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    Clinical Trial Results:
    A prospective, randomised, open-label, blinded endpoint evaluation (PROBE) parallel group study comparing edoxaban (DU-176b) with enoxaparin/warfarin followed by warfarin alone in subjects undergoing planned electrical cardioversion of nonvalvular atrial fibrillation

    Summary
    EudraCT number
    2013-003148-21
    Trial protocol
    SE   BE   DE   GB   HU   IT   DK   ES   AT   CZ   NL   RO   BG   PL  
    Global end of trial date
    04 Feb 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Jan 2017
    First version publication date
    27 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DU176b-F-E308
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02072434
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo, Inc.
    Sponsor organisation address
    399 Thornall Avenue, Edison, NJ, United States, 08837
    Public contact
    Clinical Trial Information, Daiichi Sankyo Development Ltd, +44 1753482800, euregaffairs@dsd-eu.com
    Scientific contact
    Clinical Trial Information, Daiichi Sankyo Development Ltd, +44 1753482800, euregaffairs@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
    10 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Efficacy Objective: Compare the incidences of the composite endpoints of stroke, systemic embolic event (SEE), myocardial infarction (MI) and cardiovascular (CV) mortality between the edoxaban group and the enoxaparin/warfarin group from randomization to end of follow up (FU). Primary Safety Objective: Compare the incidence of the composite endpoints of major and clinically-relevant non-major (CRNM) bleeding between the edoxaban group and the enoxaparin/warfarin group from the first administration of study drug to end of treatment + 3 days.
    Protection of trial subjects
    This study was conducted in compliance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, the International Conference on Harmonization (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and applicable regulatory requirements. Subjects, after having the study explained to them by the investigator or designee, gave voluntary and signed informed consent before participating in any study-specific procedures. For subjects in the United States (US), consent required for the Health Insurance Portability and Accountability Act (HIPAA) was included in the single, main informed consent form (ICF). The study protocol, amendments (if any), the informed consent/assent form(s), and information sheets were approved by the appropriate and applicable Independent Ethics Committees (IECs) or Institutional Review Boards (IRBs). An independent Data Monitoring committee (DMC) was created to further protect the rights, safety, and well-being of subjects who were participating in this study by monitoring their progress and results. The independent DMC was comprised of qualified scientists, who were not Investigators in the study and not otherwise directly associated with the Sponsor.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 47
    Country: Number of subjects enrolled
    Poland: 54
    Country: Number of subjects enrolled
    Romania: 122
    Country: Number of subjects enrolled
    Spain: 142
    Country: Number of subjects enrolled
    Sweden: 14
    Country: Number of subjects enrolled
    United Kingdom: 159
    Country: Number of subjects enrolled
    Austria: 32
    Country: Number of subjects enrolled
    Belgium: 41
    Country: Number of subjects enrolled
    Bulgaria: 125
    Country: Number of subjects enrolled
    Czech Republic: 173
    Country: Number of subjects enrolled
    Denmark: 57
    Country: Number of subjects enrolled
    France: 39
    Country: Number of subjects enrolled
    Germany: 123
    Country: Number of subjects enrolled
    Hungary: 179
    Country: Number of subjects enrolled
    Italy: 69
    Country: Number of subjects enrolled
    Russian Federation: 216
    Country: Number of subjects enrolled
    Ukraine: 430
    Country: Number of subjects enrolled
    Israel: 82
    Country: Number of subjects enrolled
    United States: 95
    Worldwide total number of subjects
    2199
    EEA total number of subjects
    1376
    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)
    1064
    From 65 to 84 years
    1097
    85 years and over
    38

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Of 2199 patients enrolled in 19 countries worldwide, 2149 received study drug.

    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
    Edoxaban
    Arm description
    Patients randomized to receive edoxaban
    Arm type
    Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    SUB32701
    Other name
    DU176-b
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Edoxaban was supplied in 30 mg tablets (yellow) in child resistant blister wallets of 42 tablets. Subjects taking the full dose of edoxaban for the study will take 60 mg QD (two 30 mg tablets once daily). Subjects with a dose reduction took 30 mg (one 30 mg tablet once daily) when required by the protocol dose reduction criteria. All dispensing was done via the IXRS. In addition 15 mg tablets of edoxaban (orange or yellow) were supplied in child resistant blister wallets of 42 tablets to be used as transition kits when necessary.

