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    Clinical Trial Results:
    A Phase 1, Open-Label, Single-dose, Non-randomized Study to Evaluate Pharmacokinetics and Pharmacodynamics of Edoxaban in Pediatric Patients

    Summary
    EudraCT number
    2015-005732-18
    Trial protocol
    ES   FR   IT  
    Global end of trial date
    16 Sep 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Apr 2022
    First version publication date
    02 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DU176b-A-U157
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02303431
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Daiichi Sankyo, Inc.
    Sponsor organisation address
    211 Mount Airy Rd., Basking Ridge, United States, 07920
    Public contact
    Clinical Director, Daiichi Sankyo, Inc., +1 908-992-6400, CTRinfo@dsi.com
    Scientific contact
    Clinical Director, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Sep 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To characterize the PK of Edoxaban in pediatric patients following oral single-dose administration.
    Protection of trial subjects
    The protocol, amendments, informed consent forms, and information sheets were approved by the appropriate and applicable Independent Ethics Committee (IECs) or Institutional Review Boards (IRBs). Prior to study participation, written informed consent was provided by the patient's parent or legal guardian. This study was conducted in compliance with the study protocol, the ethical principles that have their origin in the Declaration of Helsinki, the International Council of Harmonisation (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP)(Committee for Proprietary Medicinal Products/ICH/135/95), and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Nov 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    India: 11
    Country: Number of subjects enrolled
    Jordan: 5
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    Czechia: 1
    Worldwide total number of subjects
    66
    EEA total number of subjects
    11
    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)
    25
    Children (2-11 years)
    26
    Adolescents (12-17 years)
    15
    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 66 participants who met all inclusion criteria and no exclusion criteria were enrolled in the study and received treatment at 32 clinical sites in the United States, Canada, France, India, Italy, Jordan, Lebanon, Spain, Turkey, and the United Kingdom.

    Pre-assignment
    Screening details
    Participants were asked to fast for at least 4 hrs before dosing and for an additional 2 hrs after dosing. If this was not feasible because of the patient’s age, (unflavored) milk, or an equivalent substitute liquid (but not fruit juices), was allowed until 1 hr before and starting at 1 hr postdose (total volume of liquids not to exceed 240 mL).

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1a: 30 mg Edoxaban
    Arm description
    Participants who were 12 to < 18 years of age and received a single-dose, oral tablet of 30 mg edoxaban.
    Arm type
    Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single-dose, oral tablet

    Arm title
    Cohort 1b: 60 mg Edoxaban
    Arm description
    Participants who were 12 to < 18 years of age and received a single dose, oral tablet of 60 mg edoxaban.
    Arm type
    Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single-dose, oral tablet

    Arm title
    Cohort 2a: 24 mg Edoxaban
    Arm description
    Participants who were 6 to < 12 years of age and received a single dose, oral suspension of 24 mg edoxaban.
    Arm type
    Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Single-dose, oral suspension

    Arm title
    Cohort 2b: 45 mg Edoxaban
    Arm description
    Participants who were 6 to < 12 years of age and received a single dose, oral suspension of 45 mg edoxaban.
    Arm type
    Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Single-dose, oral suspension

    Arm title
    Cohort 3a: 0.7 mg/kg Edoxaban
    Arm description
    Participants who were 2 to < 6 years of age and received a single dose, oral suspension of 0.7 mg/kg (cap 24 mg) edoxaban.
    Arm type
    Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Single-dose, oral suspension

    Arm title
    Cohort 3b: 1.4 mg/kg Edoxaban
    Arm description
    Participants who were 2 to < 6 years of age and received a single dose, oral suspension of 1.4 mg/kg (cap 45 mg) edoxaban.
    Arm type
    Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Single-dose, oral suspension

    Arm title
    Cohort 4a: 0.75 mg/kg Edoxaban
    Arm description
    Participants who were 6 months to <2 years of age and received a single dose, oral suspension of 0.75 mg/kg edoxaban.
    Arm type
    Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Single-dose, oral suspension

    Arm title
    Cohort 4b: 1.5 mg/kg Edoxaban
    Arm description
    Participants who were 6 months to <2 years of age and received a single dose, oral suspension of 1.5 mg/kg edoxaban.
    Arm type
    Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Single-dose, oral suspension

    Arm title
    Cohort 5a: 0.4 mg/kg Edoxaban
    Arm description
    Participants who were 0 to 6 months of age and received a single dose, oral suspension of 0.4 mg/kg edoxaban.
    Arm type
    Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Single-dose, oral suspension

    Arm title
    Cohort 5b: 0.8 mg/kg Edoxaban
    Arm description
    Participants who were 0 to 6 months of age and received a single dose, oral suspension of 0.8 mg/kg edoxaban.
    Arm type
    Experimental

    Investigational medicinal product name
    Edoxaban
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Single-dose, oral suspension

