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    Clinical Trial Results:
    A Phase III Randomized, Open Label, Multi-center Study of the Safety and Efficacy of Apixaban for Venous Thromboembolism Prevention versus No Systemic Anticoagulant Prophylaxis during Induction Chemotherapy in Children with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (T or B cell) Treated with Asparaginase

    Summary
    EudraCT number
    		 2014-000328-47
    Trial protocol
    		 Outside EU/EEA   BE   PL   CZ  
    Global end of trial date
    07 Jul 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jan 2022
    First version publication date
    23 Jan 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CV185-155
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02369653
    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
    08 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jul 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jul 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of prophylactic oral or enteric apixaban versus no systemic anticoagulant during ~28 days of induction chemotherapy including asparaginase on the composite endpoint of adjudicated non-fatal deep vein thromboses (DVT, including symptomatic and asymptomatic), pulmonary embolism (PE), and cerebral venous sinus thrombosis (CVST); and VTE-related-death. To assess the effect of prophylactic oral or enteric apixaban versus no systemic anticoagulant during ~28 days of induction chemotherapy including asparaginase on adjudicated major bleeding events.
    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
    22 Oct 2015
    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: 12
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Czechia: 1
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Korea, Republic of: 34
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Russian Federation: 26
    Country: Number of subjects enrolled
    United States: 386
    Worldwide total number of subjects
    512
    EEA total number of subjects
    32
    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)
    8
    Children (2-11 years)
    398
    Adolescents (12-17 years)
    106
    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
    		 512 participants were randomized and received study treatment.

    Period 1
    Period 1 title
    Overall Study (overall 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 will be administered apixaban twice daily by mouth or via a NGT or GT according to weight range during approximately 28 days of induction chemotherapy including asparaginase. Weight range - Dose >/=35 kg - 2.5 mg twice daily <35 to 25 kg - 2 mg twice daily <25 to 18 kg - 1.5 mg twice daily <18 to 10.5 kg - 1 mg twice daily <10.5 to 6 kg - 0.5 mg twice daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    BMS-562247
    Investigational medicinal product code
    Other name
    apixaban
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg

    Investigational medicinal product name
    BMS-562247
    Investigational medicinal product code
    Other name
    apixaban
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Nasogastric use , Gastric use, Oral use
    Dosage and administration details
    0.4 mg/mL

    Investigational medicinal product name
    BMS-562247
    Investigational medicinal product code
    Other name
    apixaban
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg

    Investigational medicinal product name
    Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Solution for infusion
    Routes of administration
    Other use
    Dosage and administration details
    3 - 4 drug, systemic induction chemotherapy regimen consisting of a corticosteroid, vincristine, and single or multiple dose asparaginase (with or without daunorubicin)

    Arm title
    		 Standard of Care
    Arm description
    		 No systemic anticoagulant prophylaxis during induction chemotherapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Chemotherapy
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Solution for infusion
    Routes of administration
    Other use
    Dosage and administration details
    3 - 4 drug, systemic induction chemotherapy regimen consisting of a corticosteroid, vincristine, and single or multiple dose asparaginase (with or without daunorubicin)

    Number of subjects in period 1
    		Apixaban Standard of Care
    Started
    256
    256
    Completed
    242
    249
    Not completed
    14
    7
         Adverse event, serious fatal
    1
    2
         Participant withdrew consent
    13
    3
         Lost to follow-up
    -
    1
         Administrative reason by sponsor
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Apixaban
    Reporting group description
    		 Participants will be administered apixaban twice daily by mouth or via a NGT or GT according to weight range during approximately 28 days of induction chemotherapy including asparaginase. Weight range - Dose >/=35 kg - 2.5 mg twice daily <35 to 25 kg - 2 mg twice daily <25 to 18 kg - 1.5 mg twice daily <18 to 10.5 kg - 1 mg twice daily <10.5 to 6 kg - 0.5 mg twice daily

    Reporting group title
    Standard of Care
    Reporting group description
    		 No systemic anticoagulant prophylaxis during induction chemotherapy

