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    Clinical Trial Results:
    30-day, single-arm study of the safety, efficacy and the pharmacokinetic and pharmacodynamic properties of oral rivaroxaban in children with various manifestations of venous thrombosis

    Summary
    EudraCT number
    		 2011-004539-30
    Trial protocol
    		 AT   DE   IT   NL  
    Global end of trial date
    01 Sep 2016

    Results information
    Results version number
    		 v3(current)
    This version publication date
    17 Feb 2019
    First version publication date
    17 Mar 2017
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    Control of data

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY59-7939/14373
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01684423
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000430-PIP01-08
    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
    01 Sep 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess the incidence of major bleeding and clinically relevant non-major bleeding.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent explained to all subjects and/or their legally authorized representative. Participating subjects and/or their legally authorized representative signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Feb 2013
    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
    Switzerland: 4
    Country: Number of subjects enrolled
    United States: 15
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Netherlands: 3
    Worldwide total number of subjects
    64
    EEA total number of subjects
    34
    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)
    40
    Adolescents (12-17 years)
    24
    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
    		 The study was conducted at multiple centers in 10 countries worldwide between 19 February 2013 (first subject first visit) and 01 September 2016 (last subject last visit).

    Pre-assignment
    Screening details
    		 A total of 68 subjects were screened, of these 4 subjects failed screening. The remaining 64 subjects were randomized, of whom 63 subjects were treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18 years
    Arm description
    		 Subjects aged from 12 - <18 years were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) immediate-release (IR) tablet once daily under fed conditions for 30 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rivaroxaban
    Investigational medicinal product code
    BAY59-7939
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects aged from 12 - <18 years were administered with age and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) IR tablet once daily under fed conditions for 30 days. Subjects with a body weight of 14 to less than 50 kilogram (kg) received a dose (equivalent to 20 milligram [mg] in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of greater than or equal to 50 kg received a dose of 20 mg.

    Arm title
    		 Comparator, Age: 12 - <18 years
    Arm description
    		 Subjects aged from 12 - <18 years received comparator as per standard of care.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Comparator
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection, Tablet
    Routes of administration
    Oral use, Parenteral use
    Dosage and administration details
    Subjects aged from 12 - <18 years received comparator as per standard of care. The dosage given was to be adjusted based on the individual body weight (low molecular weight heparin, fondaparinux) or international normalized ratio (INR) adjusted (vitamin K antagonist).

    Arm title
    		 Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years
    Arm description
    		 Subjects aged from 6 - <12 years were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) IR tablet once daily under fed conditions for 30 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rivaroxaban
    Investigational medicinal product code
    BAY59-7939
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects aged from 6 - <12 years were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) IR tablet once daily under fed conditions for 30 days. Subjects with a body weight of 14 to less than 50 kg received a dose (equivalent to 20 mg in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of greater than or equal to 50 kg received a dose of 20 mg.

    Arm title
    		 Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years
    Arm description
    		 Subjects aged from 6 - <12 years were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) suspension under fed conditions twice daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rivaroxaban
    Investigational medicinal product code
    BAY59-7939
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects aged from 6 - <12 years were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) suspension under fed conditions twice daily. Subjects with a body weight of 9 to less than 50 kg received a total daily dose (equivalent to 20 mg in adults) ranging from 6.4 to 15 mg and subjects with a body weight of greater than or equal to 50 kg received a total daily dose of 20 mg.

    Arm title
    		 Comparator, Age: 6 - <12 years
    Arm description
    		 Subjects aged from 6 - <12 years received comparator as per standard of care.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Comparator
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection, Tablet
    Routes of administration
    Oral use, Parenteral use
    Dosage and administration details
    Subjects aged from 6 - <12 years received comparator as per standard of care. The dosage given was to be adjusted based on the individual body weight (low molecular weight heparin, fondaparinux) or INR-adjusted (vitamin K antagonist).