    Number of subjects in period 1
    Cohort 1a: 30 mg Edoxaban Cohort 1b: 60 mg Edoxaban Cohort 2a: 24 mg Edoxaban Cohort 2b: 45 mg Edoxaban Cohort 3a: 0.7 mg/kg Edoxaban Cohort 3b: 1.4 mg/kg Edoxaban Cohort 4a: 0.75 mg/kg Edoxaban Cohort 4b: 1.5 mg/kg Edoxaban Cohort 5a: 0.4 mg/kg Edoxaban Cohort 5b: 0.8 mg/kg Edoxaban
    Started
    8
    7
    7
    6
    7
    6
    7
    6
    6
    6
    Completed
    8
    7
    7
    6
    7
    6
    7
    6
    6
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1a: 30 mg Edoxaban
    Reporting group description
    Participants who were 12 to < 18 years of age and received a single-dose, oral tablet of 30 mg edoxaban.

    Reporting group title
    Cohort 1b: 60 mg Edoxaban
    Reporting group description
    Participants who were 12 to < 18 years of age and received a single dose, oral tablet of 60 mg edoxaban.

    Reporting group title
    Cohort 2a: 24 mg Edoxaban
    Reporting group description
    Participants who were 6 to < 12 years of age and received a single dose, oral suspension of 24 mg edoxaban.

    Reporting group title
    Cohort 2b: 45 mg Edoxaban
    Reporting group description
    Participants who were 6 to < 12 years of age and received a single dose, oral suspension of 45 mg edoxaban.

    Reporting group title
    Cohort 3a: 0.7 mg/kg Edoxaban
    Reporting group description
    Participants who were 2 to < 6 years of age and received a single dose, oral suspension of 0.7 mg/kg (cap 24 mg) edoxaban.

    Reporting group title
    Cohort 3b: 1.4 mg/kg Edoxaban
    Reporting group description
    Participants who were 2 to < 6 years of age and received a single dose, oral suspension of 1.4 mg/kg (cap 45 mg) edoxaban.

    Reporting group title
    Cohort 4a: 0.75 mg/kg Edoxaban
    Reporting group description
    Participants who were 6 months to <2 years of age and received a single dose, oral suspension of 0.75 mg/kg edoxaban.

    Reporting group title
    Cohort 4b: 1.5 mg/kg Edoxaban
    Reporting group description
    Participants who were 6 months to <2 years of age and received a single dose, oral suspension of 1.5 mg/kg edoxaban.

    Reporting group title
    Cohort 5a: 0.4 mg/kg Edoxaban
    Reporting group description
    Participants who were 0 to 6 months of age and received a single dose, oral suspension of 0.4 mg/kg edoxaban.

    Reporting group title
    Cohort 5b: 0.8 mg/kg Edoxaban
    Reporting group description
    Participants who were 0 to 6 months of age and received a single dose, oral suspension of 0.8 mg/kg edoxaban.

    Reporting group values
    Cohort 1a: 30 mg Edoxaban Cohort 1b: 60 mg Edoxaban Cohort 2a: 24 mg Edoxaban Cohort 2b: 45 mg Edoxaban Cohort 3a: 0.7 mg/kg Edoxaban Cohort 3b: 1.4 mg/kg Edoxaban Cohort 4a: 0.75 mg/kg Edoxaban Cohort 4b: 1.5 mg/kg Edoxaban Cohort 5a: 0.4 mg/kg Edoxaban Cohort 5b: 0.8 mg/kg Edoxaban Total
    Number of subjects
    8 7 7 6 7 6 7 6 6 6 66
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0 0 0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0 0 7 6 6 6 25
        Children (2-11 years)
    0 0 7 6 7 6 0 0 0 0 26
        Adolescents (12-17 years)
    8 7 0 0 0 0 0 0 0 0 15
        Adults (18-64 years)
    0 0 0 0 0 0 0 0 0 0 0
        From 65-84 years
    0 0 0 0 0 0 0 0 0 0 0
        85 years and over
    0 0 0 0 0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    15.9 ± 1.1 15.3 ± 1.3 9.6 ± 1.1 9.5 ± 1.9 4.3 ± 1.6 4.3 ± 1.4 1.2 ± 0.5 1.0 ± 0.5 0.2 ± 0.2 0.3 ± 0.2 -
    Gender categorical
    Units: Subjects
        Female
    5 4 3 4 3 1 3 3 2 3 31
        Male
    3 3 4 2 4 5 4 3 4 3 35

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1a: 30 mg Edoxaban
    Reporting group description
    Participants who were 12 to < 18 years of age and received a single-dose, oral tablet of 30 mg edoxaban.

    Reporting group title
    Cohort 1b: 60 mg Edoxaban
    Reporting group description
    Participants who were 12 to < 18 years of age and received a single dose, oral tablet of 60 mg edoxaban.

    Reporting group title
    Cohort 2a: 24 mg Edoxaban
    Reporting group description
    Participants who were 6 to < 12 years of age and received a single dose, oral suspension of 24 mg edoxaban.

