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

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

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)

Study Overview

• Status: Completed
• Conditions: Lymphoma; Acute Lymphoblastic Leukemia
• Intervention / Treatment: Drug: Apixaban; Other: No systemic anticoagulant prophylaxis

• Study Type: Interventional
• Enrollment (Actual): 512
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • New Lambton Heights, New South Wales, Australia, 2305
      • Local Institution
  • Queensland
    • Sth Brisbane, Queensland, Australia, 4101
      • Queensland Children's Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre Clayton
    • Parkville, Victoria, Australia, 3052
      • Local Institution
• Belgium
  • Bruxelles, Belgium, 1200
    • Local Institution
  • Bruxelles, Belgium, 1020
    • Local Institution
  • Edegem, Belgium, 2650
    • Local Institution
  • Gent, Belgium, 9000
    • Local Institution
  • Leuven, Belgium, 3000
    • Local Institution
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T3B 6A8
      • Alberta Children's Hospital
    • Edmonton, Alberta, Canada, T6G 2B7
      • Local Institution
  • Newfoundland and Labrador
    • St, John's, Newfoundland and Labrador, Canada, A1B 3V6
      • Local Institution
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • Children's Hospital London Health Sciences Centre
    • Ottawa, Ontario, Canada, K1H 8L1
      • Children's Hospital of Eastern Ontario
• Czechia
  • Brno, Czechia, 613 00
    • Klinika detske onkologie
• Hungary
  • Budapest, Hungary, 1094
    • Local Institution
  • Debrecen, Hungary, 4032
    • Local Institution
  • Pecs, Hungary, 7623
    • Local Institution
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Local Institution
  • Seoul, Korea, Republic of, 03722
    • Local Institution
• Mexico
  • Distrito Federal
    • Df, Distrito Federal, Mexico, 04530
      • Local Institution
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44340
      • Local Institution
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64460
      • Local Institution
• New Zealand
  • Christchurch, New Zealand, 8011
    • Local Institution
• Poland
  • Wroclaw, Poland, 50-556
    • Klinika Transplantacji Szpiku Onkologii i Hematologii Dzieciecej
  • Zabrze, Poland, 41-800
    • Oddzial Hematologii i Onkologii Dzieciecej
• Puerto Rico
  • Caguas, Puerto Rico, 00725
    • Local Institution
• Russian Federation
  • Kirov, Russian Federation, 610027
    • Local Institution
  • Moscow, Russian Federation, 115478
    • Local Institution
  • Moscow, Russian Federation, 117198
    • Local Institution
  • Saint Petersburg, Russian Federation, 197758
    • Local Institution
  • St.petersburg, Russian Federation, 197341
    • Local Institution
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children'S Hospital/Ctr. For Cancer & Blood Ctr.
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Loma Linda, California, United States, 92350
      • Loma Linda University Cancer Center
    • Los Angeles, California, United States, 90027
      • Childrens Hospital of LA
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital (LPCH)
    • San Diego, California, United States, 92123-4282
      • Rady Children's Hospital - San Diego
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Connecticut Children's Medical Center
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine
  • Delaware
    • Wilmington, Delaware, United States, 19803
      • Nemours / A. I. duPont Hospital for Children
  • Florida
    • Fort Myers, Florida, United States, 33908
      • Golisano Childrens Hospital of Southwest Florida
    • Gainesville, Florida, United States, 32610-0298
      • Shands Hospital at University of Florida
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic
    • Orlando, Florida, United States, 32827
      • Nemours Children's Clinic - Orlando
    • Pensacola, Florida, United States, 32504
      • Nemours Children'S Clinic-Pensacola
    • Saint Petersburg, Florida, United States, 33701
      • All Childrens Hospital Specialty Physicians
    • West Palm Beach, Florida, United States, 33407
      • St. Marys Medical Center
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Childrens Healthcare Of Atlanta - E
    • Macon, Georgia, United States, 31201
      • Navicent Health Physician Group
  • Idaho
    • Boise, Idaho, United States, 83712
      • St. Luke's Mountain State Tumor Institute
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Children'S Center For Cancer And Blood Diseases
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • Blank Childrens Hospital
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0293
      • University of Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center
    • New Orleans, Louisiana, United States, 70118
      • Childrens Hospital New Orleans
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Sinai Hospital of Baltimore
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Cancer Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Childrens Hospitals and Clinics of Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Rochester
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
    • Paterson, New Jersey, United States, 07503
      • Valerie Fund Children's Center at St. Joseph's Children's Hospital
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • Rochester, New York, United States, 14642
      • University Of Rochester General Clinical Research Center
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
    • Valhalla, New York, United States, 10595
      • New York Medical College
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Unv. Of Nc At Chapel Hill
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest Baptist Health
  • Ohio
    • Akron, Ohio, United States, 44308
      • Akron Children's Hospital
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • University Hospitals
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
      • Lehigh Valley Hospital - Muhlenberg
    • Danville, Pennsylvania, United States, 17822
      • Geisinger Medical Center
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Philadelphia, Pennsylvania, United States, 19104
      • Childrens Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Children's Hospital at TriStar Centennial
    • Nashville, Tennessee, United States, 37232
      • Monroe Carell Jr Children'S Hosp. At Vanderbilt Tower
  • Texas
    • Austin, Texas, United States, 78723
      • Dell Children's Medical Center of Central Texas
    • Corpus Christi, Texas, United States, 78411
      • Driscoll Children's Hospital
    • Houston, Texas, United States, 77030
      • Texas Children's Cancer and Hematology Centers
    • San Antonio, Texas, United States, 78207
      • Children's Hospital of San Antonio
    • San Antonio, Texas, United States, 78284
      • University Hospital
    • Temple, Texas, United States, 76502
      • Scott & White - McLane Children's Specialty Clinic
  • Washington
    • Spokane, Washington, United States, 99204
      • Providence Sacred Heart Medical Center
    • Tacoma, Washington, United States, 98405
      • MultiCare Institute for Research & Innovation
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Apixaban; 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
Placebo Comparator: No systemic anticoagulant prophylaxis	Other: No systemic anticoagulant prophylaxis

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Collaborators: Pfizer

Publications and helpful links

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• Investigator Inquiry Form
• FDA Safety Alerts and Recalls

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2015
• Primary Completion (Actual): July 7, 2021
• Study Completion (Actual): July 7, 2021

Study Registration Dates

• First Submitted: January 21, 2015
• First Submitted That Met QC Criteria: February 18, 2015
• First Posted (Estimate): February 24, 2015

Study Record Updates

• Last Update Posted (Actual): March 8, 2022
• Last Update Submitted That Met QC Criteria: February 10, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Anticoagulation
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Apixaban; Anticoagulants
• Other Study ID Numbers: CV185-155; 2014-000328-47 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No