Apixaban for the Acute Treatment of Venous Thromboembolism in Children
- Registration Number
- NCT02464969
- Lead Sponsor
- Bristol-Myers Squibb
- Brief Summary
To assess the safety and descriptive efficacy of apixaban in pediatric subjects requiring anticoagulation for the treatment of a VTE.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 229
- Birth to <18 years of age with a minimum weight of 2.6 kg at the time of randomization.
- Presence of an index VTE which is confirmed by imaging.
- Intention to manage the index VTE with anticoagulation treatment for at least 6 to 12 weeks.
- Subjects able to tolerate oral feeding, nasogastric (NG), gastric (G) feeding and are currently tolerating enteric medications, as per investigator's judgement.
- Anticoagulant treatment for the index VTE for greater than 14 days prior to randomization. Neonates that are enrolled into the PK cohort must be on a minimum of 5 days and a maximum of 14 days SOC anticoagulation prior to randomization. Neonates that are enrolled into the post PK cohort may receive SOC anticoagulation for up to 14 days prior to randomization.
- Thrombectomy, thrombolytic therapy, or insertion of a caval filter to treat the index VTE.
- A mechanical heart valve.
- Active bleeding or high risk of bleeding at the time of randomization.
- Intracranial bleed, including intraventricular hemorrhage, within 3 months prior to randomization.
- Abnormal baseline liver function at randomization.
- Inadequate renal function at the time of randomization.
- Platelet count <50×109 per L at randomization.
- Uncontrolled severe hypertension at the time of randomization.
- Use of prohibited concomitant medication at the time of randomization.
- Female subjects who are either pregnant or breastfeeding a child.
- Use of aggressive life-saving therapies such as ventricular assist devices (VAD) or extracorporeal membrane oxygenation (ECMO) at the time of enrollment.
- Unable to take oral or enteric medication via the NG or G tube.
- Known inherited or acquired antiphospholipid syndrome (APS).
- Known inherited bleeding disorder or coagulopathy with increased bleeding risk (eg, hemophilia, von Willebrand disease, etc.)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Apixaban Standard of Care Subjects between birth to \<18 years will be dosed on a body weight tiered regimen. Subjects ≥35kg will receive 10mg twice daily(BID) for 7 days followed by 5mg BID thereafter;\<35kg to 25kg will receive 8mg BID for 7 days followed by 4mg BID thereafter;\<25 to 18kg will receive 6mg BID for 7 days and then 3mg BID thereafter;\<18 to 12kg will receive 4mg BID for 7 days and then 2mg BID thereafter;\<12 to 9kg will receive 3mg BID for 7 days and then 1.5mg BID thereafter;\< 9kg to 6kg will receive 2 mg BID for 7 days and 1mg BID thereafter;\<6kg to 5kg will receive 1mg BID for 7 days and 0.5mg BID thereafter;\<5kg to 4kg will receive 0.6mg twice daily for 7 days and 0.3mg BID thereafter;PK cohort neonates ≥ 2.6kg will receive 0.1mg BID. Dose will be adjusted as determined by PK measurements (ie, to 0.2mg BID, 0.1mg daily or dose will stay the same).For the post PK cohort Neonates ˂4kg to 2.6kg, if confirmed by PK sub analysis,subjects will receive 0.2mg BID for 7 days and 0.1mg BID thereafter. Apixaban Apixaban Subjects between birth to \<18 years will be dosed on a body weight tiered regimen. Subjects ≥35kg will receive 10mg twice daily(BID) for 7 days followed by 5mg BID thereafter;\<35kg to 25kg will receive 8mg BID for 7 days followed by 4mg BID thereafter;\<25 to 18kg will receive 6mg BID for 7 days and then 3mg BID thereafter;\<18 to 12kg will receive 4mg BID for 7 days and then 2mg BID thereafter;\<12 to 9kg will receive 3mg BID for 7 days and then 1.5mg BID thereafter;\< 9kg to 6kg will receive 2 mg BID for 7 days and 1mg BID thereafter;\<6kg to 5kg will receive 1mg BID for 7 days and 0.5mg BID thereafter;\<5kg to 4kg will receive 0.6mg twice daily for 7 days and 0.3mg BID thereafter;PK cohort neonates ≥ 2.6kg will receive 0.1mg BID. Dose will be adjusted as determined by PK measurements (ie, to 0.2mg BID, 0.1mg daily or dose will stay the same).For the post PK cohort Neonates ˂4kg to 2.6kg, if confirmed by PK sub analysis,subjects will receive 0.2mg BID for 7 days and 0.1mg BID thereafter.