    Reporting group title
    Cohort 2b: 45 mg Edoxaban
    Reporting group description
    Participants who were 6 to < 12 years of age and received a single dose, oral suspension of 45 mg edoxaban.

    Reporting group title
    Cohort 3a: 0.7 mg/kg Edoxaban
    Reporting group description
    Participants who were 2 to < 6 years of age and received a single dose, oral suspension of 0.7 mg/kg (cap 24 mg) edoxaban.

    Reporting group title
    Cohort 3b: 1.4 mg/kg Edoxaban
    Reporting group description
    Participants who were 2 to < 6 years of age and received a single dose, oral suspension of 1.4 mg/kg (cap 45 mg) edoxaban.

    Reporting group title
    Cohort 4a: 0.75 mg/kg Edoxaban
    Reporting group description
    Participants who were 6 months to <2 years of age and received a single dose, oral suspension of 0.75 mg/kg edoxaban.

    Reporting group title
    Cohort 4b: 1.5 mg/kg Edoxaban
    Reporting group description
    Participants who were 6 months to <2 years of age and received a single dose, oral suspension of 1.5 mg/kg edoxaban.

    Reporting group title
    Cohort 5a: 0.4 mg/kg Edoxaban
    Reporting group description
    Participants who were 0 to 6 months of age and received a single dose, oral suspension of 0.4 mg/kg edoxaban.

    Reporting group title
    Cohort 5b: 0.8 mg/kg Edoxaban
    Reporting group description
    Participants who were 0 to 6 months of age and received a single dose, oral suspension of 0.8 mg/kg edoxaban.

    Subject analysis set title
    All Patients
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All participants included in the study (Cohorts 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, and 5b) in the Population Pharmacokinetic (PopPK) Analysis Set.

    Primary: Pharmacokinetic Parameter of Apparent Systemic Clearance (CL/F)

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    End point title
    Pharmacokinetic Parameter of Apparent Systemic Clearance (CL/F) [1]
    End point description
    A population pharmacokinetic (PK) method was used to estimate systemic clearance (CL/F). Due to sparse PK samples being collected, the median PK estimate is reported in all participants at a total of 5 blood samplings.
    End point type
    Primary
    End point timeframe
    0.25 to 1 hours, 1.5 to 3 hours, 4 to 8 hours, 9 to 14 hours, and 24 to 36 hours post-dose
    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 statistics were used to assess this outcome in the cohorts reported.
    End point values
    All Patients
    Number of subjects analysed
    64
    Units: L/h
    median (confidence interval 90%)
        CL/F
    42.9 (40.3 to 45.6)
    No statistical analyses for this end point

    Primary: Pharmacokinetic Parameter of Apparent Volume of Distribution (V/F)

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    End point title
    Pharmacokinetic Parameter of Apparent Volume of Distribution (V/F) [2]
    End point description
    A population pharmacokinetic (PK) method was used to estimate apparent volume of distribution (V/F). Due to sparse PK samples being collected, the median PK estimate is reported in all participants at a total of 5 blood samplings.
    End point type
    Primary
    End point timeframe
    0.25 to 1 hours, 1.5 to 3 hours, 4 to 8 hours, 9 to 14 hours, and 24 to 36 hours post-dose
    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 in the cohorts reported.
    End point values
    All Patients
    Number of subjects analysed
    64
    Units: Liters
    median (confidence interval 90%)
        V/F
    198 (180 to 219)
    No statistical analyses for this end point

    Secondary: Pharmacodynamic Parameter Mean Prothrombin Time (PT)

