A Study of the Safety and Effectiveness of Apixaban in Preventing Blood Clots in Children With Leukemia Who Have a Central Venous Catheter and Are Treated With Asparaginase

Study Overview
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Brief Summary
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The purpose of this study is to compare the effect of a blood thinning drug called Apixaban versus no administration of a blood thinning drug, in preventing blood clots in children with leukemia or lymphoma. Patients must be receiving chemotherapy, including asparaginase, and have a central line (a catheter inserted for administration of medications and blood sampling)

Official Title
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A Phase III Randomized, Open Label, Multi-center Study of the Safety and Efficacy of Apixaban for Thromboembolism Prevention Versus No Systemic Anticoagulant Prophylaxis During Induction Chemotherapy in Children With Newly Diagnosed Acute Lymphoblastic Leukemia (ALL) or Lymphoma (T or B Cell) Treated With Asparaginase

Conditions
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Lymphoma, Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Apixaban
* Other: No systemic anticoagulant prophylaxis


Participation Criteria
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Eligibility Criteria
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For more information regarding BMS clinical trial participation, please visit www.BMSStudyConnect.com Inclusion Criteria: New diagnosis of de novo ALL, lymphomas (T or B cell), or mixed-phenotype acute leukemia Planned 3-4 drug systemic induction chemotherapy with a corticosteroid, vincristine and a single dose or multiple doses of asparaginase, with or without daunorubicin Functioning Central Venous Access Device Must be able to tolerate oral medication or have it administered via an Nasogastric tube (NGT) or GT tube Males and females,age 1 year(365 days) to < 18 (17 years and 364 days) years. Exclusion Criteria: Subjects scheduled to have > 3 Lumbar Punctures over the course of the study treatment period Prior history of documented DVT or PE in the past 3 months Known inherited bleeding disorder or coagulopathy Major surgery [excluding Central Venous Access Device (CVAD) replacement and bone marrow aspiration and non-open biopsy] within the last 7 days prior to enrollment that may be associated with a risk of bleeding. Open biopsy is considered a major surgery. Uncontrolled severe hypertension at enrollment. Severe hypertension is defined as a systolic or diastolic blood pressure (BP) > 5 mm Hg above the 95th percentile as defined by the National High Blood Pressure Education Program Working Group (NHBPEP) established guidelines for the definition of normal and elevated blood pressure in children Extreme hyperleukocytosis, white blood cell (WBC) counts over 200 x 109/L (200,000/microL) at the time of enrollment Liver dysfunction manifested by SGTP (ALT) > 5X Upper limit of normal (ULN) and/or Aspartate aminotransferase (AST) >5 X ULN and/or direct (conjugated) bilirubin > 2X ULN Renal function < 30% of normal for age and size as determined by the Schwartz formula International normalized ratio (INR) > 1.4 and activated partial thromboplastin time (aPTT) > 3 seconds above the upper limit of normal for age, within 1 week prior to enrollment. History of allergy to apixaban or Factor Xa inhibitors History of significant adverse reaction or major bleeding related adverse reaction to other anticoagulant or antiplatelet agents History of any significant drug allergy (such as anaphylaxis or hepatotoxicity Any investigational drug being administered during the study Other protocol inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Apixaban<br>Children aged 1 to <18 years weighing 6 to <35 kg randomized to apixaban will receive a fixed dose apixaban based on body weight tier twice a day for approximately 28 days. Children aged 1 to <18 years weighing ≥ 35 kg will receive 2.5 mg of apixaban twice a day for approximately 28 days. Subjects ≥ 5 years may be administered either 2.5-mg, 0.5-mg tablets or oral solution apixaban. Subjects < 5years and < 35 kg may be administered 0.5-mg tablets only | Drug: Apixaban<br> <br> |
| Placebo Comparator: No systemic anticoagulant prophylaxis<br>No systemic anticoagulant prophylaxis | Other: No systemic anticoagulant prophylaxis<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants With Non-Fatal DVT, PE, and CVST, and VTE-Related-Death | The number of participants with 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. | From first dose up to approximately 40 days after first dose | 
| The Number of Participants With Adjudicated Major Bleeding | 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: fatal bleeding clinically overt bleeding associated with a decrease in hemoglobin of at least 20g/L (ie, 2g/dL) in a 24-hour period bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS; and/or bleeding that requires surgical intervention in an operating suite, including interventional radiology. | From first dose up to approximately 34 days after first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants With Non-fatal Asymptomatic Deep Vein Thromboses (DVT) | The number of participants with non-fatal asymptomatic deep vein thromboses (DVT) adjudicated by a blinded, independent adjudication committee | From first dose up to approximately 40 days after first dose | 