    Reporting group values
    		 Apixaban Standard of Care Total
    Number of subjects
    		 256 256 512
    Age categorical
    Units: Participants
        Infants and toddlers (28 days-23 months)
    		 1 7 8
        Children (2-11 years)
    		 206 192 398
        Adolescents (12-17 years)
    		 49 57 106
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 7.2 ± 4.34 7.1 ± 4.39 -
    Sex: Female, Male
    Units: Participants
        Female
    		 115 107 222
        Male
    		 141 149 290
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 1 2
        Asian
    		 25 27 52
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 12 12 24
        White
    		 194 194 388
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 23 22 45
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 59 63 122
        Not Hispanic or Latino
    		 196 192 388
        Unknown or Not Reported
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    Apixaban
    Reporting group description
    		 Participants will be administered apixaban twice daily by mouth or via a NGT or GT according to weight range during approximately 28 days of induction chemotherapy including asparaginase. Weight range - Dose >/=35 kg - 2.5 mg twice daily <35 to 25 kg - 2 mg twice daily <25 to 18 kg - 1.5 mg twice daily <18 to 10.5 kg - 1 mg twice daily <10.5 to 6 kg - 0.5 mg twice daily

    Reporting group title
    Standard of Care
    Reporting group description
    		 No systemic anticoagulant prophylaxis during induction chemotherapy

    Subject analysis set title
    Participants ≥ 35 kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants will be administered 2.5 mg apixaban twice daily by mouth or via a NGT or GT during approximately 28 days of induction chemotherapy including asparaginase.

    Subject analysis set title
    Participants 25 to < 35 kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants will be administered 2 mg apixaban twice daily by mouth or via a NGT or GT during approximately 28 days of induction chemotherapy including asparaginase.

    Subject analysis set title
    Participants 18 to < 25 kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants will be administered 1.5 mg apixaban twice daily by mouth or via a NGT or GT during approximately 28 days of induction chemotherapy including asparaginase.

    Subject analysis set title
    Participants 10.5 to < 18 kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants will be administered 1 mg apixaban twice daily by mouth or via a NGT or GT during approximately 28 days of induction chemotherapy including asparaginase.

    Primary: Composite of Non-Fatal DVT, PE, and CVST, and VTE-Related-Death

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    End point title
    		 Composite of Non-Fatal DVT, PE, and CVST, and VTE-Related-Death
    End point description
    The number of non-fatal deep vein thromboses (DVT) (including asymptomatic and symptomatic), pulmonary embolism (PE), cerebral venous sinus thrombosis (CVST); and venous thromboembolism (VTE) related-death objectively confirmed by a blinded, independent adjudication committee. Symptomatic events are included during the intended treatment period. Asymptomatic events are included from scans up to Day 40.
    End point type
    Primary
    End point timeframe
    From first dose up to approximately 40 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    31
    45
    Statistical analysis title
    		 Statistical Analysis of Primary Efficacy Endpoint
    Comparison groups
    Standard of Care v Apixaban
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0403
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Primary: 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 major bleeding adjudicated by a blinded, independent adjudication committee. Adjudicated major bleeding is defined as bleeding that satisfies one or more of the following criteria: 1) fatal bleeding 2) clinically overt bleeding associated with a decrease in hemoglobin of at least 20g/L (ie, 2g/dL) in a 24-hour period 3) bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS; and/or 4) bleeding that requires surgical intervention in an operating suite, including interventional radiology.
    End point type
    Primary
    End point timeframe
    From first dose up to approximately 34 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    2
    2
    Statistical analysis title
    		 Statistical Analysis of Primary Safety Endpoint
    Comparison groups
    Apixaban v Standard of Care
    Number of subjects included in analysis
    512
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 1
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: The Number of Participants with Non-fatal Asymptomatic Deep Vein Thromboses (DVT)

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    End point title
    		 The Number of Participants with Non-fatal Asymptomatic Deep Vein Thromboses (DVT)
    End point description
    The number of participants with non-fatal asymptomatic deep vein thromboses (DVT) adjudicated by a blinded, independent adjudication committee
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 40 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    27
    38
    No statistical analyses for this end point

    Secondary: The Number of Participants with Non-fatal Symptomatic Deep Vein Thromboses (DVT)