    Number of subjects in period 1 [1]
    		Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18 years Comparator, Age: 12 - <18 years Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years Comparator, Age: 6 - <12 years
    Started
    11
    13
    13
    19
    7
    Completed
    11
    13
    12
    19
    7
    Not completed
    0
    0
    1
    0
    0
         Withdrawal by subject
    -
    -
    1
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Not all enrolled subjects received treatment. Only treated subjects were included in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18 years
    Reporting group description
    		 Subjects aged from 12 - <18 years were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) immediate-release (IR) tablet once daily under fed conditions for 30 days.

    Reporting group title
    Comparator, Age: 12 - <18 years
    Reporting group description
    		 Subjects aged from 12 - <18 years received comparator as per standard of care.

    Reporting group title
    Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years
    Reporting group description
    		 Subjects aged from 6 - <12 years were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) IR tablet once daily under fed conditions for 30 days.

    Reporting group title
    Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years
    Reporting group description
    		 Subjects aged from 6 - <12 years were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) suspension under fed conditions twice daily.

    Reporting group title
    Comparator, Age: 6 - <12 years
    Reporting group description
    		 Subjects aged from 6 - <12 years received comparator as per standard of care.

    Reporting group values
    		 Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18 years Comparator, Age: 12 - <18 years Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years Comparator, Age: 6 - <12 years Total
    Number of subjects
    		 11 13 13 19 7 63
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.5 ( 1.2 ) 14.8 ( 1 ) 8.5 ( 2.1 ) 8.3 ( 1.9 ) 9 ( 2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 7 5 6 3 29
        Male
    		 3 6 8 13 4 34

    End points

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    End points reporting groups
    Reporting group title
    Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18 years
    Reporting group description
    		 Subjects aged from 12 - <18 years were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) immediate-release (IR) tablet once daily under fed conditions for 30 days.

    Reporting group title
    Comparator, Age: 12 - <18 years
    Reporting group description
    		 Subjects aged from 12 - <18 years received comparator as per standard of care.

    Reporting group title
    Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years
    Reporting group description
    		 Subjects aged from 6 - <12 years were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) IR tablet once daily under fed conditions for 30 days.

    Reporting group title
    Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years
    Reporting group description
    		 Subjects aged from 6 - <12 years were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) suspension under fed conditions twice daily.

    Reporting group title
    Comparator, Age: 6 - <12 years
    Reporting group description
    		 Subjects aged from 6 - <12 years received comparator as per standard of care.

    Subject analysis set title
    Safety analysis set (SAS)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAS (N= 63) included all subjects who received at least one dose of study medication.

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS (N= 64) included all subjects who completed screening.

    Subject analysis set title
    Pharmacokinetic analysis set (PKS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PKS (N= 42) included all subjects with at least one pharmacokinetic sample in accordance with the pharmacokinetic sampling strategy.

    Subject analysis set title
    Pharmacodynamic analysis set (PDS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PDS (N= 42) included all subjects with at least one blood sample for clotting parameters in accordance with the pharmacodynamic sampling strategy.

    Primary: Number of Subjects With Major and Clinically Relevant Non-Major Bleeding Events

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    End point title
    		 Number of Subjects With Major and Clinically Relevant Non-Major Bleeding Events [1]
    End point description
    Central independent adjudication committee (CIAC) classified bleeding as follows: Major bleeding is defined as overt bleeding and: •associated with a fall in hemoglobin of 2 gram/decilitre (g/dL) or more, or •leading to a transfusion of the equivalent of 2 or more units of packed red blood cells or whole blood in adults, or •occurring in a critical site, e.g. intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal, or •contributing to death. Clinically relevant non-major bleeding is defined as overt bleeding not meeting the criteria for major bleeding, but associated with: •medical intervention, or •unscheduled contact (visit or telephone call) with a physician, or •cessation (temporary) of study treatment, or •discomfort for the child such as pain or •impairment of activities of daily life (such as loss of school days or hospitalization).
    End point type
    Primary
    End point timeframe
    From start of study drug administration until end of the 30-day treatment period
    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 done, no inferential statistical analyses were performed.
    End point values
    		 Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18 years Comparator, Age: 12 - <18 years Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years Comparator, Age: 6 - <12 years
    Number of subjects analysed
    11 [2]
    13 [3]
    13 [4]
    19 [5]
    7 [6]
    Units: subjects
        Major bleeding events
    0
    0
    0
    0
    0
        Clinically relevant non-major bleeding events
    3
    0
    0
    1
    0
    Notes
    [2] - FAS
    [3] - FAS
    [4] - FAS
    [5] - FAS
    [6] - FAS
    No statistical analyses for this end point

