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    Clinical Trial Results:
    A Prospective, Randomized, Open Label, Multi-center Study of the Safety and Pharmacokinetics of Apixaban versus Vitamin K Antagonist or LMWH in Pediatric Subjects with Congenital or Acquired Heart Disease Requiring Chronic Anticoagulation for Thromboembolism Prevention

    Summary
    EudraCT number
    		 2016-001247-39
    Trial protocol
    		 DE   GB   IT   FI   AT   ES  
    Global end of trial date
    18 Oct 2021

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CV185-362
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02981472
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000183-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
    15 Nov 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Oct 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the safety of apixaban, compared to VKA or subcutaneous LMWH and to evaluate apixaban PK in pediatric subjects with congenital or acquired heart disease requiring chronic anticoagulation for thromboprophylaxis.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Italy: 22
    Country: Number of subjects enrolled
    Mexico: 16
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    United States: 70
    Worldwide total number of subjects
    192
    EEA total number of subjects
    53
    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)
    11
    Children (2-11 years)
    134
    Adolescents (12-17 years)
    47
    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
    		 -

    Pre-assignment
    Screening details
    		 192 participants were randomized and 188 were treated for up to 12 months or until anticoagulation is no longer needed, whichever is shorter

    Period 1
    Period 1 title
    Pre-treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Apixaban
    Arm description
    		 Participants receive thromboprophylaxis with open-label apixaban for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants weighing between >/= 3 and < 35 kg will be administered apixaban twice daily (BID) in doses between 0.2mg and 4 mg depending on body weight. Children randomized to the apixaban arm of the study weighing >/= 35 kg will be administered apixaban 5 mg twice daily (BID).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Apixaban
    Investigational medicinal product code
    Other name
    BMS-562247-01
    Pharmaceutical forms
    Capsule, Film-coated tablet, Oral solution
    Routes of administration
    Oral use, Nasogastric use , Gastric use
    Dosage and administration details
    Children between 3 and < 35 kg will be administered apixaban twice daily (BID) in doses between 0.2 mg and 4 mg depending on body weight with the 0.1 capsules, 0.5 mg mini-tablets, or oral solution. Children randomized to the apixaban arm of the study weighing >/=35 kg will be administered apixaban 5 mg twice daily (BID) as a tablet or solution.

    Arm title
    		 LMWH/VKA
    Arm description
    		 Participants receive thromboprophylaxis with Vitamin K Antagonists (VKA) or Low Molecular Weight Heparin (LMWH) for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants who receive LMWH are allowed to switch to VKA at any time during the study; conversely, participants having difficulty with VKA may switch to LMWH.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Warfarin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Use of VKA or LMWH will follow the local standard of care that is aligned with the ACCP guidelines. The dose of VKA is recommended to be titrated to achieve a target international normalized ratio (INR) of 2.0 to 3.0, and the dose of LMWH is recommended to target an anti-Xa level between 0.5 and 1.0 units/mL.

    Investigational medicinal product name
    Enoxaparin sodium (Clexane)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Use of VKA or LMWH will follow the local standard of care that is aligned with the ACCP guidelines. The dose of VKA is recommended to be titrated to achieve a target international normalized ratio (INR) of 2.0 to 3.0, and the dose of LMWH is recommended to target an anti-Xa level between 0.5 and 1.0 units/mL.

    Investigational medicinal product name
    Enoxaparin sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Use of VKA or LMWH will follow the local standard of care that is aligned with the ACCP guidelines. The dose of VKA is recommended to be titrated to achieve a target international normalized ratio (INR) of 2.0 to 3.0, and the dose of LMWH is recommended to target an anti-Xa level between 0.5 and 1.0 units/mL.

