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    Clinical Trial Results:
    An Open-label, Randomised, Parallel-group, Multicentre, Observational Trial to Evaluate Safety and Efficacy of Edoxaban Tosylate in Children From 38 Weeks Gestational Age to Less Than 18 Years of Age With Cardiac Diseases At Risk of Thromboembolic Events

    Summary
    EudraCT number
    		 2017-000475-90
    Trial protocol
    		 GB   HU   DE   ES   AT   FR   PL   HR   IT  
    Global end of trial date
    03 Dec 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jun 2022
    First version publication date
    18 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DU176b-C-U313
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03395639
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo, Inc.
    Sponsor organisation address
    211 Mount Airy Rd., Basking Ridge, United States, 07920
    Public contact
    Clinical Trial Information Contact, Daiichi Sankyo Inc, +1 908-992-6400, CTRinfo@dsi.com
    Scientific contact
    Clinical Trial Information Contact, Daiichi Sankyo Inc, +1 908-992-6400, CTRinfo@dsi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000788-PIP02-11
    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 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to compare the safety of edoxaban with the SOC in pediatric subjects with cardiac diseases at risk of thromboembolic complications who need primary or secondary anticoagulant prophylaxis with regard to the combination of major and clinically relevant non-major (CRNM) bleedings per International Society on Thrombosis and Haemostasis [ISTH] definition occurring on treatment (ie, during treatment or within 3 days of completing, interrupting or stopping study treatment during the first 3-month treatment period).
    Protection of trial subjects
    The study protocol, amendments (if any), the informed consent form(s) (ICFs), and information sheets were approved by the appropriate and applicable Independent Ethics Committees (IECs) or Institutional Review Boards (IRBs). This study was conducted in compliance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, the International Council for Harmonisation (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and applicable regulatory requirement(s).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Feb 2018
    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
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Austria: 15
    Country: Number of subjects enrolled
    Hungary: 7
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Egypt: 37
    Country: Number of subjects enrolled
    India: 4
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Lebanon: 7
    Country: Number of subjects enrolled
    United States: 34
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Turkey: 10
    Country: Number of subjects enrolled
    Ukraine: 6
    Worldwide total number of subjects
    168
    EEA total number of subjects
    52
    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)
    16
    Children (2-11 years)
    108
    Adolescents (12-17 years)
    44
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 168 participants who met all inclusion criteria and no exclusion criteria were randomized to treatment; 167 participants received treatment and were included in the modified Intent to Treat and Safety Populations.

    Pre-assignment
    Screening details
    		 All subjects at the Screening Visit were assessed for international normalized ratio (INR) and activated partial thromboplastin time (aPTT) and evaluated at the local laboratory.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open label

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Edoxaban
    Arm description
    		 Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Lixiana, Savaysa
    Pharmaceutical forms
    Granules for oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets (15- and/or 30-mg strength) or granules for oral suspension (60 mg, 6 mg/mL) were administered orally once a day, at the same time every day, with or without food. Tablets were to be swallowed with a glass of water.

    Arm title
    		 Standard of Care (SOC)
    Arm description
    		 Participants who were randomized to SOC regimen which may have included low molecular weight heparin (LMWH) and/or Vitamin K antagonist (VKA) according to the clinical site’s SOC treatment regimen.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Standard of Care (SOC)
    Investigational medicinal product code
    Other name
    Warfarin/heparin, Vitamin K antagonist
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Standard of care (SOC) was administered according to the clinical site’s SOC treatment regimen.

    Number of subjects in period 1
    		Edoxaban Standard of Care (SOC)
    Started
    110
    58
    Completed
    106
    55
    Not completed
    4
    3
         Consent withdrawn by subject
    2
    2
         Participant discontinued at Principal Investigator
    -
    1
         Adverse event, non-fatal
    1
    -
         Did not receive study drug
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Edoxaban
    Reporting group description
    		 Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.

    Reporting group title
    Standard of Care (SOC)
    Reporting group description
    		 Participants who were randomized to SOC regimen which may have included low molecular weight heparin (LMWH) and/or Vitamin K antagonist (VKA) according to the clinical site’s SOC treatment regimen.

