End point timeframe
    Day 1, 30 and 90
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: seconds
    arithmetic mean (standard deviation)
        Day 1 (n= 77, 80)
    45.35 ± 37.66
    46.24 ± 33.985
        Day 30 (n= 85, 93)
    24.98 ± 2.341
    29.51 ± 9.181
        Day 90 (n= 85, 86)
    25.13 ± 2.209
    28.2 ± 5.767
    No statistical analyses for this end point

    Secondary: Pharmacokinetic or Pharmacodynamic Parameter: Thrombin area under curve

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    End point title
    Pharmacokinetic or Pharmacodynamic Parameter: Thrombin area under curve
    End point description
    Safety Analysis Set population included all subjects who received at least 1 dose of the study drug. Here ‘n’ indicates the number of subjects analysed at specific time point.
    End point type
    Secondary
    End point timeframe
    Day 1, 30 and 90
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: nM*minute
    arithmetic mean (standard deviation)
        Day 1 (n= 95, 93)
    1443.25 ± 1870.763
    1719.53 ± 2008.222
        Day 30 (n= 86, 91)
    4253.18 ± 791.133
    3536.43 ± 1191.284
        Day 90 (n= 83, 87)
    4260.99 ± 861.846
    3576.43 ± 981.259
    No statistical analyses for this end point

    Secondary: Pharmacokinetic or Pharmacodynamic Parameter: Thrombin Generation lag time

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    End point title
    Pharmacokinetic or Pharmacodynamic Parameter: Thrombin Generation lag time
    End point description
    Safety Analysis Set population included all subjects who received at least 1 dose of the study drug. Here ‘n’ indicates the number of subjects analysed at specific time point.
    End point type
    Secondary
    End point timeframe
    Day 1, 30 and 90
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: minute
    arithmetic mean (standard deviation)
        Day 1 (n= 95, 93)
    11.81 ± 17.218
    9.59 ± 14.157
        Day 30 (n= 86, 91)
    11.04 ± 2.786
    15.53 ± 6.389
        Day 90 (n= 83, 87)
    11.03 ± 2.392
    16.62 ± 9.242
    No statistical analyses for this end point

    Secondary: Pharmacokinetic or Pharmacodynamic Parameter: Thrombin

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    End point title
    Pharmacokinetic or Pharmacodynamic Parameter: Thrombin
    End point description
    Safety Analysis Set population included all subjects who received at least 1 dose of the study drug. Here ‘n’ indicates the number of subjects analysed at specific time point.
    End point type
    Secondary
    End point timeframe
    Day 1, 30 and 90
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: nM
    arithmetic mean (standard deviation)
        Day 1 (n= 95, 93)
    178.07 ± 237.533
    204.97 ± 248.189
        Day 30 (n= 86, 91)
    494.87 ± 123.986
    357.59 ± 187.161
        Day 90 (n= 83, 87)
    509.97 ± 129.717
    346.45 ± 168.209
    No statistical analyses for this end point

    Secondary: Pharmacokinetic or Pharmacodynamic Parameter: Thrombin time to peak

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    End point title
    Pharmacokinetic or Pharmacodynamic Parameter: Thrombin time to peak
    End point description
    Change in Thrombin time to peak was evaluated as a part of Pharmacodynamic analysis. Safety Analysis Set 1 population included all subjects who received at least 1 dose of the study drug. Here ‘n’ indicates the number of subjects analysed at specific time point.
    End point type
    Secondary
    End point timeframe
    Day 1, 30 and 90
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: minute
    arithmetic mean (standard deviation)
        Day 1 (n= 95, 93)
    7.15 ± 9.314
    7.96 ± 9.304
        Day 30 (n= 86, 91)
    15.73 ± 3.921
    21.49 ± 9.436
        Day 90 (n= 83, 87)
    15.48 ± 3.041
    22 ± 8.707
    No statistical analyses for this end point

    Secondary: Pharmacokinetic or Pharmacodynamic Parameter: Thrombin velocity index

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    End point title
    Pharmacokinetic or Pharmacodynamic Parameter: Thrombin velocity index
    End point description
    Change in Thrombin velocity index was evaluated as a part of Pharmacodynamic analysis. Safety Analysis Set population included all subjects who received at least 1 dose of the study drug. Here ‘n’ indicates the number of subjects analysed at specific time point.
    End point type
    Secondary
    End point timeframe
    Day 1, 30 and 90
    End point values
    Clopidogrel Edoxaban
    Number of subjects analysed
    101
    100
    Units: nM/min
    arithmetic mean (standard deviation)
        Day 1 (n= 95, 93)
    49.49 ± 72.482
    53.97 ± 71.745
        Day 30 (n= 86, 91)
    130.1 ± 68.48
    84.14 ± 65.21
        Day 90 (n= 83, 87)
    132.03 ± 70.044
    77.91 ± 64.268
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the signing of informed consent form up to end of the study (6 months)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Edoxaban
    Reporting group description
    Subjects administered with edoxaban 60 milligram (mg) once daily (QD) (two 30 mg tablets) for approximately 3 months on a background of aspirin 100 mg tablets QD.