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    End point title
    		 The Number of Participants with Non-fatal Symptomatic Deep Vein Thromboses (DVT)
    End point description
    The number of participants with non-fatal symptomatic deep vein thromboses (DVT) adjudicated by a blinded, independent adjudication committee
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 34 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    4
    6
    No statistical analyses for this end point

    Secondary: The Number of Participants with Non-fatal Pulmonary Embolism (PE)

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    End point title
    		 The Number of Participants with Non-fatal Pulmonary Embolism (PE)
    End point description
    The number of participants with non-fatal pulmonary embolism (PE) adjudicated by a blinded, independent adjudication committee
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 34 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: The Number of Participants with Cerebral Venous Sinus Thrombosis (CVST)

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    End point title
    		 The Number of Participants with Cerebral Venous Sinus Thrombosis (CVST)
    End point description
    The number of participants with cerebral venous sinus thrombosis (CVST) adjudicated by a blinded, independent adjudication committee
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 34 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    0
    1
    No statistical analyses for this end point

    Secondary: The Number of Participants with Venous Thromboembolism (VTE)-related-death

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    End point title
    		 The Number of Participants with Venous Thromboembolism (VTE)-related-death
    End point description
    The number of participants with venous thromboembolism (VTE)-related-death adjudicated by a blinded, independent adjudication committee
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 34 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: The Number of Participants with Major and Clinically Relevant Non-Major Bleeding (CRNMB)

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    End point title
    		 The Number of Participants with Major and Clinically Relevant Non-Major Bleeding (CRNMB)
    End point description
    The number of participants with major and clinically relevant non-major bleeding (CRNMB) adjudicated by a blinded, independent adjudication committee CRNM bleeding is defined as bleeding that satisfies one or both of the following: 1) overt bleeding for which blood product is administered and not directly attributable to the subject’s underlying medical condition and 2) 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 up to approximately 34 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    13
    5
    No statistical analyses for this end point

    Secondary: The Number of Participant Deaths

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    End point title
    		 The Number of Participant Deaths
    End point description
    The number of participant deaths adjudicated by a blinded, independent adjudication committee
    End point type
    Secondary
    End point timeframe
    From first dose date until the end of the treatment period + 30 days (Up to approximately 59 days)
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    1
    3
    No statistical analyses for this end point

    Secondary: The Number of Participants with an Arterial Thromboembolic Event

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    End point title
    		 The Number of Participants with an Arterial Thromboembolic Event
    End point description
    The number of participants with an arterial thromboembolic event including paradoxical embolism and stroke adjudicated by a blinded, independent adjudication committee
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 34 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: The Number of Participants with a CVAD-Related Infection

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    End point title
    		 The Number of Participants with a CVAD-Related Infection
    End point description
    The number of participants with a central venous access device (CVAD)-related infection adjudicated by a blinded, independent adjudication committee
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 34 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    1
    6
    No statistical analyses for this end point

    Secondary: The Number of Catheter Replacements Needed During the Study

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    End point title
    		 The Number of Catheter Replacements Needed During the Study
    End point description
    The number of catheter replacements needed during the study
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 34 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    3
    2
    No statistical analyses for this end point

    Secondary: The Number of CVAD Patency Restoration Events After Thrombolytic Therapy Use

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    End point title
    		 The Number of CVAD Patency Restoration Events After Thrombolytic Therapy Use
    End point description
    The number of central venous access device (CVAD) patency restoration events after thrombolytic therapy use
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 34 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: The Number Participants Experiencing Superficial Vein Thrombosis Events

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    End point title
    		 The Number Participants Experiencing Superficial Vein Thrombosis Events
    End point description
    The number participants experiencing superficial vein thrombosis events. Clots that occur in a superficial vein ie, cephalic vein, basilic vein (upper extremity) or saphenous vein (lower extremity) confirmed by radiographic imaging.
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 34 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    4
    2
    No statistical analyses for this end point

    Secondary: The Number of Participants with Clinically Relevant Non-Major Bleeding Events (CRNMB)

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    End point title
    		 The Number of Participants with Clinically Relevant Non-Major Bleeding Events (CRNMB)
    End point description
    The number of participants with clinically relevant non-major bleeding events (CRNMB) adjudicated by a blinded, independent adjudication committee. CRNM bleeding is defined as bleeding that satisfies one or both of the following: 1) overt bleeding for which blood product is administered and not directly attributable to the subject’s underlying medical condition and 2) 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 up to approximately 34 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    11
    3
    No statistical analyses for this end point