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    End point title
    Pharmacodynamic Parameter Mean Prothrombin Time (PT)
    End point description
    Descriptive statistics were used to assess Mean Prothrombin Time (PT) by cohort at a total of 6 blood samplings.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.25 to 1 hours (except for Cohorts 4a, 4b, 5a, and 5b, 0.5 to 2 hours), 1.5 to 3 hours, 4 to 8 hours, 9 to 14 hours, and 24 to 36 hours post-dose
    End point values
    Cohort 1a: 30 mg Edoxaban Cohort 1b: 60 mg Edoxaban Cohort 2a: 24 mg Edoxaban Cohort 2b: 45 mg Edoxaban Cohort 3a: 0.7 mg/kg Edoxaban Cohort 3b: 1.4 mg/kg Edoxaban Cohort 4a: 0.75 mg/kg Edoxaban Cohort 4b: 1.5 mg/kg Edoxaban Cohort 5a: 0.4 mg/kg Edoxaban Cohort 5b: 0.8 mg/kg Edoxaban
    Number of subjects analysed
    7
    7
    6
    5 [3]
    6 [4]
    4 [5]
    4 [6]
    4 [7]
    6 [8]
    5 [9]
    Units: seconds
    arithmetic mean (standard deviation)
        Predose: 0.25 to 1 hours (n= 6,7,4,4,5,4,4,4,6,5)
    13.3 ± 1.1
    13.5 ± 0.5
    14.0 ± 0.4
    13.9 ± 0.5
    14.6 ± 1.3
    13.7 ± 0.5
    13.6 ± 0.7
    13.8 ± 1.6
    16.3 ± 4.0
    15.3 ± 1.8
        Postdose: 0.25 to 1 hours (n= 6,7,4,4,5,4,4,4,6,5)
    15.0 ± 1.8
    17.3 ± 4.1
    19.1 ± 3.1
    21.3 ± 7.0
    18.7 ± 2.0
    22.0 ± 0.8
    21.4 ± 2.4
    26.5 ± 7.6
    18.3 ± 3.0
    21.8 ± 4.1
        Predose: 1.5 to 3 hours (n= 7,7,5,5,6,4,1,0,0,0)
    13.3 ± 1.0
    13.5 ± 0.5
    14.0 ± 0.4
    14.9 ± 2.2
    14.7 ± 1.3
    13.7 ± 0.5
    14.3 ± 14.3
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 1.5 to 3 hours (n= 7,7,5,5,6,4,1,0,0,0)
    17.6 ± 2.5
    23.0 ± 3.8
    26.8 ± 14.9
    25.3 ± 5.9
    21.0 ± 2.5
    21.3 ± 2.3
    20.0 ± 20.0
    0 ± 0
    0 ± 0
    0 ± 0
        Predose: 3.5 to 6 hours (n= 6,5,1,0,0,0,0,0,0,0)
    13.4 ± 1.1
    13.6 ± 0.6
    13.4 ± 13.4
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 3.5 to 6 hours (n= 6,5,1,0,0,0,0,0,0,0)
    17.9 ± 4.6
    20.1 ± 2.0
    16.5 ± 16.5
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
        Predose: 4 to 8 hours (n= 1,2,3,4,6,4,1,0,0,0)
    12.9 ± 12.9
    13.4 ± 0.1
    14.2 ± 0.2
    13.9 ± 0.5
    14.7 ± 1.3
    13.7 ± 0.5
    14.3 ± 14.3
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 4 to 8 hours (n= 1,2,3,4,6,4,1,0,0,0)
    15.9 ± 15.9
    17.5 ± 2.3
    17.9 ± 1.3
    18.0 ± 2.2
    17.3 ± 0.8
    16.1 ± 2.0
    17.4 ± 17.4
    0 ± 0
    0 ± 0
    0 ± 0
        Predose: 6.5 to 8 hours (n= 6,4,2,0,0,0,0,0,0,0)
    13.4 ± 1.1
    13.6 ± 0.7
    13.7 ± 0.4
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 6.5 to 8 hours (n= 6,4,2,0,0,0,0,0,0,0)
    14.7 ± 1.4
    16.7 ± 1.5
    15.8 ± 1.1
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
        Predose: 9 to 14 hours (n= 1,2,3,5,6,4,1,0,0,0)
    12.9 ± 12.9
    13.4 ± 0.1
    14.4 ± 0.5
    14.9 ± 2.2
    14.7 ± 1.3
    13.7 ± 0.5
    14.3 ± 14.3
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 9 to 14 hours (n= 1,2,3,5,6,4,1,0,0,0)
    13.9 ± 13.9
    15.9 ± 1.6
    15.8 ± 1.1
    17.7 ± 5.1
    16.1 ± 1.2
    16.0 ± 2.5
    16.7 ± 16.7
    0 ± 0
    0 ± 0
    0 ± 0
        Predose: 24 to 36 hours (n= 6,7,6,4,6,4,1,0,0,0)
    13.4 ± 1.1
    13.5 ± 0.5
    14.2 ± 0.5
    13.9 ± 0.5
    14.7 ± 1.3
    13.7 ± 0.5
    14.3 ± 14.3
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 24 to 36 hours (n= 6,7,6,4,6,4,1,0,0,0)
    13.1 ± 1.0
    13.8 ± 0.7
    14.5 ± 0.6
    14.5 ± 0.9
    15.5 ± 0.9
    14.9 ± 1.1
    14.1 ± 14.1
    0 ± 0
    0 ± 0
    0 ± 0
    Notes
    [3] - No subjects were analyzed at Predose and Postdose at 3.5 to 6 hours and at 6.5 to 8 hours.
    [4] - No subjects were analyzed at Predose and Postdose at 3.5 to 6 hours and at 6.5 to 8 hours.
    [5] - No subjects were analyzed at Predose and Postdose at 3.5 to 6 hours and at 6.5 to 8 hours.
    [6] - No subjects were analyzed at Predose and Postdose at 3.5 to 6 hours and at 6.5 to 8 hours.
    [7] - No subjects were analyzed beyond Predose and Postdose at 0.25 to 1 hour.
    [8] - No subjects were analyzed beyond Predose and Postdose at 0.25 to 1 hour.
    [9] - No subjects were analyzed beyond Predose and Postdose at 0.25 to 1 hour.
    No statistical analyses for this end point

