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    Clinical Trial Results:
    A PHASE 3, OPEN-LABEL, RANDOMIZED, MULTICENTER, CONTROLLED TRIAL TO EVALUATE THE PHARMACOKINETICS AND PHARMACODYNAMICS OF EDOXABAN AND TO COMPARE THE EFFICACY AND SAFETY OF EDOXABAN WITH STANDARD OF CARE ANTICOAGULANT THERAPY IN PEDIATRIC SUBJECTS FROM BIRTH TO LESS THAN 18 YEARS OF AGE WITH CONFIRMED VENOUS THROMBOEMBOLISM (VTE)

    Summary
    EudraCT number
    		 2016-000991-49
    Trial protocol
    		 CZ   PT   HU   DE   ES   SI   DK   NL   HR   BG   NO   PL   FR  
    Global end of trial date
    24 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Dec 2022
    First version publication date
    14 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DU176b-D-U312
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02798471
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo
    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
    24 May 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to demonstrate the non-inferiority of edoxaban to standard of care (SOC; including low molecular weight heparin (LMWH), vitamin K antagonist (VKA), or synthetic pentasaccharide (SP) Xa inhibitors) in the treatment and secondary prevention of VTE in pediatric subjects with regard to the composite efficacy endpoint (ie, symptomatic recurrent VTE, death as result of VTE, and no change or extension of thrombotic burden) 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
    27 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
    Netherlands: 6
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Portugal: 10
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Croatia: 6
    Country: Number of subjects enrolled
    Bulgaria: 4
    Country: Number of subjects enrolled
    Czechia: 13
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Hungary: 23
    Country: Number of subjects enrolled
    Singapore: 6
    Country: Number of subjects enrolled
    United States: 41
    Country: Number of subjects enrolled
    Malaysia: 3
    Country: Number of subjects enrolled
    Thailand: 15
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 9
    Country: Number of subjects enrolled
    El Salvador: 5
    Country: Number of subjects enrolled
    Panama: 1
    Country: Number of subjects enrolled
    Brazil: 11
    Country: Number of subjects enrolled
    Guatemala: 9
    Country: Number of subjects enrolled
    Chile: 2
    Country: Number of subjects enrolled
    Ukraine: 4
    Country: Number of subjects enrolled
    India: 8
    Country: Number of subjects enrolled
    Lebanon: 9
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    Turkey: 30
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Colombia: 11
    Worldwide total number of subjects
    290
    EEA total number of subjects
    90
    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)
    44
    Children (2-11 years)
    75
    Adolescents (12-17 years)
    171
    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 290 participants who met all inclusion criteria and no exclusion criteria were randomized to receive either edoxaban or standard of care treatment; 286 patients received at least 1 dose of study drug (modified intent-to-treat population).

    Pre-assignment
    Screening details
    		 Pre-randomization treatment was provided by the Investigator or diagnosing clinic of the index VTE. Initial treatment using LMWH, SP Xa inhibitor, or UFH for index VTE prior to randomization was within 5-15 days and up to 20 days with approval. If VKA are administrated prior randomization, INR prior to randomization is recommended to be ≤2.5.

    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
    Arm description
    		 Pediatric patients who were randomized to edoxaban treatment. Edoxaban was administered as 15 or 30 mg tablets for participants 12 years of age to <18, and 60 mg edoxaban suspension for oral administration to participants under 12 years of age.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Edoxaban was supplied as tablets (15- and/or 30-mg strength) or granules for oral suspension 60 mg (6 mg/mL). Patients were instructed to take edoxaban (tablets or granules) 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
    Arm description
    		 Pediatric patients who were randomized to standard of care (SOC) treatment. Standard of care may have included low molecular weight heparin (LMWH), vitamin K antagonist (VKA), or synthetic pentasaccharide (SP) Xa inhibitors.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Standard of care: Enoxaparin (LMWH)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Solution for injection
    Dosage and administration details
    Enoxaparin (LMWH) was provided as a solution for subcutaneous injection in prefilled syringes with 40 mg/0.4mL, 60 mg/0.6mL, 80 mg/0.8mL, and 100 mg/1.0 mL concentration for injection, or as multiple-dose vials (for patients <10 kg) for injection where allowed per standard clinical practice.

