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    Clinical Trial Results:
    A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Multi-Center, Single Ascending Dose Study to Assess the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of DS-1040b when Added to Standard of Care Anticoagulation Therapy in Subjects with Acute Submassive Pulmonary Embolism

    Summary
    EudraCT number
    2015-005211-32
    Trial protocol
    NL  
    Global end of trial date
    05 Aug 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Aug 2020
    First version publication date
    17 Aug 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DS1040-B-U107
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02923115
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo
    Sponsor organisation address
    211 Mt. Airy Road, Basking Ridge, United States, 07920
    Public contact
    Contact for Clinical Trial Information, Daiichi Sankyo, Inc., +1 908-992-6400, CTRinfo@dsi.com
    Scientific contact
    Contact for Clinical Trial Information, Daiichi Sankyo, Inc., +1 908-992-6400, CTRinfo@dsi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess the safety and tolerability of ascending doses of DS-1040b given as a single IV infusion over 12, 24, 48 and 72 hours, respectively, when added to standard of care (SOC) anticoagulation therapy, compared to placebo by evaluating the rate of clinically relevant bleeding (International Society of Thrombosis and Haemostasis (ISTH) major or clinically relevant non-major bleeding [CRNM]).
    Protection of trial subjects
    This study was conducted in compliance with the protocol, the ethical principles that have their origin in the Declaration of Helsinki, the International Council for Harmonisation (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Jun 2016
    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: 25
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    France: 47
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    United States: 25
    Country: Number of subjects enrolled
    Italy: 11
    Worldwide total number of subjects
    134
    EEA total number of subjects
    109
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    86
    From 65 to 84 years
    48
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 134 subjects who met all inclusion and no exclusion criteria were enrolled in the study at 47 clinic sites (15 in the United States and 32 in Europe). Of the 134 subjects randomized to treatment, 125 received treatment.

    Pre-assignment
    Screening details
    This study enrolled up to 5 sequential, ascending-dose, continuous infusion cohorts (starting DS1040b dose 20 mg). In Cohorts 1 and 2, eligible subjects were randomized in a 2:1 ratio to either DS-1040b or placebo. Starting with Cohort 3, the ratio changed to 3:1. All participants received standard of care enoxaparin during study drug infusion.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1: DS-1040b 20 mg
    Arm description
    Subjects who received an intravenous infusion of 20 mg DS-1040b in addition to standard of care anticoagulation therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-1040b
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single, continuous intravenous infusion over 12 to 24 hours (depending on cohort)

    Investigational medicinal product name
    Enoxaparin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection 1 mg/kg twice daily

    Arm title
    Cohort 2: DS-1040b 40 mg
    Arm description
    Subjects who received an intravenous infusion of 40 mg DS-1040b in addition to standard of care anticoagulation therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-1040b
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single, continuous intravenous infusion over 12 to 24 hours (depending on cohort)

    Investigational medicinal product name
    Enoxaparin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection 1 mg/kg twice daily

    Arm title
    Cohort 3: DS-1040b 60 mg
    Arm description
    Subjects who received an intravenous infusion of 60 mg DS-1040b in addition to standard of care anticoagulation therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-1040b
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single, continuous intravenous infusion over 12 to 24 hours (depending on cohort)

    Investigational medicinal product name
    Enoxaparin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection 1 mg/kg twice daily

    Arm title
    Cohort 4: DS-1040 80 mg
    Arm description
    Subjects who received an intravenous infusion of 80 mg DS-1040b in addition to standard of care anticoagulation therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-1040b
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single, continuous intravenous infusion over 12 to 24 hours (depending on cohort)

    Investigational medicinal product name
    Enoxaparin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection 1 mg/kg twice daily

    Arm title
    Cohort 5: DS-1040b 40 mg
    Arm description
    Subjects who received an intravenous infusion of 40 mg DS-1040b in addition to standard of care anticoagulation therapy.
    Arm type
    Experimental