    Secondary: Pharmacodynamic Parameter Mean Activated Partial Thromboplastin Time (aPTT)

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    End point title
    Pharmacodynamic Parameter Mean Activated Partial Thromboplastin Time (aPTT)
    End point description
    Descriptive statistics were used to assess Mean Activated Partial Thromboplastin Time by cohort for a total of 6 blood samplings.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.25 to 1 hours (except for Cohorts 4a, 4b, 5a, and 5b, 0.5 to 2 hours), 1.5 to 3 hours, 4 to 8 hours, 9 to 14 hours, and 24 to 36 hours post-dose
    End point values
    Cohort 1a: 30 mg Edoxaban Cohort 1b: 60 mg Edoxaban Cohort 2a: 24 mg Edoxaban Cohort 2b: 45 mg Edoxaban Cohort 3a: 0.7 mg/kg Edoxaban Cohort 3b: 1.4 mg/kg Edoxaban Cohort 4a: 0.75 mg/kg Edoxaban Cohort 4b: 1.5 mg/kg Edoxaban Cohort 5a: 0.4 mg/kg Edoxaban Cohort 5b: 0.8 mg/kg Edoxaban
    Number of subjects analysed
    7
    7
    5
    5 [10]
    6 [11]
    4 [12]
    4 [13]
    4 [14]
    6 [15]
    5 [16]
    Units: seconds
    arithmetic mean (standard deviation)
        Predose: 0.25 to 1 hours (n=6,7,3,5,4,4,4,4,6,5)
    24.1 ± 1.5
    26.0 ± 1.6
    33.9 ± 6.4
    32.7 ± 2.8
    34.3 ± 4.1
    40.7 ± 21.0
    32.9 ± 5.3
    34.9 ± 8.2
    41.0 ± 17.9
    47.7 ± 13.0
        Postdose: 0.25 to 1 hours (n=6,7,5,5,4,4,4,4,6,5)
    26.6 ± 2.0
    28.4 ± 4.8
    57.9 ± 26.3
    42.4 ± 9.9
    39.4 ± 6.4
    45.3 ± 20.1
    45.4 ± 6.3
    46.0 ± 10.9
    39.5 ± 3.8
    52.6 ± 18.1
        Predose: 1.5 to 3 hours (n=7,7,5,5,6,4,1,0,0,0)
    24.1 ± 1.4
    26.0 ± 1.6
    34.6 ± 5.8
    32.7 ± 2.8
    30.10 ± 7.2
    40.7 ± 21.0
    37.4 ± 37.4
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 1.5 to 3 hours (n=7,7,5,5,6,4,1,0,0,0)
    27.7 ± 1.1
    32.8 ± 3.0
    62.5 ± 35.7
    43.0 ± 3.9
    38.1 ± 8.9
    45.5 ± 7.9
    40.9 ± 40.9
    0 ± 0
    0 ± 0
    0 ± 0
        Predose: 3.5 to 6 hours (n=6,5,1,0,0,0,0,0,0,0)
    23.8 ± 1.1
    26.1 ± 1.9
    32.2 ± 32.2
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 3.5 to 6 hours (n=6,5,1,0,0,0,0,0,0,0)
    26.9 ± 1.4
    30.8 ± 1.5
    39.0 ± 39.0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
        Predose: 4 to 8 hours (n=1,2,5,4,6,4,1,0,0,0)
    26.2 ± 26.2
    25.5 ± 0.7
    33.9 ± 6.4
    32.8 ± 3.2
    30.1 ± 7.2
    40.7 ± 21.0
    37.4 ± 37.4
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 4 to 8 hours (n=1,2,5,4,6,4,1,0,0,0)
    24.4 ± 24.2
    28.9 ± 1.0
    35.5 ± 4.9
    38.8 ± 5.7
    36.7 ± 10.1
    35.7 ± 4.6
    35.8 ± 35.8
    0 ± 0
    0 ± 0
    0 ± 0
        Predose: 6.5 to 8 hours (n=6,4,1,0,0,0,0,0,0,0)
    23.8 ± 1.1
    26.7 ± 1.7
    32.2 ± 32.2
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 6.5 to 8 hours (n=6,4,1,0,0,0,0,0,0,0)
    26.4 ± 1.2
    30.2 ± 2.3
    34.5 ± 34.5
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
        Predose: 9 to 14 hours (n=1,2,2,5,6,4,1,0,0,0)
    26.2 ± 26.2
    25.5 ± 0.7
    35.8 ± 7.6
    32.7 ± 2.8
    30.1 ± 7.2
    40.7 ± 21.0
    37.4 ± 37.4
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 9 to 14 hours (n=1,2,2,5,6,4,1,0,0,0)
    23.7 ± 23.7
    27.7 ± 0.3
    35.3 ± 2.8
    35.9 ± 5.7
    33.8 ± 7.4
    35.1 ± 7.3
    35.0 ± 35.0
    0 ± 0
    0 ± 0
    0 ± 0
        Predose: 23 to 36 hours (n=6,7,5,5,5,4,1,0,0,0)
    24.4 ± 1.3
    26.0 ± 1.6
    32.0 ± 5.6
    32.7 ± 2.8
    29.9 ± 8.1
    40.7 ± 21.0
    37.4 ± 37.4
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 23 to 36 hours (n=6,7,5,5,5,4,1,0,0,0)
    24.8 ± 0.9
    25.8 ± 1.9
    29.0 ± 2.2
    38.2 ± 10.7
    32.9 ± 5.2
    86.1 ± 112.6
    32.5 ± 32.5
    0 ± 0
    0 ± 0
    0 ± 0
    Notes
    [10] - No subjects were analyzed at Predose and Postdose at 3.5 to 6 hours and at 6.5 to 8 hours.
    [11] - No subjects were analyzed at Predose and Postdose at 3.5 to 6 hours and at 6.5 to 8 hours.
    [12] - No subjects were analyzed at Predose and Postdose at 3.5 to 6 hours and at 6.5 to 8 hours.
    [13] - No subjects were analyzed at Predose and Postdose at 3.5 to 6 hours and at 6.5 to 8 hours.
    [14] - No subjects were analyzed beyond Predose and Postdose at 0.25 to 1 hour.
    [15] - No subjects were analyzed beyond Predose and Postdose at 0.25 to 1 hour.
    [16] - No subjects were analyzed beyond Predose and Postdose at 0.25 to 1 hour.
    No statistical analyses for this end point