    Reporting group values
    		 Edoxaban Standard of Care (SOC) Total
    Number of subjects
    		 110 58 168
    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)
    		 8 8 16
        Children (2-11 years)
    		 74 34 108
        Adolescents (12-17 years)
    		 28 16 44
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 7.7 ± 4.8 7.3 ± 5.1 -
    Gender categorical
    Units: Subjects
        Female
    		 38 21 59
        Male
    		 72 37 109

    End points

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    End points reporting groups
    Reporting group title
    Edoxaban
    Reporting group description
    		 Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.

    Reporting group title
    Standard of Care (SOC)
    Reporting group description
    		 Participants who were randomized to SOC regimen which may have included low molecular weight heparin (LMWH) and/or Vitamin K antagonist (VKA) according to the clinical site’s SOC treatment regimen.

    Subject analysis set title
    Edoxaban (Extension Period)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.

    Primary: Number of Participants With Adjudicated Bleeding Events Within the Main Treatment Period

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    End point title
    		 Number of Participants With Adjudicated Bleeding Events Within the Main Treatment Period
    End point description
    Adjudicated bleeding events included major and clinically-relevant non-major (CRNM) bleeding events per International Society on Thrombosis and Haemostasis (ISTH) definition occurring within the main treatment period. Based on modified ISTH recommendations, major bleeding is defined as a composite (ie, any) of the following: fatal bleeding; and/or symptomatic bleeding in a critical area or organ; and/or bleeding causing a decrease in hemoglobin level of >2 g/dL, or leading to transfusion of the equivalent of ≥2 units of whole blood or red cells. A CRNM bleed is an acute or sub-acute clinically overt bleed that does not meet the criteria for a major bleed but prompts a clinical response, in that it leads to at least one of the following: a hospital admission for bleeding, or a physician guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy. Minor bleeding is any other overt bleeding event that does not meet criteria for either major or CRNM bleeding
    End point type
    Primary
    End point timeframe
    Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier
    End point values
    		 Edoxaban Standard of Care (SOC)
    Number of subjects analysed
    109
    58
    Units: participants
    number (not applicable)
        Major or CRNM bleeding events
    1
    1
        Major bleeding events
    0
    0
        All bleeding events (Major, CRNM, minor)
    4
    2
    Statistical analysis title
    		 Edoxaban vs Standard of Care (SOC)
    Comparison groups
    Edoxaban v Standard of Care (SOC)
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Annualized rate difference
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0.12
    Notes
    [1] - Difference in adjudicated major or CRNM bleeding rates were assessed.
    Statistical analysis title
    		 Edoxaban vs Standard of Care (SOC)
    Comparison groups
    Edoxaban v Standard of Care (SOC)
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Annualized rate difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [2] - Difference in adjudicated major bleeding rates were assessed.
    Statistical analysis title
    		 Edoxaban vs Standard of Care (SOC)
    Comparison groups
    Edoxaban v Standard of Care (SOC)
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 Annualized rate difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0.25
    Notes
    [3] - Difference in all adjudicated bleeding (major, CRNM, minor) rates were assessed.

    Secondary: Number of Participants With Symptomatic Thromboembolic Events (TE) in the Systemic Arterial or Venous Pathways Within the Main Treatment Period

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    End point title
    		 Number of Participants With Symptomatic Thromboembolic Events (TE) in the Systemic Arterial or Venous Pathways Within the Main Treatment Period
    End point description
    Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).
    End point type
    Secondary
    End point timeframe
    Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier
    End point values
    		 Edoxaban Standard of Care (SOC)
    Number of subjects analysed
    109
    58
    Units: participants
    number (not applicable)
        Thromboembolic event, Any Event
    0
    1
        Deep vein thrombosis
    0
    1
        Pulmonary embolism
    0
    1
        Stroke
    0
    0
        Systemic embolic event
    0
    0
        Intracardiac thrombus
    0
    0
        Myocardial infarction
    0
    0
        Asymptomatic intracardiac thrombus-cardiac imaging
    0
    0
        Death as a result of TE
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants Who Died as a Result of Thromboembolic Event Within the Main Treatment Period