    Investigational medicinal product name
    DS-1040b
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single, continuous intravenous infusion over 12 to 24 hours (depending on cohort)

    Investigational medicinal product name
    Enoxaparin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection 1 mg/kg twice daily

    Arm title
    Placebo
    Arm description
    Subjects who received an intravenous infusion of placebo in addition to standard of care anticoagulation therapy.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    0.9% Sodium chloride injection
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Single, continuous intravenous infusion of 0.9% sodium chloride over 12 to 24 hours

    Investigational medicinal product name
    Enoxaparin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subcutaneous injection 1 mg/kg twice daily

    Number of subjects in period 1
    Cohort 1: DS-1040b 20 mg Cohort 2: DS-1040b 40 mg Cohort 3: DS-1040b 60 mg Cohort 4: DS-1040 80 mg Cohort 5: DS-1040b 40 mg Placebo
    Started
    12
    16
    23
    23
    22
    38
    Treated
    12
    16
    20
    22
    17
    38
    Completed
    12
    15
    20
    21
    17
    38
    Not completed
    0
    1
    3
    2
    5
    0
         Consent withdrawn by subject
    -
    1
    -
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    1
    -
    -
         Randomized, but not dosed
    -
    -
    3
    1
    5
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: DS-1040b 20 mg
    Reporting group description
    Subjects who received an intravenous infusion of 20 mg DS-1040b in addition to standard of care anticoagulation therapy.

    Reporting group title
    Cohort 2: DS-1040b 40 mg
    Reporting group description
    Subjects who received an intravenous infusion of 40 mg DS-1040b in addition to standard of care anticoagulation therapy.

    Reporting group title
    Cohort 3: DS-1040b 60 mg
    Reporting group description
    Subjects who received an intravenous infusion of 60 mg DS-1040b in addition to standard of care anticoagulation therapy.

    Reporting group title
    Cohort 4: DS-1040 80 mg
    Reporting group description
    Subjects who received an intravenous infusion of 80 mg DS-1040b in addition to standard of care anticoagulation therapy.

    Reporting group title
    Cohort 5: DS-1040b 40 mg
    Reporting group description
    Subjects who received an intravenous infusion of 40 mg DS-1040b in addition to standard of care anticoagulation therapy.

    Reporting group title
    Placebo
    Reporting group description
    Subjects who received an intravenous infusion of placebo in addition to standard of care anticoagulation therapy.

    Reporting group values
    Cohort 1: DS-1040b 20 mg Cohort 2: DS-1040b 40 mg Cohort 3: DS-1040b 60 mg Cohort 4: DS-1040 80 mg Cohort 5: DS-1040b 40 mg Placebo Total
    Number of subjects
    12 16 23 23 22 38 134
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0 0 0
        Adults (18-64 years)
    8 7 14 16 18 23 86
        From 65-84 years
    4 9 9 7 4 15 48
        85 years and over
    0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    56.1 ± 16.3 62.1 ± 10.9 55.1 ± 17.5 55.0 ± 13.5 56.5 ± 9.8 58.3 ± 10.7 -
    Gender categorical
    Units: Subjects
        Female
    4 8 5 8 7 12 44
        Male
    8 8 18 15 15 26 90

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: DS-1040b 20 mg
    Reporting group description
    Subjects who received an intravenous infusion of 20 mg DS-1040b in addition to standard of care anticoagulation therapy.

    Reporting group title
    Cohort 2: DS-1040b 40 mg
    Reporting group description
    Subjects who received an intravenous infusion of 40 mg DS-1040b in addition to standard of care anticoagulation therapy.

    Reporting group title
    Cohort 3: DS-1040b 60 mg
    Reporting group description
    Subjects who received an intravenous infusion of 60 mg DS-1040b in addition to standard of care anticoagulation therapy.