    Reporting group title
    Clopidogrel
    Reporting group description
    Subjects administered with a loading dose of clopidogrel 300 milligram (mg) (our 75-mg tablets) as first dose within 4 hours of hemostasis followed by 75 mg once daily (QD) (one 75 mg tablet) orally for a total of approximately 3 months on a background of aspirin 100 mg QD.

    Serious adverse events
    Edoxaban Clopidogrel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    31 / 100 (31.00%)
    30 / 101 (29.70%)
         number of deaths (all causes)
    3
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Femoral artery occlusion
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    2 / 100 (2.00%)
    4 / 101 (3.96%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 100 (1.00%)
    3 / 101 (2.97%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 101 (1.98%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    3 / 100 (3.00%)
    2 / 101 (1.98%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 101 (1.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 101 (1.98%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrosis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Alcohol Abuse
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arterial restenosis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery restenosis
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 101 (1.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    4 / 100 (4.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         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
    2 / 100 (2.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (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
    Carotid artery stenosis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal Ischaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin Ulcer
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Compartment syndrome
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid Overload
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium colitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (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
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Edoxaban Clopidogrel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 100 (77.00%)
    75 / 101 (74.26%)
    Vascular disorders
    Aortic dilatation
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Femoral artery occlusion
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    2
    Haematoma
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences all number
    1
    3
    Hypertensive crisis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Intermittent claudication
         subjects affected / exposed
    2 / 100 (2.00%)
    4 / 101 (3.96%)
         occurrences all number
    2
    5
    Hypotension
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    2
    Peripheral artery stenosis
         subjects affected / exposed
    3 / 100 (3.00%)
    4 / 101 (3.96%)
         occurrences all number
    3
    4
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 100 (0.00%)
    3 / 101 (2.97%)
         occurrences all number
    0
    3
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Raynaud's phenomenon
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Peripheral coldness
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Varicose vein
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Venous insufficiency
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Toe amputation
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Tooth extraction
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Calcinosis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    2
    Asthenia
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    2
    Chest discomfort
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    4 / 100 (4.00%)
    1 / 101 (0.99%)
         occurrences all number
    5
    1
    Chills
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Necrosis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    4 / 100 (4.00%)
    1 / 101 (0.99%)
         occurrences all number
    4
    1
    Oedema
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    2
    0
    Pain
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Pyrexia
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Drug dependence
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Mental status changes
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Vaginal Haemorrhage
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Arterial restenosis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Avulsion fracture
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Confusion postoperative
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Excoriation
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    2 / 100 (2.00%)
    4 / 101 (3.96%)
         occurrences all number
    2
    7
    Eye injury
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Foot fracture
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 101 (0.00%)
         occurrences all number
    2
    0
    Fractured coccyx
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Incision site haemorrhage
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 101 (0.00%)
         occurrences all number
    3
    0
    Limb injury
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Peripheral artery restenosis
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 101 (1.98%)
         occurrences all number
    2
    2
    Post procedural haematoma
         subjects affected / exposed
    6 / 100 (6.00%)
    3 / 101 (2.97%)
         occurrences all number
    6
    3
    Overdose
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Post procedural complication
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 101 (1.98%)
         occurrences all number
    1
    2
    Post procedural swelling
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Procedural pain
         subjects affected / exposed
    2 / 100 (2.00%)
    3 / 101 (2.97%)
         occurrences all number
    2
    3
    Scratch
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Scrotal haematoma
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Spinal compression fracture
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Subcutaneous haematoma
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Traumatic haematoma
         subjects affected / exposed
    4 / 100 (4.00%)
    4 / 101 (3.96%)
         occurrences all number
    4
    4
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    2
    Wound
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences all number
    1
    3
    Wound secretion
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Investigations
    Blood cholesterol increased
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 101 (0.00%)
         occurrences all number
    3
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 101 (1.98%)
         occurrences all number
    1
    2
    Blood pressure increased
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    2
    Blood testosterone decreased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 101 (0.99%)
         occurrences all number
    3
    1
    Blood uric acid increased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Carotid bruit
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Creatinine renal clearance decreased
         subjects affected / exposed
    6 / 100 (6.00%)
    3 / 101 (2.97%)
         occurrences all number
    6
    3
    Creatinine renal clearance increased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Glycosylated haemoglobin increased
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 101 (0.00%)
         occurrences all number
    2
    0
    Eosinophil count increased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Lymphocyte percentage increased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Low density lipoprotein increased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Neutrophil percentage increased
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Pedal pulse decreased