    Secondary: Pharmacodynamic Parameter Mean Anti-Factor Xa (FXa)

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    End point title
    Pharmacodynamic Parameter Mean Anti-Factor Xa (FXa)
    End point description
    Descriptive statistics were used to assess Mean Anti-Factor Xa (FXa) by cohort for a total of 6 blood samplings.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.25 to 1 hours (except for Cohorts 4a, 4b, 5a, and 5b, 0.5 to 2 hours), 1.5 to 3 hours, 4 to 8 hours, 9 to 14 hours, and 24 to 36 hours post-dose
    End point values
    Cohort 1a: 30 mg Edoxaban Cohort 1b: 60 mg Edoxaban Cohort 2a: 24 mg Edoxaban Cohort 2b: 45 mg Edoxaban Cohort 3a: 0.7 mg/kg Edoxaban Cohort 3b: 1.4 mg/kg Edoxaban Cohort 4a: 0.75 mg/kg Edoxaban Cohort 4b: 1.5 mg/kg Edoxaban Cohort 5a: 0.4 mg/kg Edoxaban Cohort 5b: 0.8 mg/kg Edoxaban
    Number of subjects analysed
    7
    7
    5
    5 [17]
    6 [18]
    5 [19]
    4 [20]
    4 [21]
    6 [22]
    5 [23]
    Units: IU/mL
    arithmetic mean (standard deviation)
        Predose: 0.25 to 1 hour (n=6,7,5,5,5,5,4,4,6,5)
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0.1
    0.1 ± 0
    0.5 ± 0.3
    0.1 ± 0.1
    0.4 ± 0.4
        Postdose: 0.25 to 1 hour (n=6,7,5,5,5,5,4,4,6,5)
    0.5 ± 0.4
    1.0 ± 1.0
    1.8 ± 0.3
    1.6 ± 0.8
    1.2 ± 0.6
    1.9 ± 0.2
    2.0 ± 0
    2.0 ± 0
    1.1 ± 0.8
    1.7 ± 0.7
        Predose: 1.5 to 3 hours (n=7,7,5,5,6,5,1,0,0,0)
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0.1
    0.1 ± 0.1
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 1.5 to 3 hours (n=7,7,5,5,6,5,1,0,0,0)
    1.3 ± 0.4
    2.6 ± 1.0
    1.3 ± 0.7
    1.9 ± 0.1
    1.7 ± 0.3
    1.9 ± 0.2
    2.0 ± 2.0
    0 ± 0
    0 ± 0
    0 ± 0
        Predose: 3.5 to 6 hours (n=6,5,1,0,0,0,0,0,0,0)
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0.1
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 3.5 to 6 hours (n=6,5,1,0,0,0,0,0,0,0)
    0.9 ± 0.4
    1.7 ± 0.4
    1.4 ± 1.4
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
        Predose: 4 to 8 hours (n=1,2,3,5,6,5,1,0,0,0)
    0.1 ± 0.1
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0.1
    0.1 ± 0.1
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 4 to 8 hours (n=1,2,3,5,6,5,1,0,0,0)
    1.0 ± 1.0
    1.2 ± 0.7
    0.8 ± 0.3
    1.5 ± 0.3
    0.7 ± 0.2
    0.8 ± 0.6
    1.2 ± 1.2
    0 ± 0
    0 ± 0
    0 ± 0
        Predose: 6.5 to 8 hours (n=6,4,1,0,0,0,0,0,0,0)
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0.1
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 6.5 to 8 hours (n=6,4,1,0,0,0,0,0,0,0)
    0.4 ± 0.1
    0.9 ± 0.4
    0.8 ± 0.8
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
        Predose: 9 to 14 hours (n=1,2,2,5,6,5,1,0,0,0)
    0.1 ± 0.1
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0.1
    0.1 ± 0.1
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 9 to 14 hours (n=1,2,2,5,6,5,1,0,0,0)
    0.4 ± 0.4
    0.6 ± 0.3
    0.3 ± 0.1
    0.8 ± 0.5
    0.2 ± 0.1
    0.4 ± 0.2
    0.3 ± 0.3
    0 ± 0
    0 ± 0
    0 ± 0
        Predose: 24 to 36 hours (n=6,7,5,5,6,5,1,0,0,0)
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0
    0.1 ± 0.1
    0.1 ± 0.1
    0 ± 0
    0 ± 0
    0 ± 0
        Postdose: 24 to 36 hours (n=6,7,5,5,6,5,1,0,0,0)
    0.1 ± 0
    0.1 ± 0.1
    0.1 ± 0
    0.2 ± 0.1
    0.3 ± 0.5
    0.4 ± 0.7
    0.1 ± 0.1
    0 ± 0
    0 ± 0
    0 ± 0
    Notes
    [17] - No subjects were analyzed at Predose and Postdose at 3.5 to 6 hours and at 6.5 to 8 hours.
    [18] - No subjects were analyzed at Predose and Postdose at 3.5 to 6 hours and at 6.5 to 8 hours.
    [19] - No subjects were analyzed at Predose and Postdose at 3.5 to 6 hours and at 6.5 to 8 hours.
    [20] - No subjects were analyzed at Predose and Postdose at 3.5 to 6 hours and at 6.5 to 8 hours.
    [21] - No subjects were analyzed beyond Predose and Postdose at 0.25 to 1 hour.
    [22] - No subjects were analyzed beyond Predose and Postdose at 0.25 to 1 hour.
    [23] - No subjects were analyzed beyond Predose and Postdose at 0.25 to 1 hour.
    No statistical analyses for this end point