    Secondary: Number of Subjects With Symptomatic Recurrent Venous Thromboembolism

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    End point title
    		 Number of Subjects With Symptomatic Recurrent Venous Thromboembolism
    End point description
    The occurrence of recurrent venous thromboembolism was summarized by age group. Symptomatic recurrence of venous thrombosis was documented by the appropriate imaging test.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration until end of the 30-day treatment period
    End point values
    		 Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18 years Comparator, Age: 12 - <18 years Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years Comparator, Age: 6 - <12 years
    Number of subjects analysed
    11 [7]
    13 [8]
    13 [9]
    19 [10]
    7 [11]
    Units: subjects
    0
    0
    0
    0
    0
    Notes
    [7] - FAS
    [8] - FAS
    [9] - FAS
    [10] - FAS
    [11] - FAS
    No statistical analyses for this end point

    Secondary: Number of Subjects With Asymptomatic Deterioration in Thrombotic Burden

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    End point title
    		 Number of Subjects With Asymptomatic Deterioration in Thrombotic Burden
    End point description
    The occurrence of asymptomatic deterioration in thrombotic burden was summarized by age group. Asymptomatic deterioration in thrombotic burden was documented by the appropriate imaging test and the results were classified as normalized, improved, no relevant change, deteriorated, not evaluable or not available.
    End point type
    Secondary
    End point timeframe
    Repeat imaging at the end of the 30 day treatment period
    End point values
    		 Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18 years Comparator, Age: 12 - <18 years Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years Comparator, Age: 6 - <12 years
    Number of subjects analysed
    11 [12]
    13 [13]
    13 [14]
    19 [15]
    7 [16]
    Units: subjects
        Normalized
    3
    2
    2
    4
    1
        Improved
    4
    0
    8
    9
    4
        No relevant change
    0
    0
    1
    2
    0
        Deteriorated
    0
    0
    0
    0
    0
        Not evaluable
    0
    2
    0
    0
    1
        Not available
    4
    9
    2
    4
    1
    Notes
    [12] - FAS
    [13] - FAS
    [14] - FAS
    [15] - FAS
    [16] - FAS
    No statistical analyses for this end point

    Secondary: Change From Baseline in Prothrombin Time at Specified Time Points

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    End point title
    		 Change From Baseline in Prothrombin Time at Specified Time Points [17]
    End point description
    Prothrombin time is a global clotting test used for the assessment of the extrinsic pathway of the blood coagulation cascade. In the below table, ‘n’ signifies those subjects who were evaluable for this measure at given time points for each group and '99999' signifies no subjects were evaluated for the given time points for respective reporting groups.
    End point type
    Secondary
    End point timeframe
    0 hours (pre-dose) to 8 hours post-dose on Day 15 and 24 hours post-dose on Day 31
    Notes
    [17] - 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: Pharmacodynamic and pharmacokinetic parameters were evaluated only for subjects who received active study medication.
    End point values
    		 Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18 years Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years
    Number of subjects analysed
    11 [18]
    12 [19]
    19 [20]
    Units: seconds
    arithmetic mean (standard deviation)
        Day 15: 2 to 4 hours post-dose (n= 11, 12, 19)
    8.964 ( 3.822 )
    9.083 ( 2.513 )
    3.147 ( 2.099 )
        Day 15: 6 to 8 hours post-dose (n= 11, 12,19)
    4.218 ( 2.977 )
    2.817 ( 1.628 )
    1.984 ( 1.341 )
        Day 31: 10 to 16 hours post-dose (n= 0, 0, 18)
    99999 ( 99999 )
    99999 ( 99999 )
    0.156 ( 1.155 )
        Day 31: 20 to 24 hours post-dose (n= 11, 11, 0)
    -0.082 ( 1.02 )
    -0.327 ( 1.332 )
    99999 ( 99999 )
    Notes
    [18] - PDS with number of subjects evaluable for this specific end point
    [19] - PDS with number of subjects evaluable for this specific end point
    [20] - PDS with number of subjects evaluable for this specific end point
    No statistical analyses for this end point