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    End point title
    		 Number of Participants Who Died as a Result of Thromboembolic Event Within the Main Treatment Period
    End point description
    Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).
    End point type
    Secondary
    End point timeframe
    Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier
    End point values
    		 Edoxaban Standard of Care (SOC)
    Number of subjects analysed
    109
    58
    Units: participants
    number (not applicable)
        Died as a result of TE
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants Who Died as a Result of Any Cause (All-Cause Mortality) Within the Main Treatment Period

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    End point title
    		 Number of Participants Who Died as a Result of Any Cause (All-Cause Mortality) Within the Main Treatment Period
    End point description
    Death due to any cause (all-cause mortality) was assessed.
    End point type
    Secondary
    End point timeframe
    Date of first dose of study drug up to the Month 4 or to the date of last dose of study drug if study treatment was discontinued, whichever was earlier
    End point values
    		 Edoxaban Standard of Care (SOC)
    Number of subjects analysed
    109
    58
    Units: participants
    number (not applicable)
        All-cause mortality
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants With Adjudicated Bleeding Events During the Extension Period

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    End point title
    		 Number of Participants With Adjudicated Bleeding Events During the Extension Period
    End point description
    Adjudicated bleeding events included major and clinically-relevant non-major (CRNM) bleeding events per International Society on Thrombosis and Haemostasis (ISTH) definition occurring within the main treatment period. Based on modified ISTH recommendations, major bleeding is defined as a composite (ie, any) of the following: fatal bleeding; and/or symptomatic bleeding in a critical area or organ; and/or bleeding causing a decrease in hemoglobin level of >2 g/dL, or leading to transfusion of the equivalent of ≥2 units of whole blood or red cells. A CRNM bleed is an acute or sub-acute clinically overt bleed that does not meet the criteria for a major bleed but prompts a clinical response, in that it leads to at least one of the following: a hospital admission for bleeding, or a physician guided medical or surgical treatment for bleeding, or a change in antithrombotic therapy. Minor bleeding is any other overt bleeding event that does not meet criteria for either major or CRNM bl
    End point type
    Secondary
    End point timeframe
    End of Month 3 up to Month 13
    End point values
    		 Edoxaban (Extension Period)
    Number of subjects analysed
    144
    Units: participants
    number (not applicable)
        Major or CRNM bleeding events
    1
        Major bleeding events
    1
        All bleeding events (Major, CRNM, minor)
    4
    No statistical analyses for this end point

    Secondary: Number of Participants With Symptomatic Thromboembolic Events (TE) in the Systemic Arterial or Venous Pathways During the Extension Period

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    End point title
    		 Number of Participants With Symptomatic Thromboembolic Events (TE) in the Systemic Arterial or Venous Pathways During the Extension Period
    End point description
    Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).
    End point type
    Secondary
    End point timeframe
    End of Month 3 up to Month 13
    End point values
    		 Edoxaban (Extension Period)
    Number of subjects analysed
    144
    Units: participants
    number (not applicable)
        Thromboembolic event, Any Event
    4
        Deep vein thrombosis
    0
        Pulmonary embolism
    0
        Stroke
    2
        Systemic embolic event
    0
        Intracardiac thrombus
    0
        Myocardial infarction
    2
        Asymptomatic intracardiac thrombus-cardiac imaging
    0
        Death as a result of TE
    0
    No statistical analyses for this end point

    Secondary: Number of Participants Who Died as a Result of Thromboembolic Event During the Extension Period

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    End point title
    		 Number of Participants Who Died as a Result of Thromboembolic Event During the Extension Period
    End point description
    Symptomatic thromboembolic events (TE) in the systemic arterial or venous pathways include deep vein thrombosis (DVT), pulmonary embolism (PE), stroke, intracardiac thrombus, and myocardial infarction (MI).
    End point type
    Secondary
    End point timeframe
    End of Month 3 up to Month 13
    End point values
    		 Edoxaban (Extension Period)
    Number of subjects analysed
    144
    Units: participant
    number (not applicable)
        Died as a result of TE
    0
    No statistical analyses for this end point

