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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 young children with various manifestations of venous thrombosis

    Summary
    EudraCT number
    		 2014-000566-22
    Trial protocol
    		 IE   IT   ES   AT   NL   BE   GB   FR   HU   FI  
    Global end of trial date
    05 Apr 2017

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

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY59-7939/14374
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02309411
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 May 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study 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 form was read by and explained to all subjects. Participating subjects 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
    15 Jan 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Japan: 1
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    46
    EEA total number of subjects
    23
    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)
    15
    Children (2-11 years)
    31
    Adolescents (12-17 years)
    0
    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
    		 Study was conducted at 27 study centers in 14 countries: Australia, Austria, Brazil, Canada, Hungary, Israel, Italy, Japan, Netherlands, Russia, Spain, Switzerland, United Kingdom, and United States between 15 January 2015 (first subject first visit) and 05 April 2017 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall, 51 subjects were screened, of these 5 subjects were screen failures; 4 subjects withdrew from study and 1 subject failed screening. Total of 46 subjects were assigned to treatment. One child (age: 2-6 years) was assigned to anticoagulant comparator, but received rivaroxaban and displayed in rivaroxaban group (age: 2-6 years) for analyses.

    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, suspension, BID, Age: 2-6 years
    Arm description
    		 Subjects aged from 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban (BAY59-7939) oral suspension twice daily (BID) under fed conditions for 30 days.
    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 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban (BAY59-7939) oral suspension BID under fed conditions for 30 days.

    Arm title
    		 Rivaroxaban suspension, BID, Age: 6 months-2 years
    Arm description
    		 Subjects aged from 6 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.
    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 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.

    Arm title
    		 Anticoagulants, Comparator, Age: 2-6 years
    Arm description
    		 Subjects aged from 2 to 6 years were 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 2 to 6 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).

    Number of subjects in period 1
    		Rivaroxaban, suspension, BID, Age: 2-6 years Rivaroxaban suspension, BID, Age: 6 months-2 years Anticoagulants, Comparator, Age: 2-6 years
    Started
    25
    15
    6
    Completed
    23
    14
    6
    Not completed
    2
    1
    0
         Physician decision
    1
    -
    -
         Consent withdrawn by subject
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rivaroxaban, suspension, BID, Age: 2-6 years
    Reporting group description
    		 Subjects aged from 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban (BAY59-7939) oral suspension twice daily (BID) under fed conditions for 30 days.

    Reporting group title
    Rivaroxaban suspension, BID, Age: 6 months-2 years
    Reporting group description
    		 Subjects aged from 6 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.

    Reporting group title
    Anticoagulants, Comparator, Age: 2-6 years
    Reporting group description
    		 Subjects aged from 2 to 6 years were received comparator as per standard of care.

    Reporting group values
    		 Rivaroxaban, suspension, BID, Age: 2-6 years Rivaroxaban suspension, BID, Age: 6 months-2 years Anticoagulants, Comparator, Age: 2-6 years Total
    Number of subjects
    		 25 15 6 46
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 3.77 ( 1.03 ) 1.26 ( 0.45 ) 3.67 ( 0.82 ) -
    Gender categorical
    Units: Subjects
        Female
    		 12 9 3 24
        Male
    		 13 6 3 22

    End points

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    End points reporting groups
    Reporting group title
    Rivaroxaban, suspension, BID, Age: 2-6 years
    Reporting group description
    		 Subjects aged from 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban (BAY59-7939) oral suspension twice daily (BID) under fed conditions for 30 days.

    Reporting group title
    Rivaroxaban suspension, BID, Age: 6 months-2 years
    Reporting group description
    		 Subjects aged from 6 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.

    Reporting group title
    Anticoagulants, Comparator, Age: 2-6 years
    Reporting group description
    		 Subjects aged from 2 to 6 years were received comparator as per standard of care.

    Subject analysis set title
    Safety Analysis Set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    SAF (N= 46) included all subjects who received at least one dose of the study medication.

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS (N=46) included all enrolled children (before Amendment 4, all children were randomized by interactive voice/web response system [IxRS], after Amendment 4 all children were assigned to rivaroxaban by IxRS). Screening failures were excluded.

    Subject analysis set title
    Pharmacokinetics Analysis Set (PKS)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PKS (N= 40) 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= 39) included all subjects with at least one blood sample for clotting tests in accordance with the pharmacodynamic sampling strategy was included.