- Primary Outcome Measures
Name Time Method Percentage of Participants With Composite of Major and Clinically Relevant Non-Major (CRNM) Bleeding From first dose (Day 1) up to 114 days Bleeding definitions are based on the Perinatal and Paediatric Haemostasis Subcommittee of the International Society on Thrombosis and Haemostasis (ISTH) criteria. Major bleeding includes: (i) fatal bleeding; (ii) clinically overt bleeding with a decrease in Hgb of at least 20 g/L (2 g/dL) in 24 hours; (iii) retroperitoneal, pulmonary, intracranial, or central nervous system bleeding; and (iv) bleeding requiring surgical intervention in an operating suite (including interventional radiology). Clinically relevant non-major bleeding includes: (i) overt bleeding requiring a blood product not attributable to the participant's underlying condition; and (ii) bleeding requiring medical or surgical intervention to restore hemostasis, other than in an operating suite.
Percentage of Participants With Symptomatic and Asymptomatic Recurrent Venous Thromboembolism (VTE) and VTE-Related Mortality From first dose (Day 1) up to 114 days Recurrent VTE, defined as either contiguous progression or non-contiguous new thrombus and including, but not limited to deep vein thrombosis (DVT), pulmonary embolism (PE) and paradoxical embolism. 95% CI was from the Agresti-Coull method.
- Secondary Outcome Measures
Name Time Method Percentage of Participants Who Died From first dose (Day 1) up to 114 days Death due to any cause was assessed. 95% CI was calculated using the Agresti-Coull method.
Percentage of Participants With Venous Thromboembolism (VTE)-Related Mortality From first dose (Day 1) up to 114 days Participants were assessed for death due to Venous Thromboembolism (VTE).
Number of Participants With Index Venous Thromboembolism (VTE) Status From first dose (Day 1) up to 91 days Index VTE status was defined as the last image obtained during the Main treatment phase for each participant's comparison to baseline imaging. Index VTE status was classified as Recurrence-contiguous; Recurrence-new; Unchanged; Regression; Resolution; Indeterminate/Nondiagnostic. Participants could have multiple concomitant index events. Regression was defined as (ie, unequivocal decrease \[\>50%\] of the total volume/mass of the thrombus compared to the index event)
Percentage of Participants With Stroke From first dose (Day 1) up to 114 days Participants were assessed for incidence of stroke.
Percentage of Participants With Symptomatic and Asymptomatic Recurrent Venous Thromboembolism (VTE) From first dose (Day 1) up to 114 days Recurrent VTE, defined as either contiguous progression or non-contiguous new thrombus and including, but not limited to deep vein thrombosis (DVT), pulmonary embolism (PE) and paradoxical embolism. 95% CI was from the Agresti-Coull method.
Number of Participants With New Symptomatic or Asymptomatic Deep Vein Thrombosis (DVT) and New Symptomatic or Asymptomatic Pulmonary Embolism (PE) From first dose (Day 1) up to 114 days Participants were assessed for incidence of Symptomatic or Asymptomatic Deep Vein Thrombosis (DVT) and New Symptomatic or Asymptomatic Pulmonary Embolism (PE).
Percentage of Participants With Other Symptomatic and Asymptomatic Venous Thromboembolism (VTE) From first dose (Day 1) up to 114 days Other VTE included events such as cerebral sinovenous thrombosis, renal vein thrombosis, portal vein thrombosis, catheter-related VTE, and splanchnic thrombosis. If VTE event type was blank, it was included in the Other VTE. 95% CI was from the Agresti-Coull method.