    Other pre-specified: Mean Palatability Score for the Liquid Formulation on a 100 mm Visual Analog Scale (VAS)

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    End point title
    Mean Palatability Score for the Liquid Formulation on a 100 mm Visual Analog Scale (VAS) [24]
    End point description
    Bitterness, sweetness, and overall taste or aroma was assessed by participants (or guardians) receiving the liquid oral suspension using a 100 mm visual analog scale (VAS), where 0 corresponded to a sad face and indicated a low palatability score (eg, patients not pleased) and 100 corresponded to a happy face and indicated a high palatability score (eg, patients were pleased). Patients who were old enough scored the VAS themselves. For younger children, the parents provided this information, if possible. For the youngest children, there was free text input available to provide information on whether the patient spat it out or may not have liked the flavor, etc.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to 30 minutes post-dose
    Notes
    [24] - 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 statistics were used to assess this outcome in the cohorts reported.
    End point values
    Cohort 2a: 24 mg Edoxaban Cohort 2b: 45 mg Edoxaban Cohort 3a: 0.7 mg/kg Edoxaban Cohort 3b: 1.4 mg/kg Edoxaban Cohort 4a: 0.75 mg/kg Edoxaban Cohort 4b: 1.5 mg/kg Edoxaban Cohort 5a: 0.4 mg/kg Edoxaban Cohort 5b: 0.8 mg/kg Edoxaban
    Number of subjects analysed
    7
    6
    7
    6
    7
    6
    6
    6
    Units: mm
    arithmetic mean (standard deviation)
        Overall palatability (n=7,6,7,6,6,6,6,6)
    53.6 ± 35.8
    63.2 ± 48.9
    55.3 ± 40.6
    83.3 ± 20.4
    77.3 ± 27.7
    73.0 ± 22.9
    67.3 ± 18.4
    83.2 ± 14.1
        Bitterness (n=7,5,7,6,6,6,6,6)
    66.1 ± 44.5
    53.2 ± 46.3
    40.6 ± 43.5
    66.7 ± 37.6
    77.5 ± 27.2
    36.3 ± 41.2
    47.0 ± 32.6
    65.7 ± 36.8
        Sweetness (n=7,6,7,6,5,6,6,6)
    39.1 ± 34.9
    54.3 ± 36.9
    65.9 ± 42.1
    81.7 ± 21.6
    86.2 ± 26.1
    76.2 ± 20.2
    68.5 ± 19.0
    86.0 ± 13.3
        Overall taste (n=7,5,7,6,6,6,6,6)
    57.9 ± 42.3
    78.2 ± 43.2
    62.6 ± 44.9
    83.3 ± 25.8
    82.8 ± 24.3
    80.5 ± 10.0
    70.8 ± 17.0
    85.2 ± 11.2
        Aroma (n=7,6,7,6,6,6,6,6)
    53.4 ± 38.4
    57.7 ± 34.0
    58.7 ± 39.5
    75.0 ± 27.4
    84.5 ± 23.9
    72.3 ± 19.7
    73.2 ± 13.9
    74.2 ± 23.3
    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 after the participant (or parent/guardian) signed the informed consent form and through the follow-up visit, up to 10 days after the single dose of edoxaban.
    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 pretreatment state.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Cohort 1a: 30 mg Edoxaban
    Reporting group description
    Participants who were 12 to < 18 years of age and received a single-dose, oral tablet of 30 mg edoxaban.