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

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    End point title
    		 Number of Subjects With Major Bleeding and Clinically Relevant Non-Major Bleeding Events [1]
    End point description
    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, for example (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
    During or within 2 days after stop of study treatment
    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, suspension, BID, Age: 2-6 years Rivaroxaban suspension, BID, Age: 6 months-2 years Anticoagulants, Comparator, Age: 2-6 years
    Number of subjects analysed
    25 [2]
    15 [3]
    6 [4]
    Units: subjects
        Major bleeding events
    0
    0
    0
        Clinically relevant non-major bleeding events
    0
    0
    1
    Notes
    [2] - SAF
    [3] - SAF
    [4] - SAF
    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
    Venous thromboembolism is the formation of a blood clot (thrombus) inside a blood vessel, obstructing the flow of blood through the circulatory system. The occurrence of recurrent venous thromboembolism was summarized by age group. Symptomatic recurrence, which is the composite of deep Vein Thrombosis (DVT), non-fatal Pulmonary Embolism (PE), and fatal PE of venous thrombosis, had to be documented using appropriate (repeat) imaging test.
    End point type
    Secondary
    End point timeframe
    From start of the study treatment up to 30-days post study treatment period (approximately 60 days)
    End point values
    		 Rivaroxaban, suspension, BID, Age: 2-6 years Rivaroxaban suspension, BID, Age: 6 months-2 years Anticoagulants, Comparator, Age: 2-6 years
    Number of subjects analysed
    25 [5]
    15 [6]
    6 [7]
    Units: subjects
    0
    0
    0
    Notes
    [5] - FAS
    [6] - FAS
    [7] - FAS
    No statistical analyses for this end point

    Secondary: Number of Subjects With Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging

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    End point title
    		 Number of Subjects With Asymptomatic Deterioration in Thrombotic Burden on Repeat Imaging
    End point description
    The occurrence of asymptomatic deterioration in thrombotic burden was summarized by age group. At the end of the 30-day treatment period, a repeat imaging of the thrombus was performed. The images of the index event and repeat imaging were adjudicated by the central independent adjudication committee (CIAC). The thrombotic burden at the time of the index event was compared to the thrombotic burden at the time of repeat imaging. The outcome of the adjudication was classified as normalized, improved, no relevant change, deteriorated, or not evaluable. Due to missing repeated imaging, thrombotic burden assessments were not done in some subjects.
    End point type
    Secondary
    End point timeframe
    At the end of the 30-day treatment period
    End point values
    		 Rivaroxaban, suspension, BID, Age: 2-6 years Rivaroxaban suspension, BID, Age: 6 months-2 years Anticoagulants, Comparator, Age: 2-6 years
    Number of subjects analysed
    25 [8]
    15 [9]
    6 [10]
    Units: subjects
        Normalized
    6
    4
    1
        Improved
    15
    4
    3
        No relevant change
    1
    3
    1
        Deteriorated
    0
    0
    0
        Not evaluable
    0
    0
    0
        Not available
    0
    0
    0
        Missing
    3
    4
    1
    Notes
    [8] - FAS
    [9] - FAS
    [10] - 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 [11]
    End point description
    Prothrombin time is a global clotting test used for the assessment of the extrinsic pathway of the blood coagulation cascade. Day 30 (10-16 hours post-dose) was considered as a baseline.
    End point type
    Secondary
    End point timeframe
    Day 1 (2.5-4 hours post-dose); Day 15 (2-8 hours post-dose)
    Notes
    [11] - 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 parameters were evaluated only for subjects who received active study medication.
    End point values
    		 Rivaroxaban, suspension, BID, Age: 2-6 years Rivaroxaban suspension, BID, Age: 6 months-2 years
    Number of subjects analysed
    22 [12]
    14 [13]
    Units: Seconds
    arithmetic mean (standard deviation)
        Day 1: 2.5-4 hours post-dose
    2.777 ( 4.845 )
    2.514 ( 3.53 )
        Day 15: 2-8 hours post-dose
    2.586 ( 2.387 )
    4.764 ( 4.738 )
    Notes
    [12] - PDS with evaluable subjects for this end point.
    [13] - PDS with evaluable subjects for this 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 [14]
    End point description
    The Activated partial thromboplastin time (aPTT) is a screening test for the intrinsic pathway. Day 30 (10-16 hours post-dose) was considered as a baseline.
    End point type
    Secondary
    End point timeframe
    Day 1 (2.5-4 hours post-dose); Day 15 (2-8 hours post-dose)
    Notes
    [14] - 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 parameters were evaluated only for subjects who received active study medication.
    End point values
    		 Rivaroxaban, suspension, BID, Age: 2-6 years Rivaroxaban suspension, BID, Age: 6 months-2 years
    Number of subjects analysed
    22 [15]
    14 [16]
    Units: Seconds
    arithmetic mean (standard deviation)
        Day 1: 2.5-4 hours post-dose
    6.455 ( 17.036 )
    -3.479 ( 40.443 )
        Day 15: 2-8 hours post-dose
    2.814 ( 6.375 )
    21 ( 66.761 )
    Notes
    [15] - PDS with evaluable subjects for this end point.
    [16] - PDS with evaluable subjects for this 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 [17]
    End point description
    Concentration of rivaroxaban in plasma was measured at Day 1, 15 and 30 at specified time points. In the below table, ‘n’ signifies those subjects who were evaluable for this measure at given time points for each group. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Secondary
    End point timeframe
    Day 1 (30-90 minutes, 2.5-4 hours post-dose); Day 15 (2-8 hours post-dose) and Day 30 (10-16 hours post-dose)
    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: Pharmacokinetic parameters were evaluated only for subjects who received active study medication.
    End point values
    		 Rivaroxaban, suspension, BID, Age: 2-6 years Rivaroxaban suspension, BID, Age: 6 months-2 years
    Number of subjects analysed
    25 [18]
    15 [19]
    Units: microgram per liter (mcg/L)
    geometric mean (geometric coefficient of variation)
        Day 1: 30-90 minutes post-dose (n=24,15)
    72.8494 ( 153.76 )
    68.0072 ( 160.77 )
        Day 1: 2.5-4 hours post-dose (n=24,14)
    108.6053 ( 58.18 )
    76.5371 ( 112.91 )
        Day 15: 2-8 hours post-dose (n=24,14)
    112.3578 ( 46.37 )
    61.3817 ( 451.46 )
        Day 30: 10-16 hours post-dose (n=23,14)
    19.8714 ( 189.49 )
    5.9545 ( 354.51 )
    Notes
    [18] - PKS
    [19] - PKS
    No statistical analyses for this end point