    Secondary: Change From Baseline in Activated Partial Thromboplastin Time at Specified Time Points

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    End point title
    		 Change From Baseline in Activated Partial Thromboplastin Time at Specified Time Points [21]
    End point description
    The Activated partial thromboplastin time (aPTT) is a screening test for the intrinsic pathway. In the below table, ‘n’ signifies those subjects who were evaluable for this measure at given time points for each group and '99999' signifies no subjects were evaluated for the given time points for respective reporting groups.
    End point type
    Secondary
    End point timeframe
    0 hours (pre-dose) to 8 hours post-dose on Day 15 and 24 hours post-dose on Day 31
    Notes
    [21] - 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: Pharmacodynamic and pharmacokinetic parameters were evaluated only for subjects who received active study medication.
    End point values
    		 Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18 years Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years
    Number of subjects analysed
    11 [22]
    12 [23]
    19 [24]
    Units: seconds
    arithmetic mean (standard deviation)
        Day 15: 2 to 4 hours post-dose (n= 11, 12, 19)
    10.982 ( 4.47 )
    12.818 ( 5.21 )
    2.995 ( 5.616 )
        Day 15: 6 to 8 hours post-dose (n= 11, 12,19)
    6.136 ( 2.641 )
    5.9 ( 4.942 )
    1.858 ( 4.774 )
        Day 31: 10 to 16 hours post-dose (n= 0, 0, 18)
    99999 ( 99999 )
    99999 ( 99999 )
    -0.483 ( 6.488 )
        Day 31: 20 to 24 hours post-dose (n= 11, 11, 0)
    1.345 ( 3.19 )
    1.24 ( 4.992 )
    99999 ( 99999 )
    Notes
    [22] - PDS with number of subjects evaluable for this specific end point
    [23] - PDS with number of subjects evaluable for this specific end point
    [24] - PDS with number of subjects evaluable for this specific end point
    No statistical analyses for this end point

    Secondary: Anti-factor Xa Values at Specified Time Points

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    End point title
    		 Anti-factor Xa Values at Specified Time Points [25]
    End point description
    The individual anti-Factor Xa activity was determined ex-vivo using a photometric method. In the below table, ‘n’ signifies those subjects who were evaluable for this measure at given time points for each group and '99999' signifies no subjects were evaluated for the given time points for respective reporting groups.
    End point type
    Secondary
    End point timeframe
    0 hours (pre-dose) to 8 hours post-dose on Day 15 and 24 hours post-dose on Day 31
    Notes
    [25] - 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: Pharmacodynamic and pharmacokinetic parameters were evaluated only for subjects who received active study medication.
    End point values
    		 Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18 years Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years
    Number of subjects analysed
    11 [26]
    12 [27]
    19 [28]
    Units: microgram per liter (mcg/L)
    arithmetic mean (standard deviation)
        Day 15: pre-dose
    16.081 ( 6.136 )
    8.136 ( 3.069 )
    31.553 ( 25.416 )
        Day 15: 2 to 4 hours post-dose (n= 11, 12, 19)
    185.481 ( 53.326 )
    252.853 ( 71.072 )
    99.415 ( 54.415 )
        Day 15: 6 to 8 hours post-dose (n= 11, 12,19)
    105.223 ( 54.339 )
    68.67 ( 32.845 )
    77.929 ( 50.074 )
        Day 31: 10 to 16 hours post-dose (n= 0, 0, 18)
    99999 ( 99999 )
    99999 ( 99999 )
    30.927 ( 18.037 )
        Day 31: 20 to 24 hours post-dose (n= 9, 10, 0)
    16.038 ( 7.653 )
    8.409 ( 3.664 )
    99999 ( 99999 )
    Notes
    [26] - PDS with number of subjects evaluable for this specific end point
    [27] - PDS with number of subjects evaluable for this specific end point
    [28] - PDS with number of subjects evaluable for this specific end point
    No statistical analyses for this end point