    Number of subjects in period 1
    		Apixaban LMWH/VKA
    Started
    129
    63
    Completed
    126
    62
    Not completed
    3
    1
         Participant withdrew consent
    2
    1
         Participant no longer meets study criteria
    1
    -
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Apixaban
    Arm description
    		 Participants receive thromboprophylaxis with open-label apixaban for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants weighing between >/= 3 and < 35 kg will be administered apixaban twice daily (BID) in doses between 0.2mg and 4 mg depending on body weight. Children randomized to the apixaban arm of the study weighing >/= 35 kg will be administered apixaban 5 mg twice daily (BID).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Apixaban
    Investigational medicinal product code
    Other name
    BMS-562247-01
    Pharmaceutical forms
    Capsule, Film-coated tablet, Oral solution
    Routes of administration
    Oral use, Nasogastric use , Gastric use
    Dosage and administration details
    Children between 3 and < 35 kg will be administered apixaban twice daily (BID) in doses between 0.2 mg and 4 mg depending on body weight with the 0.1 capsules, 0.5 mg mini-tablets, or oral solution. Children randomized to the apixaban arm of the study weighing >/=35 kg will be administered apixaban 5 mg twice daily (BID) as a tablet or solution.

    Arm title
    		 LMWH/VKA
    Arm description
    		 Participants receive thromboprophylaxis with Vitamin K Antagonists (VKA) or Low Molecular Weight Heparin (LMWH) for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants who receive LMWH are allowed to switch to VKA at any time during the study; conversely, participants having difficulty with VKA may switch to LMWH.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Warfarin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Use of VKA or LMWH will follow the local standard of care that is aligned with the ACCP guidelines. . The dose of VKA is recommended to be titrated to achieve a target international normalized ratio (INR) of 2.0 to 3.0, and the dose of LMWH is recommended to target an anti-Xa level between 0.5 and 1.0 units/mL.

    Investigational medicinal product name
    Enoxaparin sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Use of VKA or LMWH will follow the local standard of care that is aligned with the ACCP guidelines. . The dose of VKA is recommended to be titrated to achieve a target international normalized ratio (INR) of 2.0 to 3.0, and the dose of LMWH is recommended to target an anti-Xa level between 0.5 and 1.0 units/mL.

    Investigational medicinal product name
    Enoxaparin sodium (Clexane)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Use of VKA or LMWH will follow the local standard of care that is aligned with the ACCP guidelines. . The dose of VKA is recommended to be titrated to achieve a target international normalized ratio (INR) of 2.0 to 3.0, and the dose of LMWH is recommended to target an anti-Xa level between 0.5 and 1.0 units/mL.

    Number of subjects in period 2
    		Apixaban LMWH/VKA
    Started
    126
    62
    Completed
    119
    60
    Not completed
    7
    2
         Participant withdrew consent
    1
    -
         Adverse event
    6
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Apixaban
    Reporting group description
    		 Participants receive thromboprophylaxis with open-label apixaban for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants weighing between >/= 3 and < 35 kg will be administered apixaban twice daily (BID) in doses between 0.2mg and 4 mg depending on body weight. Children randomized to the apixaban arm of the study weighing >/= 35 kg will be administered apixaban 5 mg twice daily (BID).

    Reporting group title
    LMWH/VKA
    Reporting group description
    		 Participants receive thromboprophylaxis with Vitamin K Antagonists (VKA) or Low Molecular Weight Heparin (LMWH) for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants who receive LMWH are allowed to switch to VKA at any time during the study; conversely, participants having difficulty with VKA may switch to LMWH.

    Reporting group values
    		 Apixaban LMWH/VKA Total
    Number of subjects
    		 129 63 192
    Age Categorical
    Units: Participants
        28 DAYS - < 2 YEARS
    		 8 3 11
        2 YEARS - < 6 YEARS
    		 40 22 62
        6 YEARS - < 12 YEARS
    		 49 23 72
        12 YEARS - < 18 YEARS
    		 32 15 47
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 7.96 ( 4.553 ) 7.56 ( 4.408 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 67 23 90
        Male
    		 62 40 102
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 6 4 10
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 7 2 9
        White
    		 109 51 160
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 6 6 12
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 20 14 34
        Not Hispanic or Latino
    		 105 47 152
        Unknown or Not Reported
    		 4 2 6

    End points

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    End points reporting groups
    Reporting group title
    Apixaban
    Reporting group description
    		 Participants receive thromboprophylaxis with open-label apixaban for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants weighing between >/= 3 and < 35 kg will be administered apixaban twice daily (BID) in doses between 0.2mg and 4 mg depending on body weight. Children randomized to the apixaban arm of the study weighing >/= 35 kg will be administered apixaban 5 mg twice daily (BID).

