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    Clinical Trial Results:
    A Prospective, Randomized, Open-Label, Blinded Endpoint Evaluation (PROBE) Parallel Group Study Comparing Edoxaban vs. VKA in Subjects Undergoing Catheter Ablation of Non-valvular Atrial Fibrillation (ELIMINATE-AF)

    Summary
    EudraCT number
    2016-003069-25
    Trial protocol
    CZ   DE   GB   HU   ES   BE   PL  
    Global end of trial date
    24 Sep 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Jan 2020
    First version publication date
    02 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DSE-EDO-01-16-EU
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02942576
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo Europe GmbH
    Sponsor organisation address
    Zielstattstrasse 48, Munich, Germany, 81379
    Public contact
    Global Medical Affairs Edoxaban, Daiichi Sankyo Europe GmbH, +49 89 78080508, Heiko.Rauer@daiichi-sankyo.eu
    Scientific contact
    Global Medical Affairs Edoxaban, Daiichi Sankyo Europe GmbH, +49 89 78080508, Heiko.Rauer@daiichi-sankyo.eu
    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
    24 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary efficacy objective: To compare descriptively the incidence of the composite of all-cause death, stroke (ischemic, hemorrhagic, or undetermined) and Major Bleeding (International Society on Thrombosis and Hemostasis [ISTH] definition) in the edoxaban group against the vitamin K antagonist (VKA) group in subjects undergoing catheter ablation of atrial fibrillation (AF) in the period from the end of the catheter ablation procedure to Day 90/end-of-treatment (EOT). Primary safety objective: To compare descriptively the incidence of Major Bleeding (ISTH definition) in the edoxaban group against the VKA group in the period from date of first intake of study medication to Day 90/EOT.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were randomized to receive study treatment.
    Background therapy
    After Screening and randomization, eligible subjects received 21 days (+7) anticoagulation before being assessed for suitability for the catheter ablation procedure. Subjects received 90 days anticoagulation post-procedure and were followed for an additional 30 days.
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Mar 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 78
    Country: Number of subjects enrolled
    Spain: 33
    Country: Number of subjects enrolled
    United Kingdom: 60
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Czech Republic: 109
    Country: Number of subjects enrolled
    Germany: 44
    Country: Number of subjects enrolled
    Hungary: 75
    Country: Number of subjects enrolled
    Canada: 53
    Country: Number of subjects enrolled
    Korea, Republic of: 39
    Country: Number of subjects enrolled
    Taiwan: 39
    Country: Number of subjects enrolled
    Italy: 63
    Worldwide total number of subjects
    602
    EEA total number of subjects
    471
    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)
    392
    From 65 to 84 years
    210
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 614 subjects who met the inclusion and none of the exclusion criteria were randomized; 602 received the study drug.

    Pre-assignment
    Screening details
    Subjects were required to have completed between 21 to 28 days of anticoagulation with study treatment prior to the catheter ablation visit/periprocedural visit (Day 0).

    Period 1
    Period 1 title
    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-based Regimen
    Arm description
    Edoxaban-based regimen for 21 days pre- and 90 days post-ablation period.
    Arm type
    Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Edoxaban 60 mg once-daily or 30 mg once-daily in selected subjects.

    Arm title
    VKA-based Regimen
    Arm description
    VKA-based regimen for 21 days pre- and 90 days post-ablation period (control regimen)
    Arm type
    Active comparator

    Investigational medicinal product name
    Vitamin K antagonist (VKA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    VKA-Based Regimen: Dosed at International Normalised Ratio (INR) levels, which is a test of how long it takes for blood to clot. Standard of Care treatment in Canada, Italy, Poland, Hungary, Czech Republic, UK, Taiwan and Korea. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Germany and Belgium. VKA-Based Regimen: Dosed at INR levels. Standard of Care treatment in Spain.

    Number of subjects in period 1
    Edoxaban-based Regimen VKA-based Regimen
    Started
    405
    197
    Completed
    359
    174
    Not completed
    46
    23
         Physician decision
    1
    4
         Not specified
    10
    8
         Adverse event, non-fatal
    28
    6
         Consent withdrawn by subject
    7
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Edoxaban-based Regimen
    Reporting group description
    Edoxaban-based regimen for 21 days pre- and 90 days post-ablation period.