    Reporting group title
    Cohort 4: DS-1040 80 mg
    Reporting group description
    Subjects who received an intravenous infusion of 80 mg DS-1040b in addition to standard of care anticoagulation therapy.

    Reporting group title
    Cohort 5: DS-1040b 40 mg
    Reporting group description
    Subjects who received an intravenous infusion of 40 mg DS-1040b in addition to standard of care anticoagulation therapy.

    Reporting group title
    Placebo
    Reporting group description
    Subjects who received an intravenous infusion of placebo in addition to standard of care anticoagulation therapy.

    Primary: Number of Subjects Experiencing Adjudicated Clinically Relevant Bleeding Events Following Intravenous Infusion of DS-1040b or Placebo in Addition to Standard of Care Anti-coagulation Therapy in Subjects With Acute Submassive Pulmonary Embolism

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    End point title
    Number of Subjects Experiencing Adjudicated Clinically Relevant Bleeding Events Following Intravenous Infusion of DS-1040b or Placebo in Addition to Standard of Care Anti-coagulation Therapy in Subjects With Acute Submassive Pulmonary Embolism [1]
    End point description
    Clinically relevant bleeding was defined as major or clinically relevant non-major (CRNM) bleeding adjudicated by the Clinical Events Committee (CEC) based on International Society of Thrombosis and Haemostasis (ISTH) definitions and the CEC charter.
    End point type
    Primary
    End point timeframe
    Baseline up to Day 30 post infusion, up to approximately 3 years 2 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive analyses were performed based on the study groups and study drugs administered for this outcome.
    End point values
    Cohort 1: DS-1040b 20 mg Cohort 2: DS-1040b 40 mg Cohort 3: DS-1040b 60 mg Cohort 4: DS-1040 80 mg Cohort 5: DS-1040b 40 mg Placebo
    Number of subjects analysed
    12
    16
    20
    22
    17
    38
    Units: Subjects
    number (not applicable)
        At least 1 bleeding event
    4
    3
    3
    4
    1
    10
        Major bleeding event
    0
    0
    0
    1
    0
    00
        Non-major clinically relevant bleeding event
    0
    0
    0
    2
    1
    1
        Minor or nuisance bleeding event
    3
    2
    3
    2
    0
    6
        Fatal bleeding event
    0
    0
    0
    0
    0
    0
        Bleeding with Hb drop ≥2g/dL, transfusion ≥2 units
    0
    0
    0
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Mean Percent Change From Baseline in Total Thrombus Volume at 12-72 Hours Post Start of Infusion of DS-1040b Compared to Placebo When Added to Standard of Care Anticoagulation Therapy in Subjects With Acute Submassive Pulmonary Embolism

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    End point title
    Mean Percent Change From Baseline in Total Thrombus Volume at 12-72 Hours Post Start of Infusion of DS-1040b Compared to Placebo When Added to Standard of Care Anticoagulation Therapy in Subjects With Acute Submassive Pulmonary Embolism
    End point description
    The change from baseline in total thrombus volume was assessed by computed tomography angiography in segmental or larger pulmonary arteries following intravenous infusion of DS-1040b or placebo in addition to standard of care anticoagulation therapy.
    End point type
    Secondary
    End point timeframe
    Baseline to 12-72 hours post start of infusion, up to approximately 3 years 2 months
    End point values
    Cohort 1: DS-1040b 20 mg Cohort 2: DS-1040b 40 mg Cohort 3: DS-1040b 60 mg Cohort 4: DS-1040 80 mg Cohort 5: DS-1040b 40 mg Placebo
    Number of subjects analysed
    11
    15
    20
    22
    16
    36
    Units: Percent change
    arithmetic mean (standard deviation)
        Mean percent change from baseline
    -23.78 ± 24.49
    -38.67 ± 17.34
    -33.50 ± 17.41
    -37.36 ± 26.90
    -32.33 ± 19.03
    -31.35 ± 17.74
    No statistical analyses for this end point