    Reporting group title
    LMWH/VKA
    Reporting group description
    		 Participants receive thromboprophylaxis with Vitamin K Antagonists (VKA) or Low Molecular Weight Heparin (LMWH) for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants who receive LMWH are allowed to switch to VKA at any time during the study; conversely, participants having difficulty with VKA may switch to LMWH.
    Reporting group title
    Apixaban
    Reporting group description
    		 Participants receive thromboprophylaxis with open-label apixaban for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants weighing between >/= 3 and < 35 kg will be administered apixaban twice daily (BID) in doses between 0.2mg and 4 mg depending on body weight. Children randomized to the apixaban arm of the study weighing >/= 35 kg will be administered apixaban 5 mg twice daily (BID).

    Reporting group title
    LMWH/VKA
    Reporting group description
    		 Participants receive thromboprophylaxis with Vitamin K Antagonists (VKA) or Low Molecular Weight Heparin (LMWH) for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants who receive LMWH are allowed to switch to VKA at any time during the study; conversely, participants having difficulty with VKA may switch to LMWH.

    Subject analysis set title
    Participants Weight Range 6 to < 9 kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receive thromboprophylaxis with open-label apixaban for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants weighing between 6 to < 9 kg will be administered 1mg apixaban twice daily (BID).

    Subject analysis set title
    Participants Weight Range 9 to < 12 kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receive thromboprophylaxis with open-label apixaban for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants weighing between 9 to < 12 kg will be administered 1.5mg apixaban twice daily (BID).

    Subject analysis set title
    Participants Weight Range 12 to < 18 kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receive thromboprophylaxis with open-label apixaban for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants weighing between 12 to < 18 kg will be administered 2mg apixaban twice daily (BID).

    Subject analysis set title
    Participants Weight Range 18 to < 25 kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receive thromboprophylaxis with open-label apixaban for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants weighing between 18 to < 25 kg will be administered 3mg apixaban twice daily (BID).

    Subject analysis set title
    Participants Weight Range 25 to < 35 kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receive thromboprophylaxis with open-label apixaban for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants weighing between 25 to < 35 kg will be administered 4mg apixaban twice daily (BID).

    Subject analysis set title
    Participants Weight Range ≥ 35 kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants receive thromboprophylaxis with open-label apixaban for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants weighing between ≥ 35 kg will be administered 5mg apixaban twice daily (BID).

    Primary: Composite of Adjudicated Major or Clinically Relevant Non-Major (CRNM) Bleeding Events

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    End point title
    		 Composite of Adjudicated Major or Clinically Relevant Non-Major (CRNM) Bleeding Events [1]
    End point description
    The number of participants with adjudicated major or CRNM bleeding events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) criteria. Events are adjudicated by a blinded, independent events adjudication committee (EAC). Major bleeding satisfies one or more of the following criteria: fatal bleeding, clinically overt bleeding associated with a decrease in hemoglobin of at least 20 g/L (i.e., 2 g/dL) in a 24-hour period, bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS, or bleeding that requires surgical intervention in an operating suite, including interventional radiology. CRNM bleeding satisfies one or both of the following criteria: overt bleeding for which blood product is administered and not directly attributable to the subject’s underlying medical condition or bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating room.
    End point type
    Primary
    End point timeframe
    From first dose to 2 days after last dose (Up to approximately 12 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only summary statistics planned for this endpoint
    End point values
    		 Apixaban LMWH/VKA
    Number of subjects analysed
    126
    62
    Units: Participants
    1
    3
    No statistical analyses for this end point

    Secondary: The Number of Participants with Thrombotic Events and Thromboembolic Event-Related Death