    Reporting group title
    VKA-based Regimen
    Reporting group description
    VKA-based regimen for 21 days pre- and 90 days post-ablation period (control regimen)

    Reporting group values
    Edoxaban-based Regimen VKA-based Regimen Total
    Number of subjects
    405 197 602
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    262 130 392
        From 65-84 years
    143 67 210
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    59.5 ± 10.2 59.6 ± 10.0 -
    Gender categorical
    Units: Subjects
        Female
    118 51 169
        Male
    287 146 433

    End points

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    End points reporting groups
    Reporting group title
    Edoxaban-based Regimen
    Reporting group description
    Edoxaban-based regimen for 21 days pre- and 90 days post-ablation period.

    Reporting group title
    VKA-based Regimen
    Reporting group description
    VKA-based regimen for 21 days pre- and 90 days post-ablation period (control regimen)

    Primary: Number of Subjects Who Experienced the Composite of All-cause Death, Stroke (VARC-2), and Major Bleeding (ISTH) in the Edoxaban Group Compared With Vitamin K Antagonist (VKA) Group in Subjects Undergoing Catheter Ablation (Adjudicated Data)

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    End point title
    Number of Subjects Who Experienced the Composite of All-cause Death, Stroke (VARC-2), and Major Bleeding (ISTH) in the Edoxaban Group Compared With Vitamin K Antagonist (VKA) Group in Subjects Undergoing Catheter Ablation (Adjudicated Data) [1]
    End point description
    Stroke (ischemic, hemorrhagic, or undetermined) was defined by Valve Academic Research Consortium-2 (VARC-2) as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury following hemorrhage or infarction. A stroke event was based on any of the following: duration of neurological dysfunction >24 hours (h), duration of neurological dysfunction <24 h in case of imaging-documented new hemorrhage or infarction, and a neurological dysfunction resulting in death. Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) as fatal bleeding and/or bleeding that is symptomatic and occurs in a critical area or organ and/or extrasurgical site bleeding causing a fall in hemoglobin level of >2 g/dL or leads to blood transfusion, surgical site bleeding that requires a second intervention, causes hemarthrosis that delays mobilization or wound healing, or causes hemodynamic instability.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 90
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study drug(s) administered for this outcome.
    End point values
    Edoxaban-based Regimen VKA-based Regimen
    Number of subjects analysed
    316
    101
    Units: Number of subjects
    number (not applicable)
        All-cause death, stroke, and major bleeding
    1
    2
    No statistical analyses for this end point

    Primary: Number of Subjects Who Experienced Major Bleeding (International Society on Thrombosis and Hemostasis [ISTH]) in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data)

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    End point title
    Number of Subjects Who Experienced Major Bleeding (International Society on Thrombosis and Hemostasis [ISTH]) in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data) [2]
    End point description
    Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) as fatal bleeding and/or bleeding that is symptomatic and occurs in a critical area or organ and/or extrasurgical site bleeding causing a fall in hemoglobin level of >2 g/dL or leads to blood transfusion, surgical site bleeding that requires a second intervention, causes hemarthrosis that delays mobilization or wound healing, or causes hemodynamic instability.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 90
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and the study drug(s) administered for this outcome.
    End point values
    Edoxaban-based Regimen VKA-based Regimen
    Number of subjects analysed
    405
    197
    Units: Number of subjects
    number (not applicable)
        Major bleeding
    10
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Experienced the Composite of All-cause Death, Stroke (Alternative), and Major Bleeding (ISTH) in the Edoxaban Group Compared With VKA Group Among Subjects Undergoing Catheter Ablation (Adjudicated Data)

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    End point title
    Number of Subjects Who Experienced the Composite of All-cause Death, Stroke (Alternative), and Major Bleeding (ISTH) in the Edoxaban Group Compared With VKA Group Among Subjects Undergoing Catheter Ablation (Adjudicated Data)
    End point description
    An alternative definition characterized stroke (ischemic, hemorrhagic, or undetermined) as an abrupt onset, over minutes to hours, of a focal neurological deficit in the distribution of a single brain artery that was not due to an identifiable nonvascular cause (ie, brain tumor or trauma), and that either lasted at least 24 hours or resulted in death within 24 hours of onset. Major bleeding was defined by the International Society on Thrombosis and Hemostasis (ISTH) as fatal bleeding and/or bleeding that is symptomatic and occurs in a critical area or organ and/or extrasurgical site bleeding causing a fall in hemoglobin level of >2 g/dL or leads to blood transfusion, surgical site bleeding that requires a second intervention, causes hemarthrosis that delays mobilization or wound healing, or causes hemodynamic instability.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 90
    End point values
    Edoxaban-based Regimen VKA-based Regimen
    Number of subjects analysed
    316
    101
    Units: Number of subjects
    number (not applicable)
        All-cause death, stroke, and major bleeding
    1
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Experienced the Composite of Stroke (VARC-2), Systemic Embolic Events (SEE), and Cardiovascular (CV) Mortality in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data)