    Secondary: Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Specified Time Points

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    End point title
    		 Concentration of Rivaroxaban in Plasma as a Measure of Pharmacokinetics at Specified Time Points [29]
    End point description
    Geometric and percentage geometric coefficient of variation (%CV) were reported. In the below table, ‘n’ signifies those subjects who were evaluable for this measure at given time points for each group.
    End point type
    Secondary
    End point timeframe
    0 hours (pre-dose) to 8 hours post-dose on Day 15 and 20-24 hours (OD dosing) and 10-16 hours (BID dosing), respectively, post-dose on Day 31
    Notes
    [29] - 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: Pharmacodynamic and pharmacokinetic parameters were evaluated only for subjects who received active study medication.
    End point values
    		 Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18 years Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years
    Number of subjects analysed
    11 [30]
    12 [31]
    19 [32]
    Units: microgram per liter (mcg/L)
    geometric mean (geometric coefficient of variation)
        Day 15: pre-dose
    20.4822 ( 40.6726 )
    7.4367 ( 152.9768 )
    41.6025 ( 183.6873 )
        Day 15: 2 to 4 hours post-dose (n= 11, 12, 19)
    219.6933 ( 35.7518 )
    240.6319 ( 18.3387 )
    119.2201 ( 52.9889 )
        Day 15: 6 to 8 hours post-dose (n= 11, 12,19)
    124.6723 ( 49.1882 )
    96.8051 ( 41.8155 )
    100.5992 ( 52.6497 )
        Day 31: 10 to 16 hours post-dose (n= 0, 0, 19)
    99999 ( 99999 )
    99999 ( 99999 )
    43.5223 ( 81.7283 )
        Day 31: 20 to 24 hours post-dose (n= 11, 11, 0)
    21.3252 ( 43.1274 )
    9.4654 ( 167.7545 )
    99999 ( 99999 )
    Notes
    [30] - PKS with number of subjects evaluable for this specific end point
    [31] - PKS with number of subjects evaluable for this specific end point
    [32] - PKS with number of subjects evaluable for this specific end point
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration untill 30 day post study treatment (approximately 60 days).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18 years
    Reporting group description
    		 Subjects aged from 12 - <18 years were administered with age- and body weight-adjusted oral dose ofrivaroxaban (BAY59-7939) immediate-release (IR) tablet once daily under fed conditions for 30 days. Subjects with a body weight of 14 to 50 kilogram (kg) received a dose (equivalent to 20 milligram [mg] in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a dose of 20 mg.

    Reporting group title
    Anticoagulant Comparator, Age: 12 - <18 years
    Reporting group description
    		 Subjects aged from 12 - <18 years received anticoagulant comparator as per standard regimen. The dosage given was adjusted based on the individual age and body weight.

    Reporting group title
    Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years
    Reporting group description
    		 Subjects aged from 6 - <12 years were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) IR tablet once daily under fed conditions for 30 days. Subjects with a body weight of 14 to 50 kg received a dose (equivalent to 20 mg in adults) ranging from 5 to 15 mg, and subjects with a body weight (comparable to adults) of 50 to 100 kg received a dose of 20 mg.

    Reporting group title
    Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years
    Reporting group description
    		 Subjects aged from 6 - <12 years were administered with age- and body weight-adjusted oral dose of rivaroxaban (BAY59-7939) suspension under fed conditions twice daily. Subjects with a body weight of 9 to 50 kg received a total daily dose (equivalent to 20 mg in adults) ranging from 6.4 to 15 mg and subjects with a body weight of 50 to 100 kg received a total daily dose of 20 mg.

    Reporting group title
    Anticoagulant Comparator, Age: 6 - <12 years
    Reporting group description
    		 Subjects aged from 6 - <12 years received anticoagulant comparator as per standard regimen. The dosage given was adjusted based on the individual age and body weight.