    Investigational medicinal product name
    Standard of care: Fondaparinux (SP Xa inhibitor)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Oral use
    Dosage and administration details
    Fondaparinux (SP Xa inhibitor) was supplied as solution for subcutaneous injection in prefilled syringes (2.5 mg/0.5 mL, 5.0 mg/0.4 mL, 7.5 mg/0.6 mL, 10.0 mg/0.8 mL, and [where available] 1.5 mg/0.3 mL).

    Investigational medicinal product name
    Standard of care: Warfarin (VKA)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Warfarin (VKA) was supplied as tablets (0.5 mg, 1.0 mg, and 3.0 mg) and Warfarin suspension (1 mg/mL oral suspension). Various doses were available for international normalized ratio maintenance in the therapeutic range of ≥2.0 and ≤3.0.

    Number of subjects in period 1
    		Edoxaban Standard of Care
    Started
    147
    143
    Completed
    128
    119
    Not completed
    19
    24
         Physician decision
    3
    7
         Consent withdrawn by subject
    -
    6
         Adverse event, non-fatal
    7
    2
         Death
    2
    3
         Not specified
    5
    5
         Data entry error (study completion + discontinued)
    2
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Edoxaban
    Reporting group description
    		 Pediatric patients who were randomized to edoxaban treatment. Edoxaban was administered as 15 or 30 mg tablets for participants 12 years of age to <18, and 60 mg edoxaban suspension for oral administration to participants under 12 years of age.

    Reporting group title
    Standard of Care
    Reporting group description
    		 Pediatric patients who were randomized to standard of care (SOC) treatment. Standard of care may have included low molecular weight heparin (LMWH), vitamin K antagonist (VKA), or synthetic pentasaccharide (SP) Xa inhibitors.

    Reporting group values
    		 Edoxaban Standard of Care Total
    Number of subjects
    		 147 143 290
    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)
    		 22 22 44
        Children (2-11 years)
    		 38 37 75
        Adolescents (12-17 years)
    		 87 84 171
        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)
    		 10.9 ( 5.99 ) 11.1 ( 6.03 ) -
    Gender categorical
    Units: Subjects
        Female
    		 70 70 140
        Male
    		 77 73 150

    End points

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    End points reporting groups
    Reporting group title
    Edoxaban
    Reporting group description
    		 Pediatric patients who were randomized to edoxaban treatment. Edoxaban was administered as 15 or 30 mg tablets for participants 12 years of age to <18, and 60 mg edoxaban suspension for oral administration to participants under 12 years of age.

    Reporting group title
    Standard of Care
    Reporting group description
    		 Pediatric patients who were randomized to standard of care (SOC) treatment. Standard of care may have included low molecular weight heparin (LMWH), vitamin K antagonist (VKA), or synthetic pentasaccharide (SP) Xa inhibitors.

    Primary: Number of Patients With Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)

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    End point title
    		 Number of Patients With Symptomatic Recurrent Venous Thromboembolism During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)
    End point description
    Diagnosis of recurrent venous thromboembolism (VTE) requires the confirmation by diagnostic imaging and at least one of the symptoms of VTE from such areas as lower or upper extremity, catheter-related thrombosis, pulmonary embolism, or sinovenous thrombosis. Symptomatic recurrent VTE was assessed in the modified intent-to-treat population (mITT).
    End point type
    Primary
    End point timeframe
    Randomization to Month 3
    End point values
    		 Edoxaban Standard of Care
    Number of subjects analysed
    145
    141
    Units: Count of patients
    number (not applicable)
        Symptomatic Recurrent Venous Thromboembolism
    5
    2
    Statistical analysis title
    		 Composite primary efficacy endpoint
    Comparison groups
    Edoxaban v Standard of Care
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.9694
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.594
         upper limit
    		 1.719
    Notes
    [1] - The edoxaban-to-comparator hazard ratio will be computed with 95% confidence interval (CI) (two-sided) based on this model. Edoxaban will be considered non-inferior to comparator if the upper limit of the 95% CI is ≤1.5.