Number of Participants With Clinically Relevant Non-Major (CRNM) Bleeding, Major Bleeding and Minor Bleeding From first dose (Day 1) up to 114 days Bleeding definitions are based on the Perinatal and Paediatric Haemostasis Subcommittee of the International Society on Thrombosis and Haemostasis (ISTH) criteria. Major bleeding includes: (i) fatal bleeding; (ii) clinically overt bleeding with a decrease in Hgb of at least 20 g/L (2 g/dL) in 24 hours; (iii) retroperitoneal, pulmonary, intracranial, or central nervous system bleeding; and (iv) bleeding requiring surgical intervention in an operating suite (including interventional radiology). Clinically relevant non-major bleeding includes: (i) overt bleeding requiring a blood product not attributable to the participant's underlying condition; and (ii) bleeding requiring medical or surgical intervention to restore hemostasis, other than in an operating suite. Minor bleeding was defined as any overt or macroscopic evidence of bleeding that does not fulfill the above criteria for either major bleeding or clinically relevant, non-major bleeding.
Blood Concentration of Apixaban (ng/mL) 3 hour (H), 12 H, 24 H at Day 3; pre and post dose at Day 14 and Day 42 Blood samples were collected to assess the apixaban concentration at specified timepoints. Day 1 PK concentrations were only collected for participants in the Birth to ≤27 days arm. The lower limit of quantification (LLOQ) is 1.0 ng/mL for plasma samples, and 0.5 ng/mL for dried blood samples.
Concentration of Plasma Anti-Factor Xa (ng/mL) Pre and post dose at Day 14 and Day 42 Blood samples were collected to assess the Anti-Factor Xa concentration at specified timepoints. Day 1 PK concentrations were only collected for participants in the Birth to ≤27 days arm. The lower limit of quantification (LLOQ) is 35.0 ng/mL.
Trial Locations
- Locations (127)
Loma Linda University Medical Center
🇺🇸Loma Linda, California, United States
Loma Linda University Cancer Center
🇺🇸Loma Linda, California, United States
UF Health Shands Hospital
🇺🇸Gainesville, Florida, United States
Lucile Packard Children's Hosptial - Stanford University
🇺🇸Palo Alto, California, United States
Memorial Regional Hospital
🇺🇸Hollywood, Florida, United States
SUNY Upstate Medical University
🇺🇸Syracuse, New York, United States
Bass Speicalty Pharmacy
🇺🇸Palo Alto, California, United States
Inpatient Pharmacy
🇺🇸Palo Alto, California, United States
Children's Healthcare of Atlanta-Egleston
🇺🇸Atlanta, Georgia, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
CHU de Bordeaux - Hopital Haut-Leveque
🇫🇷PESSAC Cedex, France
Charite - Universitaetsmedizin Berlin - Campus Virchow-Klinikum (CVK)
🇩🇪Berlin, Germany
Hospital Universitario HM Monteprincipe
🇪🇸Boadilla del Monte, Madrid, Spain
CHRU de Montpellier - Hopital Arnaud de Villeneuve
🇫🇷Montpellier Cedex 5, France
University of Kentucky Medical Center
🇺🇸Lexington, Kentucky, United States
New York-Presbyterian Morgan Stanley Children's Hospital
🇺🇸New York, New York, United States
Levine Children's Hospital, Pediatric Research
🇺🇸Charlotte, North Carolina, United States
Universitätsklinikum Essen
🇩🇪Essen, Germany
Hospital Universitario Vall d´Hebron
🇪🇸Barcelona, Spain
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Adana Acibadem Hospital
🇹🇷Seyhan, Adana, Turkey
Hamilton Health Science Corporation/McMaster Children's Hospital
🇨🇦Hamilton, Ontario, Canada
Birmingham Women's and Children's NHS Foundation Trust
🇬🇧Birmingham, WEST Midlands, United Kingdom
University Hospitals Cleveland Medical Center
🇺🇸Cleveland, Ohio, United States
Cleveland Clinic
🇺🇸Cleveland, Ohio, United States
Texas Children's Hospital- Main Hospital
🇺🇸Houston, Texas, United States