    Serious adverse events
    		 Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18 years Anticoagulant Comparator, Age: 12 - <18 years Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years Anticoagulant Comparator, Age: 6 - <12 years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    2 / 19 (10.53%)
    0 / 7 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Investigations
    Influenza B virus test positive
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    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
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    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
    Endocrine disorders
    Hypothalamo-pituitary disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Rivaroxaban (BAY59-7939) tablet, OD, Age: 12 - <18 years Anticoagulant Comparator, Age: 12 - <18 years Rivaroxaban (BAY59-7939) tablet, OD, Age: 6 - <12 years Rivaroxaban (BAY59-7939) suspension, BID, Age: 6 - <12 years Anticoagulant Comparator, Age: 6 - <12 years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 11 (81.82%)
    8 / 13 (61.54%)
    6 / 13 (46.15%)
    12 / 19 (63.16%)
    2 / 7 (28.57%)
    Vascular disorders
    Post thrombotic syndrome
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Hot flush
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    2 / 19 (10.53%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    Pyrexia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    2 / 19 (10.53%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    Peripheral swelling
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Localised oedema
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Vessel puncture site haematoma
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Vessel puncture site swelling
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    4 / 11 (36.36%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    8
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Epistaxis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    Nasal congestion
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Contusion
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 13 (0.00%)
    2 / 13 (15.38%)
    3 / 19 (15.79%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    2
    3
    0
    Vocal cord paralysis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Multiple sclerosis relapse
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Increased tendency to bruise
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    2 / 13 (15.38%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    3
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    1
    0
    1
    Dyspepsia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    Nausea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Tooth loss
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    2 / 19 (10.53%)
    1 / 7 (14.29%)
         occurrences all number
    1
    1
    0
    2
    1
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    3
    0
    Swelling face
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Back pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Flank pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    1
    1
    0
    Pain in jaw
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    1 / 19 (5.26%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
    0 / 19 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    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
    25 Jun 2013
    The following modifications were done in this amendment: •Addition of thrombotic burden assessment as a secondary objective. The secondary outcomes text was modified to reflect the addition of the asymptomatic deterioration in the thrombotic burden. •Study indication was broadened to include right atrial thrombosis and catheter-related thrombosis. Also the inclusion criterion was broadened to include children with catheter-related thrombosis who had been treated with standard of care anticoagulant for at least 6 weeks. •Lab tests for bilirubin and alanine aminotransferase (ALT) were added in the inclusion and exclusion criteria. •Visit window at Day 15 was extended from +/-3 days to +/- 5 days. The text explaining when the repeat imaging needs to be done was also included. •Addition of height collection and lab tests during the days Day -60 to Day -10 and at Day 1 (10 days prior to randomization) •Clarification that the blood test as well as repeat imaging (when clinically feasible) was to be collected also at Day 31. •Deletion of description of the type of thrombosis to be considered as outcomes •Addition of the pharmacokinetic/pharmacodynamic sampling instructions for the case rivaroxaban dose was temporarily interrupted •Adverse events of special interest were clarified to reflect the newly added exclusion criterion •Added that subjects with concomitant therapy with other anticoagulants or fibrinolytic during the study treatment were to be prematurely discontinued from study treatment •Clarifications for the: dose confirmation, catheter related thrombosis, results of the EINSTEIN adult studies, definition of vascular events, and for the content of the study booklet were done
    16 Sep 2014
    In this amendment a more detailed description for the rivaroxaban oral suspension was added with clear separation from the tablet group.
    14 Apr 2015
    The following modifications were done in this amendment: •The comparator arm was removed. The sample size was considered too small to support meaningful comparison of rivaroxaban versus standard of care with regard to safety and efficacy. Also, due to the comparator arm removal the total subject number was reduced. •There was a change in the Inclusion criterion 1 to enable enrollment of children who are on long-term anticoagulant treatment. In addition to this, instructions on how to safely handle the switch from heparin, fondaparinux, and vitamin K antagonist to rivaroxaban and vice versa were made available in the protocol. •The platelet count threshold for exclusion of children was adjusted from < 100 * 10^9/liter to < 50 * 10^9/liter

    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.
    Occurrence of "±” in relation with geometric CV is auto-generated. Decimal places were automatically truncated if last decimal equals zero.
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