    Secondary: The Number of Participants with Minor Bleeding Events

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    End point title
    		 The Number of Participants with Minor Bleeding Events
    End point description
    The number of participants with minor bleeding events adjudicated by a blinded, independent adjudication committee. Minor bleeding defined as any overt or macroscopic evidence of bleeding that does not fulfill the criteria for either major bleeding or CRNMB
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 34 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Participants
    37
    20
    No statistical analyses for this end point

    Secondary: The Number of Platelet Transfusions Needed During the Study

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    End point title
    		 The Number of Platelet Transfusions Needed During the Study
    End point description
    The number of platelet transfusions needed during the study. The events are not adjudicated. A subject could have more than one platelet transfusion.
    End point type
    Secondary
    End point timeframe
    From first dose up to approximately 34 days after first dose
    End point values
    		 Apixaban Standard of Care
    Number of subjects analysed
    256
    256
    Units: Platelet Transfusions
    266
    248
    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
    The maximum observed concentration (Cmax) was measured to assess the pharmacokinetics of oral or enteric apixaban in pediatric subjects receiving induction chemotherapy.
    End point type
    Secondary
    End point timeframe
    pre-dose, 1-4 hours post dose
    End point values
    		 Participants ≥ 35 kg Participants 25 to < 35 kg Participants 18 to < 25 kg Participants 10.5 to < 18 kg
    Number of subjects analysed
    71
    30
    50
    73
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    56.5 ± 36.5
    63.6 ± 38.6
    61.4 ± 43.9
    54.2 ± 46.8
    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
    The trough observed concentration (Cmin) was measured to assess the pharmacokinetics of oral or enteric apixaban in pediatric subjects receiving induction chemotherapy.
    End point type
    Secondary
    End point timeframe
    pre-dose, 1-4 hours post dose
    End point values
    		 Participants ≥ 35 kg Participants 25 to < 35 kg Participants 18 to < 25 kg Participants 10.5 to < 18 kg
    Number of subjects analysed
    71
    30
    50
    73
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    18.8 ± 57.8
    18.1 ± 97.4
    12 ± 142
    12.9 ± 113
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-Time Curve [AUC(TAU)]

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    End point title
    		 Area Under the Concentration-Time Curve [AUC(TAU)]
    End point description
    The area under the concentration-time curve [AUC(TAU)] was measured to assess the pharmacokinetics of oral or enteric apixaban in pediatric subjects receiving induction chemotherapy.
    End point type
    Secondary
    End point timeframe
    pre-dose, 1-4 hours post dose
    End point values
    		 Participants ≥ 35 kg Participants 25 to < 35 kg Participants 18 to < 25 kg Participants 10.5 to < 18 kg
    Number of subjects analysed
    71
    30
    50
    73
    Units: ng•h/mL
        geometric mean (geometric coefficient of variation)
    470 ± 35.3
    510 ± 42.7
    453 ± 44.8
    416 ± 48.5
    No statistical analyses for this end point

    Secondary: Anti-FXa Activity

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    End point title
    		 Anti-FXa Activity [1]
    End point description
    Anti-FXa Activity was measured to characterize the relationship between apixaban plasma concentration and anti-FXa activity in pediatric subjects receiving induction chemotherapy
    End point type
    Secondary
    End point timeframe
    pre-dose and 2.5 hours after dosing on day 7. Day 8 and day 15.
    Notes
    [1] - 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: Anti-FXa Activity endpoint is measured for only participants randomized to apixaban.
    End point values
    		 Apixaban
    Number of subjects analysed
    210
    Units: Anti-FXa activity (ng/mL)
        arithmetic mean (standard deviation)
    70.1 ± 31.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAE's collected between first dose and 30 days after last dose of study therapy. NSAE's collected between first dose and 2 days after last dose of study therapy. All Cause Mortality collected from first dose up to DBL date: Sep-13-2021.
    Adverse event reporting additional description
    256 is the number of subjects who randomized to each of Apixaban or SOC arm respectively. Only 250 subjects received apixaban dose. So the additional 6 subjects who randomized to apixaban but received no dose were classified into SOC.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Standard of care
    Reporting group description
    		 Subjects with ALL or Lymphoblastic Lymphoma (T or B cell) received Standard of care with no administration of systemic prophylactic anticoagulant for approximately 28 days.