Seattle Children's Hospital
🇺🇸Seattle, Washington, United States
Valley Children's Hospital
🇺🇸Madera, California, United States
Children's Hospital and Research Center Oakland
🇺🇸Oakland, California, United States
Nemours/ Alfred I. duPont Hospital for Children
🇺🇸Wilmington, Delaware, United States
JDCH Division of Pediatric Hematology and Oncology
🇺🇸Hollywood, Florida, United States
Connecticut Children's Medical Center Pharmacy
🇺🇸Hartford, Connecticut, United States
Children's Healthcare of Atlanta Center for Advanced Pediatrics-IDS Pharmacy
🇺🇸Atlanta, Georgia, United States
Bleeding and Clotting Disorders Institute
🇺🇸Peoria, Illinois, United States
Riley Hospital for Children at IU Health
🇺🇸Indianapolis, Indiana, United States
University of Iowa Hospitals and Clinics
🇺🇸Iowa City, Iowa, United States
Sanford Roger Maris Cancer Center
🇺🇸Fargo, North Dakota, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
Texas Children's Hospital- Wallace Tower
🇺🇸Houston, Texas, United States
Prince of Wales Hospital
🇦🇺Sydney, New South Wales, Australia
Kids Cancer Centre
🇦🇺Randwick, New South Wales, Australia
The Royal Childrens Hospital
🇦🇺Parkville, Victoria, Australia
Technische Universitat, Deutsches Herzzentrum Munchen
🇩🇪Munchen, Germany
Instituto Nacional De Cardiologia Ignacio Chavez
🇲🇽Mexico City, Mexico
State Autonomous Healthcare Institution of Sverdlovsk Region
🇷🇺Yekaterinburg, Sverdlovsk Region, Russian Federation
Hospital Sant Joan de Deu
🇪🇸Esplugues de Llobregat, Barcelona, Spain
Communal Enterprise "Dnipropetrovsk Specialized Clinical Medical Center of Mother and Child
🇺🇦Dnipro, Ukraine
Municipal enterprise "Dnipropetrovsk Regional Children's Clinical Hospital"
🇺🇦Dnipro, Ukraine
Newcastle Upon Tyne Hospitals NHS Foundation Trust
🇬🇧Newcastle upon Tyne, Tyne & Wear, United Kingdom
IU Health Pharmacy
🇺🇸Indianapolis, Indiana, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
The Children's Hospital of San Antonio
🇺🇸San Antonio, Texas, United States
University of Texas Health San Antonio
🇺🇸San Antonio, Texas, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Investigational Drug Service, Duke University Hospital
🇺🇸Durham, North Carolina, United States
Sanford Children's Hospital
🇺🇸Fargo, North Dakota, United States
Pediatric Cardiology Clinic
🇺🇸Birmingham, Alabama, United States
University of Alabama
🇺🇸Birmingham, Alabama, United States
Phoenix Children's Hospital
🇺🇸Phoenix, Arizona, United States
UCSF Benioff Children's Hospital
🇺🇸San Francisco, California, United States
UCSF Mission Bay Pediatric Clinical Research Center
🇺🇸San Francisco, California, United States
OU Medical Center Investigational Drug Pharmacy
🇺🇸Oklahoma City, Oklahoma, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Monroe Carell Jr. Children's Hospital at Vanderbilt
🇺🇸Nashville, Tennessee, United States
Primary Children's Hospital
🇺🇸Salt Lake City, Utah, United States
Birmingham Children's Hospital NHS Foundation Trust
🇬🇧Birmingham, WEST Midlands, United Kingdom
Hopital de la Timone Enfants
🇫🇷Marseille, France
Hopital Necker-Enfants malades
🇫🇷Paris, France
Service d'Imagerie Medicale du Pr F. Laurent
🇫🇷PESSAC Cedex, France
The Hospital For Sick Children
🇨🇦Toronto, Ontario, Canada
Loma Linda University Children's Hospital
🇺🇸Loma Linda, California, United States
Loma Linda University Health Care
🇺🇸San Bernardino, California, United States
Joe DiMaggio Children's Hospital
🇺🇸Hollywood, Florida, United States
Nicklaus Children's Hospital
🇺🇸Miami, Florida, United States
Children's Hematology and Oncology a division of Kidz medical Service
🇺🇸West Palm Beach, Florida, United States
Children's Healthcare of Atlanta Center for Advanced Pediatrics - Pediatric Research Unit