    Secondary: Subjects Achieving Reductions in Total Thrombus Volume at 12-72 Hours Post Infusion of DS-1040b Compared to Placebo When Added to Standard of Care Anticoagulation Therapy in Subjects With Acute Submassive Pulmonary Embolism

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    End point title
    Subjects Achieving Reductions in Total Thrombus Volume at 12-72 Hours Post Infusion of DS-1040b Compared to Placebo When Added to Standard of Care Anticoagulation Therapy in Subjects With Acute Submassive Pulmonary Embolism
    End point description
    Change in total pulmonary thrombus burden (total thrombus volume) was assessed by computed tomography pulmonary angiography (CTPA). All CTPA scans were evaluated by a central imaging laboratory in a blinded manner by radiologists.
    End point type
    Secondary
    End point timeframe
    Baseline to 12-72 hours post start of infusion, up to approximately 3 years 2 months
    End point values
    Cohort 1: DS-1040b 20 mg Cohort 2: DS-1040b 40 mg Cohort 3: DS-1040b 60 mg Cohort 4: DS-1040 80 mg Cohort 5: DS-1040b 40 mg Placebo
    Number of subjects analysed
    12
    15
    20
    22
    17
    38
    Units: Subjects
    number (not applicable)
        No change or increase
    2
    0
    1
    0
    1
    3
        <20% reduction
    2
    3
    3
    5
    3
    5
        ≥20% reduction
    7
    12
    16
    17
    12
    28
        Missing data
    1
    0
    0
    0
    1
    2
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Parameter Maximum Concentration (Cmax) Following Intravenous Infusion of DS-1040b in Addition to Standard of Care Anti-coagulation Therapy in Subjects With Acute Submassive Pulmonary Embolism

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    End point title
    Pharmacokinetic (PK) Parameter Maximum Concentration (Cmax) Following Intravenous Infusion of DS-1040b in Addition to Standard of Care Anti-coagulation Therapy in Subjects With Acute Submassive Pulmonary Embolism [2]
    End point description
    Plasma concentrations at each time point and PK parameter Cmax of DS 1040b was calculated using noncompartmental analysis.
    End point type
    Secondary
    End point timeframe
    Cohort 1: 0 up to 72 h post infusion; Cohorts 2 and 3: 0 up to 96 h post infusion; Cohort 4 and 5: 0 up to 120 h post infusion
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive analyses were performed based on the study groups and study drugs administered for this outcome.
    End point values
    Cohort 1: DS-1040b 20 mg Cohort 2: DS-1040b 40 mg Cohort 3: DS-1040b 60 mg Cohort 4: DS-1040 80 mg Cohort 5: DS-1040b 40 mg
    Number of subjects analysed
    11
    15
    19
    22
    17
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cmax
    970.09 ± 1373.43
    421.73 ± 515.57
    608.84 ± 562.94
    1006.41 ± 1883.49
    526.12 ± 535.03
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter Area Under the Concentration Versus Time Curve (0 to Last) Following Intravenous Infusion of DS-1040b In Addition to Standard of Care Anti-coagulation Therapy in Participants With Acute Submassive Pulmonary Embolism

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    End point title
    Pharmacokinetic Parameter Area Under the Concentration Versus Time Curve (0 to Last) Following Intravenous Infusion of DS-1040b In Addition to Standard of Care Anti-coagulation Therapy in Participants With Acute Submassive Pulmonary Embolism [3]
    End point description
    Plasma concentrations at each time point and PK parameter of Area Under the Concentration Versus Time Curve (0 to last) of DS 1040b was calculated using non-compartmental analysis.
    End point type
    Secondary
    End point timeframe
    Cohort 1: 0 up to 72 h post infusion; Cohorts 2 and 3: 0 up to 96 h post infusion; Cohort 4 and 5: 0 up to 120 h post infusion
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive analyses were performed based on the study groups and study drugs administered for this outcome.
    End point values
    Cohort 1: DS-1040b 20 mg Cohort 2: DS-1040b 40 mg Cohort 3: DS-1040b 60 mg Cohort 4: DS-1040 80 mg Cohort 5: DS-1040b 40 mg
    Number of subjects analysed
    11
    15
    19
    22
    17
    Units: ng*h/mL
    arithmetic mean (standard deviation)
        AUC(0 to last)
    5532.92 ± 4090.34
    7819.53 ± 2870.13
    13403.15 ± 8047.13
    17147.27 ± 15024.61
    8014.73 ± 2870.19
    No statistical analyses for this end point