    Primary: Number of Patients Who Died as a Result of VTE During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)

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    End point title
    		 Number of Patients Who Died as a Result of VTE During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite) [2]
    End point description
    Death from venous thromboembolism (VTE) is based on objective diagnostic testing, autopsy or death which cannot be attributed to documented cause for which VTE cannot be ruled out. Death was assessed in the modified intent-to-treat population (mITT).
    End point type
    Primary
    End point timeframe
    Randomization to Month 3
    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 statistics were used to assess this outcome measure.
    End point values
    		 Edoxaban Standard of Care
    Number of subjects analysed
    145
    141
    Units: Count of patients
    number (not applicable)
        Pulmonary embolism with or without DVT
    0
    1
        Fatal pulmonary embolism
    0
    0
        Non-fatal pulmonary embolism
    0
    1
        Deep vein thrombosis (DVT) only
    5
    1
        Fatal DVT
    0
    0
        Non-fatal DVT
    4
    0
        Unexplained death which VTE cannot be ruled out
    1
    1
    No statistical analyses for this end point

    Primary: Number of Patients With No Change or Extension of Thrombotic Burden During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)

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    End point title
    		 Number of Patients With No Change or Extension of Thrombotic Burden During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite) [3]
    End point description
    No change or extension of thrombotic burden as assessed by quantitative diagnostic imaging of the index qualifying VTE thrombus at baseline and at Month 3. Change in thrombotic burden was assessed in the modified intent-to-treat population (mITT).
    End point type
    Primary
    End point timeframe
    Randomization to Month 3
    Notes
    [3] - 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 statistics were used to assess this outcome.
    End point values
    		 Edoxaban Standard of Care
    Number of subjects analysed
    145
    141
    Units: Count of patients
    number (not applicable)
        No Change or Extension of Thrombotic Burden
    21
    29
    No statistical analyses for this end point

    Secondary: Number of Patients With Symptomatic Recurrent Venous Thromboembolism During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)

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    End point title
    		 Number of Patients With Symptomatic Recurrent Venous Thromboembolism During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)
    End point description
    Diagnosis of recurrent venous thromboembolism (VTE) requires the confirmation by diagnostic imaging and at least one of the symptoms of VTE from such areas as lower or upper extremity, catheter related thrombosis, pulmonary embolism, or sinovenous thrombosis. Symptomatic VTE was assessed in the modified intent-to-treat (mITT) population.
    End point type
    Secondary
    End point timeframe
    From randomization to the date of last study drug plus 30 days, up to approximately 5 years 2 months
    End point values
    		 Edoxaban Standard of Care
    Number of subjects analysed
    145
    141
    Units: Count of patients
    number (not applicable)
        Symptomatic Recurrent Venous Thromboembolism
    7
    2
    No statistical analyses for this end point

    Secondary: Number of Patients With Symptomatic Recurrent VTE During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Individual Component of Primary Efficacy Endpoint)

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    End point title
    		 Number of Patients With Symptomatic Recurrent VTE During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Individual Component of Primary Efficacy Endpoint)
    End point description
    Diagnosis of recurrent venous thromboembolism (VTE) requires the confirmation by diagnostic imaging and at least one of the symptoms of VTE from such areas as lower or upper extremity, catheter related thrombosis, pulmonary embolism (PE), or sinovenous thrombosis. Symptomatic recurrent VTE was assessed in the modified intent-to-treat population (mITT).
    End point type
    Secondary
    End point timeframe
    Randomization to Month 3
    End point values
    		 Edoxaban Standard of Care
    Number of subjects analysed
    145
    141
    Units: Count of patients
    number (not applicable)
        Symptomatic VTE
    4
    1
        Pulmonary embolism with or without DVT
    0
    1
        Deep vein thrombosis (DVT) only
    4
    0
    No statistical analyses for this end point

    Secondary: Number of Patients Who Died as a Result of VTE During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)

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    End point title
    		 Number of Patients Who Died as a Result of VTE During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)
    End point description
    Death from venous thromboembolism (VTE) is based on objective diagnostic testing, autopsy or death which cannot be attributed to documented cause for which VTE cannot be ruled out. Death was assessed in the modified intent-to-treat population (mITT).
    End point type
    Secondary
    End point timeframe
    From randomization to the date of last study drug plus 30 days, up to approximately 5 years 2 months
    End point values
    		 Edoxaban Standard of Care
    Number of subjects analysed
    145
    141
    Units: Count of patients
    number (not applicable)
        Pulmonary embolism (PE) with or without DVT
    1
    1
        Fatal PE
    0
    0
        Non-fatal PE
    1
    1
        Deep vein thrombosis (DVT) only
    6
    1
        Fatal DVT
    0
    0
        Non-fatal DVT
    5
    0
        Unexplained death which VTE cannot be ruled out
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Patients Who Died as a Result of VTE During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Individual Component of Primary Efficacy Endpoint)