🇺🇸Atlanta, Georgia, United States
Unity Point Methodist Medical Center
🇺🇸Peoria, Illinois, United States
St. Mary's Medical Center
🇺🇸West Palm Beach, Florida, United States
OSF Saint Francis Medical Center
🇺🇸Peoria, Illinois, United States
Levine Children's Specialty Center
🇺🇸Charlotte, North Carolina, United States
Levine Children's Hospital
🇺🇸Charlotte, North Carolina, United States
Akron Children's Hospital
🇺🇸Akron, Ohio, United States
The Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
St. Christopher's Hospital for Children
🇺🇸Philadelphia, Pennsylvania, United States
UPMC Children's Hospital of Pittsburgh
🇺🇸Pittsburgh, Pennsylvania, United States
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
Indiana University
🇺🇸Indianapolis, Indiana, United States
Ann & Robert H Lurie Children's Hospital of Chicago
🇺🇸Chicago, Illinois, United States
University of California Davis Comprehensive Cancer Center
🇺🇸Sacramento, California, United States
AdventHealth Orlando
🇺🇸Orlando, Florida, United States
Children's Hospital Colorado - Investigational Drug Services
🇺🇸Aurora, Colorado, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
AdventHealth Orlando-Pharmacy Investigational Drug Services
🇺🇸Orlando, Florida, United States
AdventHealth Pediatric Oncology Hematology at Orlando
🇺🇸Orlando, Florida, United States
St. Joseph's Hospital
🇺🇸Tampa, Florida, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Children's Hospital of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Versiti Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Children's Mercy Hospital
🇺🇸Kansas City, Missouri, United States
Medical University of South Carolina: Investigational Drug Services
🇺🇸Charleston, South Carolina, United States
Medical University of South Carolina: Shawn Jenkins Women's and Children's Hospital
🇺🇸Charleston, South Carolina, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Connecticut Children's Medical Center
🇺🇸Hartford, Connecticut, United States
Hadassah Medical Center (Ein Kerem)
🇮🇱Jerusalem, Israel
Dnipropetrovsk Regional Children's Hospital
🇺🇦Dnipro, Ukraine
Childrens National Medical Center
🇺🇸Washington, District of Columbia, United States
A.o.Landeskrankenhaus Innsbruck
🇦🇹Innsbruck, Tyrol, Austria
Royal Hospital for Children
🇬🇧Glasgow, Scotland, United Kingdom
Noah's Ark Children's Hospital for Wales
🇬🇧Cardiff, Wales, United Kingdom
Communal Institution "Zaporizhzhia Regional Clinical Children's Hospital"
🇺🇦Zaporizhzhia, Ukraine
Stollery Children's Hospital
🇨🇦Edmonton, Alberta, Canada
O.P.D Hospital Civil de Guadalajara, Hospital Civil Fray Antonio Alcalde
🇲🇽Guadalajara, Jalisco, Mexico
FSBI "NRMC PHOI n.a.Dmitry Rogachev" of Minzdrav Russia
🇷🇺Moscow, Russian Federation
Cardiff & Vale NHS Health Board
🇬🇧Cardiff, Wales, United Kingdom
State Autonomous Healthcare Institution "Children's Republican Clinical Hospital of Ministry of
🇷🇺Kazan, Republic Tatarstan, Russian Federation
Baskent Universitesi Tip Fakultesi Cocuk Sagligi ve Hastaliklari ABD Cocuk Hematoloji Onkoloji BD
🇹🇷Bahcelievler, Ankara, Turkey
Ege Universitesi Tip Fakultesi Cocuk Hastanesi Cocuk Hematoloji Bilim Dali
🇹🇷Izmir, Turkey
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
University of Mississippi Medical Center
🇺🇸Jackson, Mississippi, United States
Children's Hospital of Michigan
🇺🇸Detroit, Michigan, United States
Medizinische Universitaet Innsbruck
🇦🇹Innsbruck, Austria
Hacettepe University Faculty of Medicine, Ihsan Dogramaci Children's Hospital
🇹🇷Ankara, Turkey
Medizinische Universitaet Wien
🇦🇹Wien, Austria
CHU Sainte-Justine
🇨🇦Montreal, Quebec, Canada
Ankara City Hospital Pediatric Hematology and Oncology Clinic
🇹🇷Ankara, Turkey
Kaye Edmonton Clinic
🇨🇦Edmonton, Alberta, Canada