    Reporting group title
    Apixaban
    Reporting group description
    		 Subjects aged 1-18 years with Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (T or B cell) with body weight greater than or equal to (>=) 35 kilogram (kg) were administered 2.5 milligram (mg) Apixaban, less than 35 to 25 kg were administered 2 mg Apixaban, less than 25 to 18 kg were administered 1.5 mg Apixaban, less than 18 to 10.5 kg were administered 1 mg Apixaban, less than 10.5 to 6 kg were administered 0.5 mg Apixaban orally twice daily including Asparaginase for approximately 28 days

    Serious adverse events
    		 Standard of care Apixaban
    Total subjects affected by serious adverse events
         subjects affected / exposed
    83 / 262 (31.68%)
    91 / 250 (36.40%)
         number of deaths (all causes)
    4
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    6 / 262 (2.29%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    3 / 262 (1.15%)
    9 / 250 (3.60%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 262 (0.00%)
    3 / 250 (1.20%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    2 / 262 (0.76%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 262 (0.38%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device related thrombosis
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 262 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 262 (2.67%)
    7 / 250 (2.80%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    2 / 262 (0.76%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         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
    Testicular cyst
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heavy menstrual bleeding
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 262 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 262 (0.38%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human rhinovirus test positive
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Epidural haemorrhage
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis chemical
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post lumbar puncture syndrome
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    2 / 262 (0.76%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 262 (0.38%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Intracardiac thrombus
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumopericardium
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral venous sinus thrombosis
         subjects affected / exposed
    3 / 262 (1.15%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    2 / 262 (0.76%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Guillain-Barre syndrome
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukoencephalopathy
         subjects affected / exposed
    0 / 262 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    2 / 262 (0.76%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 262 (0.76%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 262 (1.15%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coagulopathy
         subjects affected / exposed
    1 / 262 (0.38%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    16 / 262 (6.11%)
    15 / 250 (6.00%)
         occurrences causally related to treatment / all
    0 / 17
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 262 (1.15%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Ocular hypertension
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 262 (1.15%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    5 / 262 (1.91%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    5 / 262 (1.91%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 262 (0.38%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 262 (1.15%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    3 / 262 (1.15%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 262 (0.38%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 262 (0.38%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         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 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 262 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (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
    Appendicitis
         subjects affected / exposed
    2 / 262 (0.76%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 262 (0.76%)
    3 / 250 (1.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fungal sepsis
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus bacteraemia
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective thrombosis
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 262 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 262 (1.15%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 262 (1.91%)
    6 / 250 (2.40%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 262 (0.38%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatococcal infection
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 262 (0.38%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 262 (0.00%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 262 (1.53%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 262 (0.76%)
    4 / 250 (1.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperlipidaemia
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 262 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 262 (0.38%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Standard of care Apixaban