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    End point title
    		 Number of Patients Who Died as a Result of VTE During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Individual Component of Primary Efficacy Endpoint)
    End point description
    Death from venous thromboembolism (VTE) is based on objective diagnostic testing, autopsy or death which cannot be attributed to documented cause for which VTE cannot be ruled out. Death was assessed in the modified intent-to-treat population (mITT).
    End point type
    Secondary
    End point timeframe
    Randomization to Month 3
    End point values
    		 Edoxaban Standard of Care
    Number of subjects analysed
    145
    141
    Units: Count of patients
    number (not applicable)
        Death as a result of VTE
    1
    1
        Unexplained death which VTE cannot be ruled out
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Patients With No Change or Extension of Thrombotic Burden During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)

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    End point title
    		 Number of Patients With No Change or Extension of Thrombotic Burden During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)
    End point description
    No change or extension of thrombotic burden as assessed by quantitative diagnostic imaging of the index qualifying VTE thrombus at baseline and at Month 3. Change in thrombotic burden was assessed in the modified intent-to-treat population (mITT).
    End point type
    Secondary
    End point timeframe
    Randomization to the date of last study drug plus 30 days, up to approximately 5 years 2 months
    End point values
    		 Edoxaban Standard of Care
    Number of subjects analysed
    145
    141
    Units: Count of patients
    number (not applicable)
        No Change or Extension of Thrombotic Burden
    35
    47
    No statistical analyses for this end point

    Secondary: Number of Patients With No Change or Extension of Thrombotic Burden During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Individual Component of Primary Efficacy Endpoint)

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    End point title
    		 Number of Patients With No Change or Extension of Thrombotic Burden During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Individual Component of Primary Efficacy Endpoint)
    End point description
    No change or extension of thrombotic burden as assessed by quantitative diagnostic imaging of the index qualifying VTE thrombus at baseline and at Month 3. Change in thrombotic burden was assessed in the modified intent-to-treat population (mITT).
    End point type
    Secondary
    End point timeframe
    Randomization to Month 3
    End point values
    		 Edoxaban Standard of Care
    Number of subjects analysed
    145
    141
    Units: Count of patients
    number (not applicable)
        No Change or Extension of Thrombotic Burden
    21
    29
    No statistical analyses for this end point

    Secondary: Number of Patients Reporting All-Cause Mortality During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated)

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    End point title
    		 Number of Patients Reporting All-Cause Mortality During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated)
    End point description
    All-cause mortality is defined as death due to any cause. All-cause mortality was assessed in the modified intent-to-treat (mITT) population.
    End point type
    Secondary
    End point timeframe
    Randomization to the date of last study drug plus 30 days, up to approximately 5 years 2 months
    End point values
    		 Edoxaban Standard of Care
    Number of subjects analysed
    145
    141
    Units: Count of patients
    number (not applicable)
        Participants with all-cause mortality
    2
    3
        Venous thromboembolism (VTE)-related death
    1
    1
        Unexplained death which VTE cannot be ruled out
    1
    1
        Other known causes of death
    1
    2
        Cancer
    0
    1
        Infectious disease
    0
    1
        Other
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Patients With Deep Vein Thrombosis, Catheter-related Thrombosis, Sino-venous Thrombosis, and Pulmonary Embolism During the Main, Extension, and Overall Treatment Periods Following Edoxaban or Standard of Care Treatment