    Secondary: Number of Participants Who Died as a Result of Any Cause (All-Cause Mortality) During the Extension Period

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    End point title
    		 Number of Participants Who Died as a Result of Any Cause (All-Cause Mortality) During the Extension Period
    End point description
    Death due to any cause (all-cause mortality) was assessed.
    End point type
    Secondary
    End point timeframe
    End of Month 3 up to Month 13
    End point values
    		 Edoxaban (Extension Period)
    Number of subjects analysed
    144
    Units: participants
    number (not applicable)
        All-cause mortality
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected from the time of signing the informed consent form up to 30 days after the last dose of study drug, up to 13 months.
    Adverse event reporting additional description
    Adverse events (AEs) were defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Edoxaban
    Reporting group description
    		 Participants who were randomized to edoxaban solution or tablets orally once a day. Participants 12 to <18 years of age were administered 30 mg, 45 mg, or 60 mg edoxaban tablets or offered granules for oral suspension if they did not have the capacity to swallow. Participants under 12 years of age were administered edoxaban granules (dosed as mg/kg), with maximum dose of 45 mg for 6 months to <12 years, maximum dose of 12 mg for >28 days to <6 months, and maximum dose of 6 mg for 38 weeks gestation to ≤28 days.

    Reporting group title
    Standard of Care (SOC)
    Reporting group description
    		 Participants who were randomized to SOC regimen which may have included low molecular weight heparin (LMWH) and/or Vitamin K antagonist (VKA) according to the clinical site’s SOC treatment regimen.

    Serious adverse events
    		 Edoxaban Standard of Care (SOC)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 109 (21.10%)
    3 / 58 (5.17%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (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 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 109 (1.83%)
    0 / 58 (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
    Dyspnoea
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery stenosis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 109 (1.83%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Pulmonary arterial pressure increased
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (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
    Skin laceration
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic liver injury
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Coarctation of the aorta
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (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 thrombosis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 109 (1.83%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery thrombosis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (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
    Cerebellar infarction
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haematoma
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (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 / 109 (0.92%)
    0 / 58 (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
    Haemolysis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune thrombocytopenia
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gingival bleeding
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucous stools
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 109 (0.92%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (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
    Acute kidney injury
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 109 (0.92%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 109 (0.00%)
    1 / 58 (1.72%)
         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: 5%
    Non-serious adverse events
    		 Edoxaban Standard of Care (SOC)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 109 (44.04%)
    12 / 58 (20.69%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    13 / 109 (11.93%)
    2 / 58 (3.45%)
         occurrences all number
    19
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    17 / 109 (15.60%)
    1 / 58 (1.72%)
         occurrences all number
    19
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    7 / 109 (6.42%)
    1 / 58 (1.72%)
         occurrences all number
    11
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 109 (12.84%)
    2 / 58 (3.45%)
         occurrences all number
    18
    2
    Epistaxis
         subjects affected / exposed
    8 / 109 (7.34%)
    2 / 58 (3.45%)
         occurrences all number
    14
    2
    Rhinorrhoea
         subjects affected / exposed
    8 / 109 (7.34%)
    1 / 58 (1.72%)
         occurrences all number
    10
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    6 / 109 (5.50%)
    0 / 58 (0.00%)
         occurrences all number
    6
    0
    Nasopharyngitis
         subjects affected / exposed
    8 / 109 (7.34%)
    3 / 58 (5.17%)
         occurrences all number
    8
    3
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 109 (8.26%)
    2 / 58 (3.45%)
         occurrences all number
    16
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Oct 2017
    Risk/Benefit section was added, eligibility criteria were updated, drug formulation and administration procedures were clarified, study assessment procedures were clarified, and vendors were updated.
    27 Mar 2018
    Timeframe for primary/secondary objectives was updated and the secondary objectives, primary/secondary endpoints, statistical analysis, drug administration, and study design were revised
    03 Jun 2019
    Drug administration and study procedures were clarified and eligibility criteria 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
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