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    End point title
    		 The Number of Participants with Thrombotic Events and Thromboembolic Event-Related Death
    End point description
    The number of participants with thromboembolic events (intra-cardiac, shunt, inside Fontan pathway, pulmonary embolism (PE), stroke, other arterial or venous thromboembolic events, etc.) and thromboembolic event-related death detected by imaging or clinical diagnosis. Death and thromboembolic events are adjudicated by a blinded, independent events adjudication committee (EAC)
    End point type
    Secondary
    End point timeframe
    From randomization to 2 days after last dose (Up to approximately 12 months)
    End point values
    		 Apixaban LMWH/VKA
    Number of subjects analysed
    129
    63
    Units: Participants
        Thromboembolic events
    0
    0
        Thromboembolic event-related death
    0
    0
    No statistical analyses for this end point

    Secondary: The Number of Participants with Adjudicated Major Bleeding

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    End point title
    		 The Number of Participants with Adjudicated Major Bleeding
    End point description
    The number of participants with adjudicated major bleeding events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) criteria. Major bleeding events are adjudicated by a blinded, independent events adjudication committee (EAC). Major bleeding is defined as bleeding that satisfies one or more of the following criteria: -fatal bleeding -clinically overt bleeding associated with a decrease in hemoglobin of at least 20 g/L (i.e., 2 g/dL) in a 24-hour period -bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS -bleeding that requires surgical intervention in an operating suite, including interventional radiology
    End point type
    Secondary
    End point timeframe
    From first dose to 2 days after last dose (Up to approximately 12 months)
    End point values
    		 Apixaban LMWH/VKA
    Number of subjects analysed
    126
    62
    Units: Participants
    1
    1
    No statistical analyses for this end point

    Secondary: The Number of Participants with Adjudicated CRNM bleeding

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    End point title
    		 The Number of Participants with Adjudicated CRNM bleeding
    End point description
    The number of participants with adjudicated clinically relevant non-major (CRNM) bleeding events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) criteria. CRNM bleeding events are adjudicated by a blinded, independent events adjudication committee (EAC). CRNM bleeding is defined as bleeding that satisfies one or both of the following criteria: -overt bleeding for which blood product is administered and not directly attributable to the subject’s underlying medical condition -bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating room
    End point type
    Secondary
    End point timeframe
    From first dose to 2 days after last dose (Up to approximately 12 months)
    End point values
    		 Apixaban LMWH/VKA
    Number of subjects analysed
    126
    62
    Units: Participants
    1
    2
    No statistical analyses for this end point

    Secondary: The Number of Participants with All Adjudicated Bleeding

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    End point title
    		 The Number of Participants with All Adjudicated Bleeding
    End point description
    The number of participants with all adjudicated bleeding events
    End point type
    Secondary
    End point timeframe
    From first dose to 2 days after last dose (Up to approximately 12 months)
    End point values
    		 Apixaban LMWH/VKA
    Number of subjects analysed
    126
    62
    Units: Participants
    47
    23
    No statistical analyses for this end point

    Secondary: The Number of Participants with Drug Discontinuation Due to Adverse Effects, Intolerability, or Bleeding

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    End point title
    		 The Number of Participants with Drug Discontinuation Due to Adverse Effects, Intolerability, or Bleeding
    End point description
    The number of participants with drug discontinuation due to adverse effects, intolerability, or bleeding.
    End point type
    Secondary
    End point timeframe
    From first dose to 2 days after last dose (Up to approximately 12 months)
    End point values
    		 Apixaban LMWH/VKA
    Number of subjects analysed
    126
    62
    Units: Participants
    7
    1
    No statistical analyses for this end point

    Secondary: The Number of Participant Deaths in the Study

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    End point title
    		 The Number of Participant Deaths in the Study
    End point description
    The number of participant deaths in the study.
    End point type
    Secondary
    End point timeframe
    From first dose to 2 days after last dose (Up to approximately 12 months)
    End point values
    		 Apixaban LMWH/VKA
    Number of subjects analysed
    126
    62
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Anti-FXa Activity