    Reporting group title
    Cohort 1b: 60 mg Edoxaban
    Reporting group description
    Participants who were 12 to < 18 years of age and received a single dose, oral tablet of 60 mg edoxaban.

    Reporting group title
    Cohort 2a: 24 mg Edoxaban
    Reporting group description
    Participants who were 6 to < 12 years of age and received a single dose, oral suspension of 24 mg edoxaban.

    Reporting group title
    Cohort 2b: 45 mg Edoxaban
    Reporting group description
    Participants who were 6 to < 12 years of age and received a single dose, oral suspension of 45 mg edoxaban.

    Reporting group title
    Cohort 3a: 0.7 mg/kg Edoxaban
    Reporting group description
    Participants who were 2 to < 6 years of age and received a single dose, oral suspension of 0.7 mg/kg (cap 24 mg) edoxaban.

    Reporting group title
    Cohort 3b: 1.4 mg/kg Edoxaban
    Reporting group description
    Participants who were 2 to < 6 years of age and received a single dose, oral suspension of 1.4 mg/kg (cap 45 mg) edoxaban.

    Reporting group title
    Cohort 4a: 0.75 mg/kg Edoxaban
    Reporting group description
    Participants who were 6 months to <2 years of age and received a single dose, oral suspension of 0.75 mg/kg edoxaban.

    Reporting group title
    Cohort 4b: 1.5 mg/kg Edoxaban
    Reporting group description
    Participants who were 6 months to <2 years of age and received a single dose, oral suspension of 1.5 mg/kg edoxaban.

    Reporting group title
    Cohort 5a: 0.4 mg/kg Edoxaban
    Reporting group description
    Participants who were 0 to 6 months of age and received a single dose, oral suspension of 0.4 mg/kg edoxaban.

    Reporting group title
    Cohort 5b: 0.8 mg/kg Edoxaban
    Reporting group description
    Participants who were 0 to 6 months of age and received a single dose, oral suspension of 0.8 mg/kg edoxaban.

    Serious adverse events
    Cohort 1a: 30 mg Edoxaban Cohort 1b: 60 mg Edoxaban Cohort 2a: 24 mg Edoxaban Cohort 2b: 45 mg Edoxaban Cohort 3a: 0.7 mg/kg Edoxaban Cohort 3b: 1.4 mg/kg Edoxaban Cohort 4a: 0.75 mg/kg Edoxaban Cohort 4b: 1.5 mg/kg Edoxaban Cohort 5a: 0.4 mg/kg Edoxaban Cohort 5b: 0.8 mg/kg Edoxaban
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort 1a: 30 mg Edoxaban Cohort 1b: 60 mg Edoxaban Cohort 2a: 24 mg Edoxaban Cohort 2b: 45 mg Edoxaban Cohort 3a: 0.7 mg/kg Edoxaban Cohort 3b: 1.4 mg/kg Edoxaban Cohort 4a: 0.75 mg/kg Edoxaban Cohort 4b: 1.5 mg/kg Edoxaban Cohort 5a: 0.4 mg/kg Edoxaban Cohort 5b: 0.8 mg/kg Edoxaban
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 7 (28.57%)
    4 / 7 (57.14%)
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    3 / 7 (42.86%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Congenital, familial and genetic disorders
    Sickle cell anaemia with crisis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Frequent bowel movements
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 May 2014
    Changed the doses of study drug, clarified the drug formulation that patients <12 years of age would receive, provided a definition of a completer, added a palatability assessment, and clarified the time period in which AEs would be assessed.
    21 Jan 2015
    Clarified language for patient eligibility, updated inclusion criteria, and specified patient fasting requirements.
    03 Nov 2015
    Updated and further clarified eligibility criteria.
    14 Jul 2016
    Added a fifth cohort and increased sample size, revised PK/PD time points and clarified blood collection methods, and updated the study visit schedule.
    08 Aug 2018
    Updated the eligibility criteria, revised the PK/PD schedules, and revised the study endpoints.
    16 Sep 2019
    Updated requirements for enrollment initiation of Cohort 5 and revised and updated exclusion criteria.

    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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