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    End point title
    Number of Subjects Who Experienced the Composite of Stroke (VARC-2), Systemic Embolic Events (SEE), and Cardiovascular (CV) Mortality in the Edoxaban Group Compared With VKA Group Among Participants Undergoing Catheter Ablation (Adjudicated Data)
    End point description
    Stroke (ischemic, hemorrhagic, or undetermined) was defined by Valve Academic Research Consortium-2 (VARC-2) as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury following hemorrhage or infarction. A stroke event was based on any of the following: duration of neurological dysfunction >24 hours (h), duration of neurological dysfunction <24 h in case of imaging-documented new hemorrhage or infarction, and a neurological dysfunction resulting in death. SEE was defined as an arterial embolism resulting in clinical ischemia, excluding the central nervous system, coronary, and pulmonary arterial circulation. CV mortality was defined as cardiac or vascular death according to Academic Research Consortium.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 90
    End point values
    Edoxaban-based Regimen VKA-based Regimen
    Number of subjects analysed
    316
    101
    Units: Number of subjects
    number (not applicable)
        Stroke, systemic embolic events, CV mortality
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data were collected from the first dose of the study drug to 30 days after last dose of study drug.
    Adverse event reporting additional description
    Adverse events that emerge (or worsen) from the first dose of the study drug to the last dose of the study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Edoxaban-based Regimen
    Reporting group description
    Edoxaban-based regimen for 21 days pre- and 90 days post-ablation period.

    Reporting group title
    VKA-based Regimen
    Reporting group description
    VKA-based regimen for 21 days pre- and 90 days post-ablation period (control regimen)