    Secondary: Pharmacokinetic Parameter Terminal Half-life Following Intravenous Infusion of DS-1040b Combined With Standard of Care Anti-coagulation Therapy in Subjects With Acute Submassive Pulmonary Embolism

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    End point title
    Pharmacokinetic Parameter Terminal Half-life Following Intravenous Infusion of DS-1040b Combined With Standard of Care Anti-coagulation Therapy in Subjects With Acute Submassive Pulmonary Embolism [4]
    End point description
    Plasma concentrations at each time point and PK parameter Terminal Half-life of DS 1062b was calculated using noncompartmental analysis.
    End point type
    Secondary
    End point timeframe
    Cohort 1: 0 up to 72 h post infusion; Cohorts 2 and 3: 0 up to 96 h post infusion; Cohort 4 and 5: 0 up to 120 h post infusion
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive analyses were performed based on the study groups and study drugs administered for this outcome.
    End point values
    Cohort 1: DS-1040b 20 mg Cohort 2: DS-1040b 40 mg Cohort 3: DS-1040b 60 mg Cohort 4: DS-1040 80 mg Cohort 5: DS-1040b 40 mg
    Number of subjects analysed
    9
    13
    18
    5
    9
    Units: hours
    arithmetic mean (standard deviation)
        Terminal half-life
    22.81 ± 3.13
    28.44 ± 5.75
    29.06 ± 7.60
    36.39 ± 2.07
    30.06 ± 3.45
    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 (TEAEs) were collected from baseline up to Day 30 post infusion, up to approximately 3 years 2 months.
    Adverse event reporting additional description
    A TEAE is defined as an adverse event that emerges during treatment, having been absent pretreatment, or worsening relative to the pre-treatment state.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Cohort 1: DS-1040b 20 mg
    Reporting group description
    Subjects who received an intravenous infusion of 20 mg DS-1040b in addition to standard of care anticoagulation therapy.

    Reporting group title
    Cohort 2: DS-1040b 40 mg
    Reporting group description
    Subjects who received an intravenous infusion of 40 mg DS-1040b in addition to standard of care anticoagulation therapy.

    Reporting group title
    Cohort 3: DS-1040b 60 mg
    Reporting group description
    Subjects who received an intravenous infusion of 60 mg DS-1040b in addition to standard of care anticoagulation therapy.

    Reporting group title
    Cohort 4: DS-1040 80 mg
    Reporting group description
    Subjects who received an intravenous infusion of 80 mg DS-1040b in addition to standard of care anticoagulation therapy.

    Reporting group title
    Cohort 5: DS-1040b 40 mg
    Reporting group description
    Subjects who received an intravenous infusion of 40 mg DS-1040b in addition to standard of care anticoagulation therapy.

    Reporting group title
    Placebo
    Reporting group description
    Subjects who received an intravenous infusion of placebo in addition to standard of care anticoagulation therapy.