| The Number of Participants With Non-fatal Symptomatic Deep Vein Thromboses (DVT) | The number of participants with non-fatal symptomatic deep vein thromboses (DVT) adjudicated by a blinded, independent adjudication committee | From first dose up to approximately 34 days after first dose | 
| The Number of Participants With Non-fatal Pulmonary Embolism (PE) | The number of participants with non-fatal pulmonary embolism (PE) adjudicated by a blinded, independent adjudication committee | From first dose up to approximately 34 days after first dose | 
| The Number of Participants With Cerebral Venous Sinus Thrombosis (CVST) | The number of participants with cerebral venous sinus thrombosis (CVST) adjudicated by a blinded, independent adjudication committee | From first dose up to approximately 34 days after first dose | 
| The Number of Participants With Venous Thromboembolism (VTE)-Related-death | The number of participants with venous thromboembolism (VTE)-related-death adjudicated by a blinded, independent adjudication committee | From first dose up to approximately 34 days after first dose | 
| The Number of Participants With Major and Clinically Relevant Non-Major Bleeding (CRNMB) | 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: overt bleeding for which blood product is administered and not directly attributable to the subject's underlying medical condition and bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating room | From first dose up to approximately 34 days after first dose | 
| The Number of Participant Deaths | The number of participant deaths adjudicated by a blinded, independent adjudication committee | From first dose date until the end of the treatment period + 30 days (Up to approximately 59 days) | 
| The Number of Participants With an Arterial Thromboembolic Event | The number of participants with an arterial thromboembolic event including paradoxical embolism and stroke adjudicated by a blinded, independent adjudication committee | From first dose up to approximately 34 days after first dose | 
| The Number of Participants With a CVAD-Related Infection | The number of participants with a central venous access device (CVAD)-related infection adjudicated by a blinded, independent adjudication committee | From first dose up to approximately 34 days after first dose | 
| The Number of Participants Needing Catheter Replacements During the Study | The number of participants needing catheter replacements during the study | From first dose up to approximately 34 days after first dose | 
| The Number of Participants With CVAD Patency Restoration Events After Thrombolytic Therapy Use | The number of participants with central venous access device (CVAD) patency restoration events after thrombolytic therapy use | From first dose up to approximately 34 days after first dose | 
| The Number Participants Experiencing Superficial Vein Thrombosis Events | 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. | From first dose up to approximately 34 days after first dose | 
| The Number of Participants With Clinically Relevant Non-Major Bleeding Events (CRNMB) | 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: overt bleeding for which blood product is administered and not directly attributable to the subject's underlying medical condition and bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating room | From first dose up to approximately 34 days after first dose | 
| The Number of Participants With Minor Bleeding Events | 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 | From first dose up to approximately 34 days after first dose | 
| The Number of Platelet Transfusions Needed During the Study | The number of platelet transfusions needed during the study. The events are not adjudicated. A subject could have more than one platelet transfusion. | From first dose up to approximately 34 days after first dose | 
| Maximum Observed Concentration (Cmax) | The maximum observed concentration (Cmax) was measured to assess the pharmacokinetics of oral or enteric apixaban in pediatric subjects receiving induction chemotherapy. | pre-dose, 1-4 hours post dose | 
| Trough Observed Concentration (Cmin) | The trough observed concentration (Cmin) was measured to assess the pharmacokinetics of oral or enteric apixaban in pediatric subjects receiving induction chemotherapy. | pre-dose, 1-4 hours post dose | 
| Area Under the Concentration-Time Curve [AUC(TAU)] | 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. | pre-dose, 1-4 hours post dose | 
| Anti-FXa Activity | Anti-FXa Activity was measured to characterize the relationship between apixaban plasma concentration and anti-FXa activity in pediatric subjects receiving induction chemotherapy | pre-dose and 2.5 hours after dosing on day 7. Day 8 and day 15. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Anticoagulation