    Arm title
    Warfarin
    Arm description
    Patients randomised to receive the comparator product.
    Arm type
    Active comparator

    Investigational medicinal product name
    Warfarin
    Investigational medicinal product code
    SUB12396MIG
    Other name
    Warfarin Sodium Clathrate, Warfarin Teva 1 mg Tablet
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Warfarin, was the active control and was provided by the Sponsor in dosage strengths of 1.0 mg (brown) and 2.5 mg (green). Individual doses were made by combining the strengths provided. Investigators determined the dose strength(s) of warfarin necessary to achieve the prescribed dose, and the quantity dispensed was determined by the dose. Subjects randomized to the warfarin treatment group were dispensed active warfarin. These subjects could also have been dispensed enoxaparin. All dispensing was done via the IXRS. Should a dose change be required between visits, additional quantity and/or strengths were dispensed via the IXRS.

    Number of subjects in period 1
    Edoxaban Warfarin
    Started
    1095
    1104
    Intention to Treat Analysis Set
    1095
    1104
    Received Study Drug
    1067
    1082
    Safety Analysis Set
    1067
    1082
    Completed
    1041
    1014
    Not completed
    54
    90
         Protocol deviation
    10
    9
         Physician decision
    5
    10
         Adverse event, serious fatal
    1
    6
         Adverse event, non-fatal
    7
    6
         Consent withdrawn by subject
    17
    29
         No reason provided
    14
    29
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Edoxaban
    Reporting group description
    Patients randomized to receive edoxaban

    Reporting group title
    Warfarin
    Reporting group description
    Patients randomised to receive the comparator product.

    Reporting group values
    Edoxaban Warfarin Total
    Number of subjects
    1095 1104 2199
    Age categorical
    Units: Subjects
        Adults <75 Years of Age
    923 917 1840
        Adults >= 75 Years of Age
    172 187 359
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    64.3 ± 10.34 64.2 ± 10.75 -
    Gender categorical
    Units: Subjects
        Female
    374 382 756
        Male
    721 722 1443

    End points

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    End points reporting groups
    Reporting group title
    Edoxaban
    Reporting group description
    Patients randomized to receive edoxaban

    Reporting group title
    Warfarin
    Reporting group description
    Patients randomised to receive the comparator product.

    Subject analysis set title
    Edoxaban Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Patients randomized to and treated with edoxaban.

    Subject analysis set title
    Warfarin Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Patients randomized to and treated with warfarin.

    Primary: Percentage of patients with composite endpoint of stroke, systemic embolic stroke(SEE), myocardial infarction (MI) and cardiovascular (CV) mortality from randomization to end of follow up (FU)

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    End point title
    Percentage of patients with composite endpoint of stroke, systemic embolic stroke(SEE), myocardial infarction (MI) and cardiovascular (CV) mortality from randomization to end of follow up (FU)
    End point description
    End point type
    Primary
    End point timeframe
    Randomization to end of follow up
    End point values
    Edoxaban Warfarin
    Number of subjects analysed
    1095
    1104
    Units: Percentage of Patients
        number (not applicable)
    0.5
    1
    Statistical analysis title
    Odds Ratio
    Comparison groups
    Edoxaban v Warfarin
    Number of subjects included in analysis
    2199
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.12
         upper limit
    1.43
    Notes
    [1] - Exact

    Primary: Percentage of patients with composite endpoints of major and clinically-relevant non-major (CRNM) bleeding

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    End point title
    Percentage of patients with composite endpoints of major and clinically-relevant non-major (CRNM) bleeding
    End point description
    End point type
    Primary
    End point timeframe
    from first administration of study drug to end of treatment + 3 days
    End point values
    Edoxaban Safety Analysis Set Warfarin Safety Analysis Set
    Number of subjects analysed
    1067
    1082
    Units: Percentage of Patients
        number (not applicable)
    1.5
    1
    Statistical analysis title
    Odds Ratio
    Comparison groups
    Edoxaban Safety Analysis Set v Warfarin Safety Analysis Set
    Number of subjects included in analysis
    2149
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    Method
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.64
         upper limit
    3.55
    Notes
    [2] - exact

    Secondary: Percentage of patients with composite endpoints of stroke, SEE MI, CV mortality and major bleeding