    Serious adverse events
    Cohort 1: DS-1040b 20 mg Cohort 2: DS-1040b 40 mg Cohort 3: DS-1040b 60 mg Cohort 4: DS-1040 80 mg Cohort 5: DS-1040b 40 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 16 (0.00%)
    2 / 20 (10.00%)
    1 / 22 (4.55%)
    3 / 17 (17.65%)
    5 / 38 (13.16%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon neoplasm
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to liver
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to nervous system
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Testicular cancer metastatic
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary infarction
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Cohort 1: DS-1040b 20 mg Cohort 2: DS-1040b 40 mg Cohort 3: DS-1040b 60 mg Cohort 4: DS-1040 80 mg Cohort 5: DS-1040b 40 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 12 (66.67%)
    6 / 16 (37.50%)
    13 / 20 (65.00%)
    10 / 22 (45.45%)
    8 / 17 (47.06%)
    25 / 38 (65.79%)
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    2
    0
    1
    0
    0
    1
    Haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 16 (6.25%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Surgical and medical procedures
    Sinus operation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to nervous system
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Testicular cancer metastatic
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 16 (6.25%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Feeling cold
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Feeling hot
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Infusion site extravasation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Infusion site phlebitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Peripheral swelling
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 16 (6.25%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vessel puncture site haematoma
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    2 / 20 (10.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Delirium
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Reproductive system and breast disorders
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gynaecomastia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Synovial rupture
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Urinary retention postoperative
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Blood pressure increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Crystal urine present
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Liver function test increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Mean cell volume increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Occult blood positive
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Urobilinogen urine increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Bundle branch block right
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Right ventricular dysfunction
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 16 (6.25%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    2 / 12 (16.67%)
    2 / 16 (12.50%)
    2 / 20 (10.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    3 / 38 (7.89%)
         occurrences all number
    2
    2
    2
    0
    0
    3
    Haemoptysis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    1 / 22 (4.55%)
    1 / 17 (5.88%)
    3 / 38 (7.89%)
         occurrences all number
    0
    0
    1
    1
    1
    3
    Hyperventilation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pleural effusion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    2 / 20 (10.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    2 / 38 (5.26%)
         occurrences all number
    1
    0
    2
    0
    1
    2
    Pleurisy
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Pulmonary infarction
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    1 / 17 (5.88%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Microcytic anaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    3 / 20 (15.00%)
    2 / 22 (9.09%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    3
    2
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Migraine
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Muscle spasticity
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Presyncope
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Tremor
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 16 (6.25%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 16 (6.25%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 16 (6.25%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Anal haemorrhage
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    2 / 20 (10.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 16 (6.25%)
    2 / 20 (10.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    2
    1
    2
    0
    0
    0
    Faeces discoloured
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 16 (6.25%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Paraesthesia oral
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    2 / 20 (10.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Ketonuria
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Urine abnormality
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 16 (6.25%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    Arthritis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 16 (6.25%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Bursitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Groin pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Muscle contracture
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    Spinal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Folate deficiency
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hyperphosphataemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Anal abscess
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    1 / 20 (5.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Appendicitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 16 (6.25%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Bacteriuria
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Lung infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 16 (0.00%)
    2 / 20 (10.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    1
    0
    2
    0
    0
    2
    Oral fungal infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    0 / 20 (0.00%)
    0 / 22 (0.00%)
    2 / 17 (11.76%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 16 (0.00%)
    2 / 20 (10.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 38 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 16 (6.25%)
    2 / 20 (10.00%)
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    1
    2
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Mar 2016
    Included information on assessment of the cardiac biomarkers troponin and NT-proBNP, added information regarding stopping the study due to excessive mortality rates or incidence of major bleeding, and included instruction on recording RV/LV ratio at baseline
    09 Jan 2017
    Updated details of administration of edoxaban; stated changes made for measuring total thrombus volume; clarified definitions for clinically relevant bleeding, highly effective contraception, and venous thromboembolism; updated procedures for subject enrollment; clarified inclusion and exclusion criteria, updated protocol for disposal of Investigational Product
    26 Apr 2017
    Updated inclusion and exclusion criteria, clarified the details for the supply of edoxaban, specified details of the administration of enoxaparin, and updated the documentation procedure for adverse events

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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