    Other pre-specified: Anti-factor Xa Values at Specified Time Points

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    End point title
    		 Anti-factor Xa Values at Specified Time Points [20]
    End point description
    The individual anti-Factor Xa activity was determined ex-vivo using a photometric method. The anti-factor Xa assay is designed to measure plasma heparin, low molecular weight heparin and other anticoagulants. In the below table, ‘n’ signifies those subjects who were evaluable for this measure at given time points for each group.
    End point type
    Other pre-specified
    End point timeframe
    Day 1 (2.5-4 hours post-dose); Day 15 (2-8 hours post-dose) and Day 30 (10-16 hours post-dose)
    Notes
    [20] - 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 parameters were evaluated only for subjects who received active study medication.
    End point values
    		 Rivaroxaban, suspension, BID, Age: 2-6 years Rivaroxaban suspension, BID, Age: 6 months-2 years
    Number of subjects analysed
    25 [21]
    14 [22]
    Units: microgram per liter (mcg/L)
    arithmetic mean (standard deviation)
        Day 1: 2.5-4 hours post-dose (n=22,14)
    128.457 ( 69.615 )
    87.831 ( 84.178 )
        Day 15: 2-8 hours post-dose (n=22,13)
    103.105 ( 58.343 )
    131.369 ( 96.489 )
        Day 30: 10-16 hours post-dose (n=22,14)
    19.069 ( 17.463 )
    16.952 ( 19.725 )
    Notes
    [21] - PDS
    [22] - PDS
    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 until 30 day post study treatment (approximately 60 days)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Rivaroxaban BID (suspension) (2 - 6 years group)
    Reporting group description
    		 Subjects aged from 2 to 6 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.

    Reporting group title
    Rivaroxaban BID (suspension) (6 months - 2 years group)
    Reporting group description
    		 Subjects aged from 6 months to 2 years were administered with age- and body weight-adjusted dose of rivaroxaban oral suspension BID under fed conditions for 30 days.

    Reporting group title
    Anticoagulants, comparator (2 - 6 years group)
    Reporting group description
    		 Subjects aged from 2 to 6 years were received comparator as per standard of care.

    Serious adverse events
    		 Rivaroxaban BID (suspension) (2 - 6 years group) Rivaroxaban BID (suspension) (6 months - 2 years group) Anticoagulants, comparator (2 - 6 years group)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 15 (13.33%)
    1 / 6 (16.67%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Optic atrophy
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory disorder
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Rivaroxaban BID (suspension) (2 - 6 years group) Rivaroxaban BID (suspension) (6 months - 2 years group) Anticoagulants, comparator (2 - 6 years group)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 25 (56.00%)
    11 / 15 (73.33%)
    3 / 6 (50.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Surgical and medical procedures
    Catheter placement
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Feeling cold
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Pulmonary congestion
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Pulmonary granuloma
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Bronchomalacia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Tracheomalacia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Blood fibrinogen decreased
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Bronchoscopy
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Scratch
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Subcutaneous haematoma
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    Wound haemorrhage
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Lip injury
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Polyneuropathy
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    Febrile neutropenia
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    1
    Monocytosis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Neutropenia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Thrombocytosis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Cytopenia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Eye pruritus
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Anal erosion
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Erythema
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Myopathy
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Neck pain
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Infections and infestations
    Ear infection
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Scarlet fever
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth abscess
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Tracheobronchitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Viral rash
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Viral tonsillitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    0
    1
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Sep 2014
    This amendment was issued for the following modifications: •Erroneous dosing information was corrected •The suspension information was adjusted and summary of oral suspension preparation was provided.
    14 Apr 2015
    This amendment covered the following changes: •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. Furthermore, due to the comparator arm removal, the total subject number was reduced. •Inclusion criterion was changed to enable enrollment of children who are on long-term anticoagulant treatment. Additionally, instructions on how to safely handle the switch from heparin, fondaparinux, and Vitamin K antagonist (VKA) to rivaroxaban and vice versa were made available in the protocol. •The platelet count threshold for exclusion of children was adjusted from less than (<) 100 X 10^9 per liter (/L) to < 50 X 10^9/L. •Minor clarifications for consistency.

    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.
    In this study, sample size calculation was based on feasibility assessment due to low incidence of venous thrombosis in children and on pharmacokinetic moderate inter-individual variability of rivaroxaban.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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