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    End point title
    		 Number of Patients With Deep Vein Thrombosis, Catheter-related Thrombosis, Sino-venous Thrombosis, and Pulmonary Embolism During the Main, Extension, and Overall Treatment Periods Following Edoxaban or Standard of Care Treatment
    End point description
    Deep vein thrombosis was assessed by ultrasonography or magnetic resonance venography (MRV), catheter-related thrombosis was assessed by ultrasonography or echocardiography, sino-venous thrombosis was assessed by brain MRI, and pulmonary embolism was assessed by nuclear ventilation/perfusion (V/Q) scanning. Deep vein thrombosis, catheter-related thrombosis, sino-venous thrombosis, and pulmonary embolism were assessed in the modified intent-to-treat (mITT) population.
    End point type
    Secondary
    End point timeframe
    Randomization to the date of last study drug plus 30 days, up to approximately 5 years 2 months
    End point values
    		 Edoxaban Standard of Care
    Number of subjects analysed
    145
    141
    Units: Count of patients
    number (not applicable)
        Main Treatment: DVT only
    4
    0
        Main Treatment: Catheter-related thrombosis
    1
    0
        Main Treatment: Cerebral sinovenous DVT thrombosis
    0
    0
        Main Treatment: PE with or without DVT
    0
    1
        Extension Treatment: DVT
    1
    0
        Extension Treatment: Catheter-related thrombosis
    0
    0
        Extension Treatment: Sino-venous DVT thrombosis
    1
    0
        Extension Treatment: PE
    1
    0
        Overall Treatment: DVT
    5
    0
        Overall Treatment: Catheter-related thrombosis
    1
    0
        Overall Treatment: Sino-venous DVT thrombosis
    1
    0
        Overall Treatment: PE
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Patients With Major and Clinically Relevant Non-Major Bleeding Events (On Treatment) During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)

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    End point title
    		 Number of Patients With Major and Clinically Relevant Non-Major Bleeding Events (On Treatment) During the Main Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)
    End point description
    Any bleeding event defined as major and clinically relevant non-major bleeding (CRNM) events was reported. Major bleeding was defined as defined as a composite of any of the following: fatal bleeding; and/or symptomatic bleeding in critical area or organ such as intracranial, intra-spinal, intraocular, retroperitoneal, intra-articular, pulmonary, or pericardial, or intramuscular with compartment syndrome; and/or bleeding that causes a decrease in hemoglobin of at least 2 g/dL or more, or leading to transfusion of the equivalent of two or more units of whole blood or red blood cells. CRNM was defined as 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; a physician-guided medical or surgical treatment for bleeding or a change in antithrombotic therapy (including interruption or discontinuation of study drug). [Safety Analysis]
    End point type
    Secondary
    End point timeframe
    Randomization to Month 3
    End point values
    		 Edoxaban Standard of Care
    Number of subjects analysed
    145
    141
    Units: Count of patients
    number (not applicable)
        Major and CRNM
    3
    5
    No statistical analyses for this end point

    Secondary: Number of Patients With All Bleeding Events (On Treatment) During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)

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    End point title
    		 Number of Patients With All Bleeding Events (On Treatment) During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)
    End point description
    All bleeding events included major bleeding defined as a composite of any of the following: fatal bleeding; and/or symptomatic bleeding in critical area or organ such as intracranial, intra-spinal, intraocular, retroperitoneal, intraarticular, pulmonary, or pericardial, or intramuscular with compartment syndrome; and/or bleeding that causes a decrease in hemoglobin of at least 2 g/dL or more, or leading to transfusion of the equivalent of two or more units of whole blood or red blood cells (RBCs), clinically relevant non-major bleeding defined as 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; a physician-guided medical or surgical treatment for bleeding or a change in antithrombotic therapy (including interruption or discontinuation of study drug), nuisance bleeding, or a combination of bleeding events. [Safety Analysis Set
    End point type
    Secondary
    End point timeframe
    Randomization to the date of last study drug plus 30 days, up to approximately 5 years 2 months
    End point values
    		 Edoxaban Standard of Care
    Number of subjects analysed
    145
    141
    Units: Count of patients
    number (not applicable)
        All Bleeding Events
    25
    24
    No statistical analyses for this end point

    Secondary: Number of Patients With Major and Clinically Relevant Non-Major Bleeding Events (On Treatment) During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)