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    End point title
    		 Anti-FXa Activity
    End point description
    Anti-FXa Activity was measured to assess participant plasma apixaban levels.
    End point type
    Secondary
    End point timeframe
    From first dose up to 6 months after first dose
    End point values
    		 Apixaban
    Number of subjects analysed
    125
    Units: ng/mL
    arithmetic mean (standard error)
        Day 1 (4 HRS POSTDOSE)
    147.69 ( 7.243 )
        Week 2 (PREDOSE)
    86.24 ( 7.652 )
        Week 2 (2 HRS POSTDOSE)
    242.34 ( 18.966 )
        Month 3 (2 HRS POSTDOSE)
    228.88 ( 14.263 )
        Month 6 (PREDOSE)
    66.93 ( 6.532 )
    No statistical analyses for this end point

    Secondary: Chromogenic FX Assay (apparent FX level)

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    End point title
    		 Chromogenic FX Assay (apparent FX level)
    End point description
    Chromogenic FX was measured to assess (apparent) FX levels in participants and inhibition of FXa by apixaban.
    End point type
    Secondary
    End point timeframe
    From first dose up to 6 months after first dose
    End point values
    		 Apixaban
    Number of subjects analysed
    125
    Units: Percent
    arithmetic mean (standard error)
        Day 1 (PREDOSE)
    58.87 ( 2.368 )
        Day 1 (4 HRS POSTDOSE)
    18.90 ( 1.205 )
        Week 2 (PREDOSE)
    35.88 ( 1.973 )
        Week 2 (2 HRS POSTDOSE)
    21.26 ( 1.680 )
        Month 3 (2 HRS POSTDOSE)
    18.25 ( 0.970 )
        Month 6 (PREDOSE)
    36.57 ( 1.943 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Concentration (Cmax)

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    End point title
    		 Maximum Observed Concentration (Cmax)
    End point description
    Maximum observed concentration (Cmax) was measured to assess the pharmacokinetics of apixaban
    End point type
    Secondary
    End point timeframe
    From first dose up to 6 months after first dose
    End point values
    		 Participants Weight Range 6 to < 9 kg Participants Weight Range 9 to < 12 kg Participants Weight Range 12 to < 18 kg Participants Weight Range 18 to < 25 kg Participants Weight Range 25 to < 35 kg Participants Weight Range ≥ 35 kg
    Number of subjects analysed
    6
    2
    28
    29
    24
    35
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    185 ( 48.8 )
    218 ( 23.4 )
    222 ( 39.6 )
    244 ( 30.7 )
    249 ( 37.7 )
    203 ( 35.9 )
    No statistical analyses for this end point

    Secondary: Trough Observed Concentration (Cmin)

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    End point title
    		 Trough Observed Concentration (Cmin)
    End point description
    Trough observed concentration (Cmin) was measured to assess the pharmacokinetics of apixaban
    End point type
    Secondary
    End point timeframe
    From first dose up to 6 months after first dose
    End point values
    		 Participants Weight Range 6 to < 9 kg Participants Weight Range 9 to < 12 kg Participants Weight Range 12 to < 18 kg Participants Weight Range 18 to < 25 kg Participants Weight Range 25 to < 35 kg Participants Weight Range ≥ 35 kg
    Number of subjects analysed
    6
    2
    28
    29
    24
    35
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    57.9 ( 90.3 )
    82.7 ( 21.5 )
    64.3 ( 69.5 )
    67.4 ( 58.9 )
    73.1 ( 64.7 )
    72.7 ( 46.8 )
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve in One Dosing Interval (AUC (TAU))

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    End point title
    		 Area Under the Concentration-Time Curve in One Dosing Interval (AUC (TAU))
    End point description
    Area under the concentration-time curve in one dosing interval (AUC (TAU)) was measured to assess the pharmacokinetics of apixaban
    End point type
    Secondary
    End point timeframe
    From first dose up to 6 months after first dose
    End point values
    		 Participants Weight Range 6 to < 9 kg Participants Weight Range 9 to < 12 kg Participants Weight Range 12 to < 18 kg Participants Weight Range 18 to < 25 kg Participants Weight Range 25 to < 35 kg Participants Weight Range ≥ 35 kg
    Number of subjects analysed
    6
    2
    28
    29
    24
    35
    Units: ng • h/mL
        geometric mean (geometric coefficient of variation)
    1460 ( 61.2 )
    1840 ( 20.7 )
    1610 ( 49.6 )
    1760 ( 38.3 )
    1840 ( 43.3 )
    1630 ( 37.3 )
    No statistical analyses for this end point