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    White blood cell count increased
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Bradycardia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 101 (0.00%)
         occurrences all number
    2
    0
    Dyspnoea
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 101 (0.00%)
         occurrences all number
    2
    0
    Cough
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 101 (1.98%)
         occurrences all number
    1
    2
    Emphysema
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    7 / 100 (7.00%)
    7 / 101 (6.93%)
         occurrences all number
    12
    15
    Haemoptysis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Leukocytosis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Thrombocytosis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Normochromic Normocytic Anaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Nervous system disorders
    Amputation stump pain
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Convulsion
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    5 / 100 (5.00%)
    1 / 101 (0.99%)
         occurrences all number
    5
    1
    Headache
         subjects affected / exposed
    5 / 100 (5.00%)
    0 / 101 (0.00%)
         occurrences all number
    5
    0
    Hypoaesthesia
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 101 (0.00%)
         occurrences all number
    2
    0
    Migraine
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Loss of consciousness
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 101 (0.99%)
         occurrences all number
    3
    1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    2
    Sciatica
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Tremor
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Eye disorders
    Blepharitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Cataract
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Retinal tear
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 101 (1.98%)
         occurrences all number
    1
    3
    Abdominal distension
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 101 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    4 / 100 (4.00%)
    2 / 101 (1.98%)
         occurrences all number
    4
    2
    Dental caries
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 101 (0.00%)
         occurrences all number
    2
    0
    Flatulence
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal angiodysplasia haemorrhagic
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Gastritis alcoholic
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    2
    Haematemesis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Gingival bleeding
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 101 (0.00%)
         occurrences all number
    3
    0
    Haematochezia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Hiatus hernia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Stomatitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Pancreatitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences all number
    1
    2
    Tooth loss
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 101 (0.99%)
         occurrences all number
    3
    1
    Nausea
         subjects affected / exposed
    6 / 100 (6.00%)
    4 / 101 (3.96%)
         occurrences all number
    6
    5
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Nephrolithiasis
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 101 (0.00%)
         occurrences all number
    2
    0
    Haematuria
         subjects affected / exposed
    4 / 100 (4.00%)
    4 / 101 (3.96%)
         occurrences all number
    5
    4
    Renal failure acute
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Renal failure
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Renal impairment
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Dermal cyst
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Dermatitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Dermatitis contact
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Diabetic foot
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Eczema
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Ecchymosis
         subjects affected / exposed
    0 / 100 (0.00%)
    2 / 101 (1.98%)
         occurrences all number
    0
    3
    Hyperhidrosis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Increased tendency to bruise
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    2 / 100 (2.00%)
    0 / 101 (0.00%)
         occurrences all number
    2
    0
    Ingrowing nail
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Neurodermatitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Night sweats
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    1 / 100 (1.00%)
    2 / 101 (1.98%)
         occurrences all number
    1
    2
    Pruritus generalised
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Skin fissures
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Scab
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Skin ulcer
         subjects affected / exposed
    1 / 100 (1.00%)
    3 / 101 (2.97%)
         occurrences all number
    1
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 100 (4.00%)
    1 / 101 (0.99%)
         occurrences all number
    4
    2
    Chondrocalcinosis pyrophosphate
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Arthralgia
         subjects affected / exposed
    6 / 100 (6.00%)
    2 / 101 (1.98%)
         occurrences all number
    6
    2
    Costochondritis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Gouty arthritis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Flank pain
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Groin pain
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Joint swelling
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 101 (1.98%)
         occurrences all number
    2
    2
    Muscle spasms
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 101 (0.99%)
         occurrences all number
    3
    1
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    2 / 100 (2.00%)
    2 / 101 (1.98%)
         occurrences all number
    2
    2
    Pain in extremity
         subjects affected / exposed
    9 / 100 (9.00%)
    7 / 101 (6.93%)
         occurrences all number
    9
    8
    Sensation of heaviness
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 101 (0.00%)
         occurrences all number
    3
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Gout
         subjects affected / exposed
    1 / 100 (1.00%)
    3 / 101 (2.97%)
         occurrences all number
    1
    3
    Hyperglycaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Hyperlipidaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 101 (0.99%)
         occurrences all number
    2
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Obesity
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Multi-vitamin deficiency
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 100 (1.00%)
    3 / 101 (2.97%)
         occurrences all number
    1
    3
    Cellulitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Cystitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Gangrene
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    2 / 100 (2.00%)
    1 / 101 (0.99%)
         occurrences all number
    2
    1
    Herpes zoster
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 101 (0.99%)
         occurrences all number
    1
    1
    Localised infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    4 / 100 (4.00%)
    5 / 101 (4.95%)
         occurrences all number
    4
    6
    Osteomyelitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 101 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 100 (2.00%)
    3 / 101 (2.97%)
         occurrences all number
    3
    4
    Urinary tract infection
         subjects affected / exposed
    4 / 100 (4.00%)
    3 / 101 (2.97%)
         occurrences all number
    4
    3
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 101 (0.99%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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