    Serious adverse events
    Edoxaban-based Regimen VKA-based Regimen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 405 (9.88%)
    15 / 197 (7.61%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Ateriovenous fistula
         subjects affected / exposed
    2 / 405 (0.49%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon adenoma
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (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
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (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
    Foot fracture
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (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
    15 / 405 (3.70%)
    6 / 197 (3.05%)
         occurrences causally related to treatment / all
    0 / 15
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    3 / 405 (0.74%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 197 (1.02%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial thrombosis
         subjects affected / exposed
    1 / 405 (0.25%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    2 / 405 (0.49%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (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
    1 / 405 (0.25%)
    0 / 197 (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
    Anemia
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Normochromic normocytic anaemia
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary edema
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal perforation
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal mass
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral obstruction
         subjects affected / exposed
    1 / 405 (0.25%)
    0 / 197 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 405 (0.00%)
    1 / 197 (0.51%)
         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
    2 / 405 (0.49%)
    1 / 197 (0.51%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Edoxaban-based Regimen VKA-based Regimen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    210 / 405 (51.85%)
    99 / 197 (50.25%)
    Vascular disorders
    Arteriovenous fistula
         subjects affected / exposed
    3 / 405 (0.74%)
    2 / 197 (1.02%)
         occurrences all number
    3
    2
    Hypertension
         subjects affected / exposed
    8 / 405 (1.98%)
    3 / 197 (1.52%)
         occurrences all number
    8
    3
    Hypotension
         subjects affected / exposed
    8 / 405 (1.98%)
    2 / 197 (1.02%)
         occurrences all number
    8
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 405 (1.23%)
    3 / 197 (1.52%)
         occurrences all number
    5
    3
    Non-cardiac chest pain
         subjects affected / exposed
    5 / 405 (1.23%)
    2 / 197 (1.02%)
         occurrences all number
    5
    2
    Pyrexia
         subjects affected / exposed
    19 / 405 (4.69%)
    3 / 197 (1.52%)
         occurrences all number
    19
    3
    Injury, poisoning and procedural complications
    Post procedural complication
         subjects affected / exposed
    3 / 405 (0.74%)
    2 / 197 (1.02%)
         occurrences all number
    3
    2
    Procedural pain
         subjects affected / exposed
    4 / 405 (0.99%)
    2 / 197 (1.02%)
         occurrences all number
    4
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 405 (1.23%)
    0 / 197 (0.00%)
         occurrences all number
    5
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    41 / 405 (10.12%)
    21 / 197 (10.66%)
         occurrences all number
    41
    21
    Atrial flutter
         subjects affected / exposed
    15 / 405 (3.70%)
    8 / 197 (4.06%)
         occurrences all number
    15
    8
    Atrial tachycardia
         subjects affected / exposed
    3 / 405 (0.74%)
    5 / 197 (2.54%)
         occurrences all number
    3
    5
    Atrial thrombosis
         subjects affected / exposed
    2 / 405 (0.49%)
    2 / 197 (1.02%)
         occurrences all number
    2
    2
    Atrioventricular block first degree
         subjects affected / exposed
    3 / 405 (0.74%)
    2 / 197 (1.02%)
         occurrences all number
    3
    2
    Bradycardia
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 197 (1.02%)
         occurrences all number
    0
    2
    Cardiac flutter
         subjects affected / exposed
    4 / 405 (0.99%)
    5 / 197 (2.54%)
         occurrences all number
    4
    5
    Palpitations
         subjects affected / exposed
    12 / 405 (2.96%)
    4 / 197 (2.03%)
         occurrences all number
    12
    4
    Pericarditis
         subjects affected / exposed
    6 / 405 (1.48%)
    2 / 197 (1.02%)
         occurrences all number
    6
    2
    Blood and lymphatic system disorders
    Leukocytosis
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 197 (1.02%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 405 (1.48%)
    3 / 197 (1.52%)
         occurrences all number
    6
    3
    Dyspnea
         subjects affected / exposed
    14 / 405 (3.46%)
    1 / 197 (0.51%)
         occurrences all number
    14
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 405 (1.98%)
    3 / 197 (1.52%)
         occurrences all number
    8
    3
    Headache
         subjects affected / exposed
    8 / 405 (1.98%)
    5 / 197 (2.54%)
         occurrences all number
    8
    5
    Phrenic nerve paralysis
         subjects affected / exposed
    1 / 405 (0.25%)
    2 / 197 (1.02%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    5 / 405 (1.23%)
    1 / 197 (0.51%)
         occurrences all number
    5
    1
    Diarrhea
         subjects affected / exposed
    3 / 405 (0.74%)
    3 / 197 (1.52%)
         occurrences all number
    3
    3
    Flatulence
         subjects affected / exposed
    2 / 405 (0.49%)
    2 / 197 (1.02%)
         occurrences all number
    2
    2
    Nausea
         subjects affected / exposed
    6 / 405 (1.48%)
    1 / 197 (0.51%)
         occurrences all number
    6
    1
    Vomiting
         subjects affected / exposed
    5 / 405 (1.23%)
    2 / 197 (1.02%)
         occurrences all number
    5
    2
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    1 / 405 (0.25%)
    2 / 197 (1.02%)
         occurrences all number
    1
    2
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    2 / 405 (0.49%)
    2 / 197 (1.02%)
         occurrences all number
    2
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 405 (0.49%)
    2 / 197 (1.02%)
         occurrences all number
    2
    2
    Back pain
         subjects affected / exposed
    6 / 405 (1.48%)
    1 / 197 (0.51%)
         occurrences all number
    6
    1
    Pain in extremity
         subjects affected / exposed
    5 / 405 (1.23%)
    1 / 197 (0.51%)
         occurrences all number
    5
    1
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 405 (0.00%)
    2 / 197 (1.02%)
         occurrences all number
    0
    2
    Hypokalaemia
         subjects affected / exposed
    2 / 405 (0.49%)
    5 / 197 (2.54%)
         occurrences all number
    2
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 405 (0.99%)
    3 / 197 (1.52%)
         occurrences all number
    4
    3
    Nasopharyngitis
         subjects affected / exposed
    9 / 405 (2.22%)
    1 / 197 (0.51%)
         occurrences all number
    9
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 405 (0.49%)
    2 / 197 (1.02%)
         occurrences all number
    2
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Feb 2017
    Analyses relating to anticoagulation under "other objectives" as well as any other reference to anticoagulation markers in the protocol were deleted; administration of study drug and active comparator were clarified; eligibility criteria were updated; and the method of treatment allocation section was revised
    27 Jul 2017
    Administration of the study drug was further clarified; the method of assessing regimen compliance section was updated; and the list of hematology analyses required prior to randomization and protocol for assessing these markers were updated

    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
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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