    Secondary: Time of Maximum Observed Concentration (Tmax)

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    End point title
    		 Time of Maximum Observed Concentration (Tmax)
    End point description
    Time of maximum observed concentration (Tmax) was measured to assess the pharmacokinetics of apixaban
    End point type
    Secondary
    End point timeframe
    From first dose up to 6 months after first dose
    End point values
    		 Participants Weight Range 6 to < 9 kg Participants Weight Range 9 to < 12 kg Participants Weight Range 12 to < 18 kg Participants Weight Range 18 to < 25 kg Participants Weight Range 25 to < 35 kg Participants Weight Range ≥ 35 kg
    Number of subjects analysed
    6
    2
    28
    29
    24
    35
    Units: hours
        median (full range (min-max))
    2.24 (1.41 to 2.83)
    2.47 (2.23 to 2.71)
    1.72 (0.938 to 3.35)
    1.74 (0.775 to 2.18)
    1.65 (1.26 to 2.85)
    1.85 (1.47 to 2.93)
    No statistical analyses for this end point

    Secondary: The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL)

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    End point title
    		 The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL)
    End point description
    Subjects' quality of life was measured using the PedsQL instrument administered only to English-speaking children/parents. Only subjects who completed the questionnaires at both baseline and post-baseline visits were included in the analyses. PedsQL consists of 23 items scored on a 5-point Likert scale from 0 (never) to 4 (almost always) or for the child report for younger children ages 5-7, a 3-point Likert scale: 0 (Not at all), 2 (Sometimes), and 4 (A lot). Scores are reverse scored and transformed to a 0-100 scale as follows: 0=100, 1=75, 3=25, 4=0. Higher scores indicate a better HRQOL and/or lower problems.
    End point type
    Secondary
    End point timeframe
    from randomization up to 12 months after randomization
    End point values
    		 Apixaban LMWH/VKA
    Number of subjects analysed
    129
    63
    Units: Score on a scale
    arithmetic mean (standard deviation)
        GENERAL-SPECIFIC MODULE BY CHILD - BASELINE
    69.64 ( 15.512 )
    60.71 ( 17.374 )
        GENERAL-SPECIFIC MODULE BY CHILD - MONTH 12
    73.37 ( 19.998 )
    64.81 ( 22.327 )
        GENERAL-SPECIFIC MODULE BY PARENT - BASELINE
    65.61 ( 16.625 )
    65.42 ( 18.000 )
        GENERAL-SPECIFIC MODULE BY PARENT - MONTH 12
    70.00 ( 19.560 )
    70.32 ( 21.949 )
        HEART PROBLEMS AND TREATMENT BY CHILD - BASELINE
    65.34 ( 22.130 )
    64.70 ( 18.465 )
        HEART PROBLEMS AND TREATMENT BY CHILD - MONTH 12
    69.46 ( 21.119 )
    63.44 ( 19.836 )
        TREATMENT II BY CHILD - BASELINE
    87.39 ( 22.994 )
    85.68 ( 15.857 )
        TREATMENT II BY CHILD - MONTH 12
    91.77 ( 10.896 )
    86.27 ( 16.400 )
        PERCEIVED PHYSICAL APPEARANCE BY CHILD - BASELINE
    75.51 ( 27.477 )
    78.44 ( 23.390 )
        PERCEIVED PHYSICAL APPEARANCE BY CHILD - MONTH 12
    80.56 ( 22.408 )
    81.37 ( 30.689 )
        TREATMENT ANXIETY BY CHILD - BASELINE
    80.52 ( 23.420 )
    60.31 ( 34.162 )
        TREATMENT ANXIETY BY CHILD - MONTH 12
    80.71 ( 25.480 )
    60.31 ( 38.333 )
        COGNITIVE PROBLEMS BY CHILD - BASELINE
    69.85 ( 20.871 )
    53.24 ( 20.382 )
        COGNITIVE PROBLEMS BY CHILD - MONTH 12
    68.24 ( 24.367 )
    53.53 ( 26.796 )
        COMMUNICATION BY CHILD - BASELINE
    66.15 ( 30.000 )
    63.55 ( 28.998 )
        COMMUNICATION BY CHILD - MONTH 12
    70.31 ( 26.681 )
    57.28 ( 38.948 )
        HEART PROBLEMS AND TREATMENT BY PARENT - BASELINE
    63.68 ( 20.727 )
    67.71 ( 22.668 )
        HEART PROBLEMS AND TREATMENT BY PARENT - MONTH 12
    66.37 ( 20.811 )
    69.00 ( 23.688 )
        TREATMENT II BY PARENT - BASELINE
    91.41 ( 11.557 )
    85.27 ( 17.325 )
        TREATMENT II BY PARENT - MONTH 12
    90.30 ( 12.381 )
    83.80 ( 18.915 )
        PERCEIVED PHYSICAL APPEARANCE BY PARENT - BASELINE
    79.16 ( 22.571 )
    79.66 ( 22.958 )
        PERCEIVED PHYSICAL APPEARANCE BY PARENT - MONTH 12
    79.38 ( 21.012 )
    74.33 ( 26.998 )
        TREATMENT ANXIETY BY PARENT - BASELINE
    61.44 ( 30.804 )
    56.27 ( 33.997 )
        TREATMENT ANXIETY BY PARENT - MONTH 12
    64.03 ( 29.567 )
    57.77 ( 34.199 )
        COGNITIVE PROBLEMS BY PARENT - BASELINE
    60.29 ( 29.558 )
    61.60 ( 25.807 )
        COGNITIVE PROBLEMS BY PARENT - MONTH 12
    58.69 ( 29.560 )
    58.53 ( 33.432 )
        COMMUNICATION BY PARENT - BASELINE
    65.57 ( 27.342 )
    67.33 ( 28.257 )
        COMMUNICATION BY PARENT - MONTH 12
    68.20 ( 24.037 )
    66.17 ( 28.067 )
    No statistical analyses for this end point