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    End point title
    Percentage of patients with composite endpoints of stroke, SEE MI, CV mortality and major bleeding
    End point description
    End point type
    Secondary
    End point timeframe
    from randomization to end of follow up
    End point values
    Edoxaban Warfarin
    Number of subjects analysed
    1095
    1104
    Units: Percentage of patients
        number (not applicable)
    0.7
    1.4
    Statistical analysis title
    Difference in Percent
    Comparison groups
    Edoxaban v Warfarin
    Number of subjects included in analysis
    2199
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.59
         upper limit
    0.15

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) were defined as events that started on or after the first dose of study drug or start prior to but then worsen after the first dose of study drug, through 30 days after the last dose of study drug.
    Adverse event reporting additional description
    This table includes counts of patients in the safety analysis set. Patients who experienced more than one episode of an adverse event are counted only once within a preferred term. Patients who experienced more than one adverse event within a system organ class are counted once for each preferred term, but only once for the system organ class.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Edoxaban Safety Analysis Set
    Reporting group description
    Patients randomized to and treated with edoxaban.

    Reporting group title
    Warfarin Safety Analysis Set
    Reporting group description
    Patients randomized to and treated with warfarin.

    Serious adverse events
    Edoxaban Safety Analysis Set Warfarin Safety Analysis Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    85 / 1067 (7.97%)
    83 / 1082 (7.67%)
         number of deaths (all causes)
    1
    5
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    1 / 1067 (0.09%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm rupture
    Additional description: Aneurysm with Rupture Abdominal Aorta
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Deep vein thrombosis
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
    Additional description: General Disorder Death
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Drug effect increased
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site bruising
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (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
    Alcohol poisoning
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic haemorrhage
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    4 / 1067 (0.37%)
    10 / 1082 (0.92%)
         occurrences causally related to treatment / all
    1 / 4
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    2 / 1067 (0.19%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood urine present
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulation test abnormal
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio fluctuation
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    20 / 1067 (1.87%)
    14 / 1082 (1.29%)
         occurrences causally related to treatment / all
    0 / 20
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
    Additional description: Decompensated heart failure
         subjects affected / exposed
    3 / 1067 (0.28%)
    6 / 1082 (0.55%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure congestive
    Additional description: Acute, congestive heart failure
         subjects affected / exposed
    5 / 1067 (0.47%)
    3 / 1082 (0.28%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Atrial flutter
         subjects affected / exposed
    3 / 1067 (0.28%)
    2 / 1082 (0.18%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    2 / 1067 (0.19%)
    2 / 1082 (0.18%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 1067 (0.09%)
    2 / 1082 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    2 / 1067 (0.19%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    3 / 1067 (0.28%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    2 / 1067 (0.19%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 1067 (0.09%)
    2 / 1082 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    2 / 1067 (0.19%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 1067 (0.00%)
    2 / 1082 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    2 / 1067 (0.19%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
    Additional description: Cardiac arrest, ventricular fibrillation
         subjects affected / exposed
    0 / 1067 (0.00%)
    2 / 1082 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Angina pectoris
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chordae tendinae rupture
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Torsade de pointes
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary oedema
         subjects affected / exposed
    2 / 1067 (0.19%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 1067 (0.09%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 1067 (0.19%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinal cyst
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 1067 (0.19%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocoagulable state
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (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
    Cerebrovascular accident
         subjects affected / exposed
    1 / 1067 (0.09%)
    2 / 1082 (0.18%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 1067 (0.19%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 1067 (0.09%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 1067 (0.00%)
    2 / 1082 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 1067 (0.19%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spigelian hernia
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    3 / 1067 (0.28%)
    2 / 1082 (0.18%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 1067 (0.09%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    0 / 1067 (0.00%)
    2 / 1082 (0.18%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperadrenocorticism
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 1067 (0.37%)
    4 / 1082 (0.37%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 1067 (0.09%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 1067 (0.09%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective aneurysm
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 1067 (0.00%)
    1 / 1082 (0.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 1067 (0.09%)
    0 / 1082 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Edoxaban Safety Analysis Set Warfarin Safety Analysis Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    53 / 1067 (4.97%)
    53 / 1082 (4.90%)
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    53 / 1067 (4.97%)
    53 / 1082 (4.90%)
         occurrences all number
    53
    53

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Oct 2014
    To clarify that all patients transitioning from edoxaban to other anticoagulants receive an edoxaban transition kit

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    09 Oct 2014
    For approval of substantial protocol amendment - restart dates were dependent on the date each health authority approved the amendment
    -

    Limitations and caveats

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