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    End point title
    		 Number of Patients With Major and Clinically Relevant Non-Major Bleeding Events (On Treatment) During the Overall Treatment Period Following Edoxaban or Standard of Care Treatment (Adjudicated Composite)
    End point description
    Any bleeding event defined as major and clinically relevant non-major bleeding (CRNM) events was reported. Major bleeding was defined as defined as a composite of any of the following: fatal bleeding; and/or symptomatic bleeding in critical area or organ such as intracranial, intra-spinal, intraocular, retroperitoneal, intra-articular, pulmonary, or pericardial, or intramuscular with compartment syndrome; and/or bleeding that causes a decrease in hemoglobin of at least 2 g/dL or more, or leading to transfusion of the equivalent of two or more units of whole blood or red blood cells. CRNM was defined as 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; a physician-guided medical or surgical treatment for bleeding or a change in antithrombotic therapy (including interruption or discontinuation of study drug). [Safety Analysis]
    End point type
    Secondary
    End point timeframe
    Randomization to the date of last study drug plus 30 days, up to approximately 5 years 2 months
    End point values
    		 Edoxaban Standard of Care
    Number of subjects analysed
    145
    141
    Units: Count of patients
    number (not applicable)
        Major and CRNM
    8
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events were collected from the date the Informed Consent Form was signed up to 30 days after the last dose of study drug, up to approximately 5 years 2 months.
    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
    		 Pediatric patients who were randomized to edoxaban treatment. Edoxaban was administered as 15 or 30 mg tablets for participants 12 years of age to <18, and 60 mg edoxaban suspension for oral administration to participants under 12 years of age.

    Reporting group title
    Standard of Care
    Reporting group description
    		 Pediatric patients who were randomized to standard of care (SOC) treatment. Standard of care may have included low molecular weight heparin (LMWH), vitamin K antagonist (VKA), or synthetic pentasaccharide (SP) Xa inhibitors.

    Serious adverse events
    		 Edoxaban Standard of Care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 145 (30.34%)
    37 / 141 (26.24%)
         number of deaths (all causes)
    3
    3
         number of deaths resulting from adverse events
    3
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anaplastic astrocytoma
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post thrombotic syndrome
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava occlusion
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venoocclusive disease
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (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
    Asthenia
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device site rash
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (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
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menometrorrhagia
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (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
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchomalacia
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoventilation
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiogenic pulmonary oedema
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         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
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 145 (1.38%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric decompensation
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    2 / 145 (1.38%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma complication
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma site haemorrhage
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Chronic granulomatous disease
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 145 (0.69%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebral venous sinus thrombosis
         subjects affected / exposed
    2 / 145 (1.38%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 145 (1.38%)
    3 / 141 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic intracranial hypertension
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    2 / 145 (1.38%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    6 / 145 (4.14%)
    6 / 141 (4.26%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypereosinophilic syndrome
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sickle cell anemia with crisis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (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
    2 / 145 (1.38%)
    3 / 141 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eyelid ptosis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papilloedema
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         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 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (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
    2 / 145 (1.38%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (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 / 145 (0.69%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest wall haematoma
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (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
    Anal abscess
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (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 / 145 (0.00%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis viral
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (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 / 145 (0.69%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective pulmonary exacerbation of cystic fibrosis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia
         subjects affected / exposed
    4 / 145 (2.76%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    0 / 145 (0.00%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 145 (2.07%)
    0 / 141 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 145 (0.69%)
    0 / 141 (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 / 145 (0.69%)
    2 / 141 (1.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipoedema
         subjects affected / exposed
    0 / 145 (0.00%)
    1 / 141 (0.71%)
         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
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    51 / 145 (35.17%)
    46 / 141 (32.62%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 145 (13.79%)
    14 / 141 (9.93%)
         occurrences all number
    35
    21
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    12 / 145 (8.28%)
    11 / 141 (7.80%)
         occurrences all number
    18
    12
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    16 / 145 (11.03%)
    9 / 141 (6.38%)
         occurrences all number
    21
    12
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    12 / 145 (8.28%)
    10 / 141 (7.09%)
         occurrences all number
    44
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 145 (5.52%)
    3 / 141 (2.13%)
         occurrences all number
    9
    3
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 145 (6.21%)
    8 / 141 (5.67%)
         occurrences all number
    14
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jan 2018
    Update the sample size for PK evaluation, updated exclusion criteria, and revised dose administration procedures.
    07 Jun 2019
    Revised dose administration procedures, updated exclusion criteria, clarified bleeding definitions, revised screening and re-screening procedures, updated reporting requirements for AEs, and revised echocardiogram assessment procedures.
    08 Jun 2021
    Updated dosing requirements for patients ≤28 days old, revised anticoagulation treatment, increased sample size, and updated procedures for renal function monitoring and radiologic VTE imaging.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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