    Secondary: Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score

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    End point title
    		 Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score
    End point description
    Subjects' quality of life was measured using the KIDCLOT instrument administered only to English-speaking children/parents. Only subjects who completed the questionnaires at both baseline and post-baseline visits were included in the analyses. KIDCLOT Parent inventory uses a 5 point Likert scale from 1 (N/A), 2 (Never), 3 (Rarely), 4 ( Now and then), 5 (Often). Child inventory uses a 4 point Likert scale 1 (N/A), 2 (Never), 3 (Now and then), 5 (Always). Values are scores as follows 1=0, 2=1, 3=2, 4=3, 5=4. Score interpretation is 0 to 100 percent IMPACT of anticoagulation on a child's life therefore, higher scores indicates a more negative effect.
    End point type
    Secondary
    End point timeframe
    from randomization up to 12 months after randomization
    End point values
    		 Apixaban LMWH/VKA
    Number of subjects analysed
    46
    30
    Units: Score on a scale
    arithmetic mean (standard deviation)
        BASELINE CHILD REPORTED - 6 MONTHS
    24.35 ( 12.887 )
    26.45 ( 12.114 )
        POST BASELINE CHILD REPORTED - 6 MONTHS
    22.81 ( 13.380 )
    22.57 ( 16.049 )
        BASELINE CHILD REPORTED - 12 MONTHS
    22.50 ( 11.787 )
    25.32 ( 11.719 )
        POST BASELINE CHILD REPORTED - 12 MONTHS
    21.52 ( 13.251 )
    18.01 ( 10.408 )
        BASELINE PARENT REPORTED - 6 MONTHS
    37.97 ( 20.493 )
    39.02 ( 17.932 )
        POST BASELINE PARENT REPORTED - 6 MONTHS
    32.32 ( 17.060 )
    37.94 ( 20.626 )
        BASELINE PARENT REPORTED - 12 MONTHS
    38.37 ( 18.874 )
    39.36 ( 16.057 )
        POST BASELINE PARENT REPORTED - 12 MONTHS
    31.10 ( 16.021 )
    33.61 ( 17.943 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs collected from first dose to last dose + 2 days/ SAEs collected from first dose until last dose date + 30 days (Up to approximately 13 months) All Cause Mortality was assessed from first dose to study completion (up to approximately 57 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    VKA/LMWH
    Reporting group description
    		 Participants receive thromboprophylaxis with Vitamin K Antagonists (VKA) or Low Molecular Weight Heparin (LMWH) for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants who receive LMWH are allowed to switch to VKA at any time during the study; conversely, participants having difficulty with VKA may switch to LMWH.