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    211 / 262 (80.53%)
    221 / 250 (88.40%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    39 / 262 (14.89%)
    46 / 250 (18.40%)
         occurrences all number
    49
    68
    Aspartate aminotransferase increased
         subjects affected / exposed
    18 / 262 (6.87%)
    28 / 250 (11.20%)
         occurrences all number
    21
    35
    Blood bilirubin increased
         subjects affected / exposed
    16 / 262 (6.11%)
    17 / 250 (6.80%)
         occurrences all number
    21
    34
    Neutrophil count decreased
         subjects affected / exposed
    26 / 262 (9.92%)
    19 / 250 (7.60%)
         occurrences all number
    48
    38
    Platelet count decreased
         subjects affected / exposed
    55 / 262 (20.99%)
    53 / 250 (21.20%)
         occurrences all number
    122
    133
    White blood cell count decreased
         subjects affected / exposed
    28 / 262 (10.69%)
    20 / 250 (8.00%)
         occurrences all number
    65
    38
    Vascular disorders
    Hypertension
         subjects affected / exposed
    26 / 262 (9.92%)
    21 / 250 (8.40%)
         occurrences all number
    36
    29
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    13 / 262 (4.96%)
    15 / 250 (6.00%)
         occurrences all number
    16
    16
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 262 (7.63%)
    15 / 250 (6.00%)
         occurrences all number
    21
    17
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    88 / 262 (33.59%)
    81 / 250 (32.40%)
         occurrences all number
    173
    154
    Febrile neutropenia
         subjects affected / exposed
    7 / 262 (2.67%)
    13 / 250 (5.20%)
         occurrences all number
    7
    14
    Neutropenia
         subjects affected / exposed
    15 / 262 (5.73%)
    17 / 250 (6.80%)
         occurrences all number
    34
    42
    Thrombocytopenia
         subjects affected / exposed
    25 / 262 (9.54%)
    25 / 250 (10.00%)
         occurrences all number
    84
    67
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    20 / 262 (7.63%)
    14 / 250 (5.60%)
         occurrences all number
    20
    14
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    12 / 262 (4.58%)
    17 / 250 (6.80%)
         occurrences all number
    12
    17
    Abdominal pain
         subjects affected / exposed
    48 / 262 (18.32%)
    34 / 250 (13.60%)
         occurrences all number
    55
    40
    Constipation
         subjects affected / exposed
    50 / 262 (19.08%)
    54 / 250 (21.60%)
         occurrences all number
    52
    58
    Diarrhoea
         subjects affected / exposed
    16 / 262 (6.11%)
    24 / 250 (9.60%)
         occurrences all number
    18
    26
    Nausea
         subjects affected / exposed
    20 / 262 (7.63%)
    13 / 250 (5.20%)
         occurrences all number
    24
    14
    Vomiting
         subjects affected / exposed
    17 / 262 (6.49%)
    17 / 250 (6.80%)
         occurrences all number
    20
    19
    Stomatitis
         subjects affected / exposed
    15 / 262 (5.73%)
    12 / 250 (4.80%)
         occurrences all number
    20
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 262 (4.58%)
    16 / 250 (6.40%)
         occurrences all number
    12
    17
    Epistaxis
         subjects affected / exposed
    14 / 262 (5.34%)
    22 / 250 (8.80%)
         occurrences all number
    16
    32
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    19 / 262 (7.25%)
    28 / 250 (11.20%)
         occurrences all number
    19
    34
    Pain in extremity
         subjects affected / exposed
    25 / 262 (9.54%)
    27 / 250 (10.80%)
         occurrences all number
    27
    30
    Pain in jaw
         subjects affected / exposed
    15 / 262 (5.73%)
    14 / 250 (5.60%)
         occurrences all number
    16
    14
    Arthralgia
         subjects affected / exposed
    14 / 262 (5.34%)
    12 / 250 (4.80%)
         occurrences all number
    15
    12
    Muscular weakness
         subjects affected / exposed
    14 / 262 (5.34%)
    9 / 250 (3.60%)
         occurrences all number
    14
    9
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    30 / 262 (11.45%)
    19 / 250 (7.60%)
         occurrences all number
    54
    29
    Hypoalbuminaemia
         subjects affected / exposed
    34 / 262 (12.98%)
    29 / 250 (11.60%)
         occurrences all number
    41
    44
    Hyponatraemia
         subjects affected / exposed
    30 / 262 (11.45%)
    35 / 250 (14.00%)
         occurrences all number
    39
    54
    Hypocalcaemia
         subjects affected / exposed
    21 / 262 (8.02%)
    11 / 250 (4.40%)
         occurrences all number
    30
    16

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Aug 2015
    Dose adjustment, expanded age of eligible subjects, and exclusion Criteria updates
    14 Dec 2016
    Added to Secondary endpoints apixaban pharmacokinetics and anti-FXa activity. Exclusion criteria updates. Indicated that SAEs need to be collected up to 30 days after the last dose of study medication
    08 Dec 2017
    Changed apixaban dosing scheme from a mg/kg dosing to a fixed-dose, body weight-tiered regimen. Introduced the 0.5 mg tablet with dosing instructions. Changed design of study to indicate that all forms of asparaginase could be used. Changed enrollment to include children >/= 1 and < 18 years of age and >/=6 kg of weight.

    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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