    Reporting group title
    APIXABAN
    Reporting group description
    		 Participants receive thromboprophylaxis with open-label apixaban for up to 12 months or until the need for anticoagulant is resolved, whichever occurs first. Participants weighing between >/= 3 and < 35 kg will be administered apixaban twice daily (BID) in doses between 0.2mg and 4 mg depending on body weight. Children randomized to the apixaban arm of the study weighing >/= 35 kg will be administered apixaban 5 mg twice daily (BID).

    Serious adverse events
    		 VKA/LMWH APIXABAN
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 62 (20.97%)
    26 / 126 (20.63%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    Generalised oedema
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Penile haematoma
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracardiac pressure increased
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial pressure increased
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incorrect dose administered
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt thrombosis
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 126 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital cystic kidney disease
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoplastic left heart syndrome
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial septal defect acquired
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac dysfunction
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gingival bleeding
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Protein-losing gastroenteropathy
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 VKA/LMWH APIXABAN
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 62 (83.87%)
    101 / 126 (80.16%)
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    4 / 62 (6.45%)
    0 / 126 (0.00%)
         occurrences all number
    4
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    5 / 62 (8.06%)
    9 / 126 (7.14%)
         occurrences all number
    5
    15
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 62 (1.61%)
    8 / 126 (6.35%)
         occurrences all number
    1
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 62 (6.45%)
    4 / 126 (3.17%)
         occurrences all number
    6
    6
    Headache
         subjects affected / exposed
    3 / 62 (4.84%)
    19 / 126 (15.08%)
         occurrences all number
    3
    34
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    8 / 62 (12.90%)
    20 / 126 (15.87%)
         occurrences all number
    12
    27
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 62 (6.45%)
    12 / 126 (9.52%)
         occurrences all number
    7
    17
    Vomiting
         subjects affected / exposed
    9 / 62 (14.52%)
    20 / 126 (15.87%)
         occurrences all number
    14
    39
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 62 (6.45%)
    8 / 126 (6.35%)
         occurrences all number
    4
    12
    Epistaxis
         subjects affected / exposed
    6 / 62 (9.68%)
    20 / 126 (15.87%)
         occurrences all number
    10
    38
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    4 / 62 (6.45%)
    7 / 126 (5.56%)
         occurrences all number
    4
    8
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 62 (6.45%)
    14 / 126 (11.11%)
         occurrences all number
    5
    26
    Nasopharyngitis
         subjects affected / exposed
    8 / 62 (12.90%)
    13 / 126 (10.32%)
         occurrences all number
    11
    19

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Dec 2017
    Added to exclusion criteria confirmed diagnosis of a GI ulcer. Adjusted QOL assessment based on initiation of anticoagulation therapy. Opened up the younger age group to allow enrollment of children >/= 3 months of age and indicated that only children > 6 kg can be enrolled. Changed apixaban dosing scheme from a mg/kg dosing to a fixed-dose, body weight-tiered regimen.
    07 Jun 2019
    Exclusion criteria was revised for those patients with a known inherited or acquired thrombotic disorder
    27 Jan 2020
    Open enrollment to patients 28 days to < 3 months and >/= 3 kg. Update exclusion criteria for subjects with known inherited bleeding disorders, coagulopathies, and antiphospholipid syndrome
    16 Jul 2020
    Neonates (subjects < 28 days of age) will no longer be included in the study, Subjects < 3 kg are excluded.

    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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