A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist (VKA) or Low Molecular Weight Heparin (LMWH) in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation

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

To investigate the safety and pharmacokinetics of apixaban in children with congenital or acquired heart disease who have a need for anticoagulation.

Study Overview

• Status: Completed
• Conditions: Thrombosis
• Intervention / Treatment: Drug: Apixaban; Drug: Vitamin K Antagonist (VKA); Drug: Low Molecular Weight Heparin (LMWH)

• Study Type: Interventional
• Enrollment (Actual): 192
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, 1426
      • Local Institution
• Australia
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Local Institution - 0030
• Austria
  • Vienna, Austria, 1090
    • Local Institution - 0001
• Brazil
  • Sao Paulo, Brazil, 01227-200
    • Instituto de Pesquisa PENSI
  • Sao Paulo, Brazil, 04024-002
    • Universidade Federal de Sao Paulo
  • Parana
    • Curitiba, Parana, Brazil, 80250-060
      • Local Institution - 0022
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90620-001
      • Instituto de Cardiologia do Rio Grande do Sul
  • Sao Paulo
    • Campinas, Sao Paulo, Brazil, 13060-080
      • Local Institution - 0020
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Local Institution - 0015
• Finland
  • HUS, Finland, 00029
    • Local Institution - 0031
• Germany
  • Freiburg, Germany, 79106
    • Local Institution - 0002
  • Hamburg, Germany, 20246
    • Local Institution - 0004
  • Muenchen, Germany, 80636
    • Local Institution - 0003
• Israel
  • Petach Tikva, Israel
    • Local Institution - 0047
  • Tel Hashomer, Israel, 52620
    • Local Institution - 0046
• Italy
  • Bologna, Italy, 40138
    • Local Institution - 0028
  • Milano, Italy, 20097
    • Local Institution - 0027
  • Roma
    • Rome, Roma, Italy, 00165
      • Local Institution - 0026
• Mexico
  • Distrito Federal
    • Mexico City, Distrito Federal, Mexico, 04530
      • Local Institution - 0018
    • Mexico City, Distrito Federal, Mexico, 06720
      • Local Institution - 0019
    • Mexico City, Distrito Federal, Mexico, 14080
      • Local Institution - 0016
  • Guanajuato
    • Leon, Guanajuato, Mexico, 37000
      • Local Institution - 0044
• Russian Federation
  • Ekaterinburg, Russian Federation, 620134
    • Local Institution - 0062
  • Kazan, Russian Federation, 420012
    • Local Institution
  • Kemerovo, Russian Federation, 650002
    • Local Institution
  • Novosibirsk, Russian Federation, 630055
    • Local Institution - 0057
• Spain
  • Barcelona, Spain, 08950
    • Local Institution - 0049
  • Madrid, Spain, 28007
    • Local Institution
  • Madrid, Spain, 28046
    • Local Institution - 0048
• United Kingdom
  • Manchester, United Kingdom, M13 9WL
    • Local Institution
  • Leicestershire
    • Leicester, Leicestershire, United Kingdom, LE3 9QP
      • Local Institution - 0040
  • Somerset
    • Bristol, Somerset, United Kingdom, BS2 8BJ
      • Local Institution - 0042
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • La Jolla, California, United States, 92093-0641
      • University of California San Diego
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Childrens Healthcare Of Atlanta
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Local Institution - 0008
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Local Institution - 0009
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Local Institution - 0013
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Childrens Mercy Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Local Institution - 0006
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Childrens Hospital of Philadelphia
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Local Institution - 0012
  • Texas
    • Houston, Texas, United States, 77030-2399
      • Local Institution - 0011
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Hospital
  • Washington
    • Seattle, Washington, United States, 98105
      • Local Institution - 0055

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 weeks to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

For more information regarding Bristol-Myers Squibb Clinical Trial participation, please visit www.BMSStudyConnect.com

Inclusion Criteria:

• Males and Females, 28 days to < 18 years of age, inclusive
• Congenital or acquired heart diseases requiring chronic anticoagulation for thromboprophylaxis (eg, single ventricle physiology including all 3 stages of palliation, dilated cardiomyopathy, Kawasaki disease with coronary aneurysms, and pulmonary hypertension)
• Eligible participants include those who newly start anticoagulants and those who are currently on VKA or LMWH or other anticoagulants for thromboprophylaxis
• Able to tolerate enteral medication [eg, by mouth, nasogastric tube, or gastric tube]
• Participants 28 days to < 3 months must be able to tolerate oral/nasogastric tube (NGT)/gastric tube (GT) feeds for at least 5 days prior to randomization

Exclusion Criteria:

• Recent thromboembolic events less than 6 months prior to enrollment
• Weight < 3 kg
• Use of aggressive life-saving therapies such as ventricular assist devices (VAD) or extracorporeal membrane oxygenation (ECMO) at the time of enrollment
• Artificial heart valves and mechanical heart valves
• Known inherited bleeding disorder or coagulopathy (e.g. hemophilia, von Willebrand disease, etc.)
• Active bleeding at the time of enrollment
• Any major bleeding other than perioperative in the preceding 3 months
• Known intracranial congenital vascular malformation or tumor
• Confirmed diagnosis of a GI ulcer
• Known antiphospholipid syndrome (APS).

Other protocol defined inclusion/exclusion criteria apply

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Apixaban	Drug: Apixaban; Specified dose on specified days; Other Names: Eliquis
Active Comparator: LMWH/VKA	Drug: Vitamin K Antagonist (VKA); Specified dose on specified days; Other Names: Warfarin; Drug: Low Molecular Weight Heparin (LMWH); Specified dose on specified days; Other Names: Enoxaparin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite of Adjudicated Major or Clinically Relevant Non-Major (CRNM) Bleeding Events	The number of participants with adjudicated major or CRNM bleeding events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) criteria. Events are adjudicated by a blinded, independent events adjudication committee (EAC). Major bleeding satisfies one or more of the following criteria: fatal bleeding, clinically overt bleeding associated with a decrease in hemoglobin of at least 20 g/L (i.e., 2 g/dL) in a 24-hour period, bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS, or bleeding that requires surgical intervention in an operating suite, including interventional radiology. CRNM bleeding satisfies one or both of the following criteria: overt bleeding for which blood product is administered and not directly attributable to the subject's underlying medical condition or bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating room.	From first dose to 2 days after last dose (Up to approximately 12 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Number of Participants With Thrombotic Events and Thromboembolic Event-Related Death	The number of participants with thromboembolic events (intra-cardiac, shunt, inside Fontan pathway, pulmonary embolism (PE), stroke, other arterial or venous thromboembolic events, etc.) and thromboembolic event-related death detected by imaging or clinical diagnosis. Death and thromboembolic events are adjudicated by a blinded, independent events adjudication committee (EAC)	From randomization to 2 days after last dose (Up to approximately 12 months)
The Number of Participants With Adjudicated Major Bleeding	The number of participants with adjudicated major bleeding events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) criteria. Major bleeding events are adjudicated by a blinded, independent events adjudication committee (EAC). Major bleeding is defined as bleeding that satisfies one or more of the following criteria: fatal bleeding; clinically overt bleeding associated with a decrease in hemoglobin of at least 20 g/L (i.e., 2 g/dL) in a 24-hour period; bleeding that is retroperitoneal, pulmonary, intracranial, or otherwise involves the CNS; bleeding that requires surgical intervention in an operating suite, including interventional radiology	From first dose to 2 days after last dose (Up to approximately 12 months)
The Number of Participants With Adjudicated CRNM Bleeding	The number of participants with adjudicated clinically relevant non-major (CRNM) bleeding events per the Perinatal and Paediatric Haemostasis Subcommittee of International Society on Thrombosis and Haemostasis (ISTH) criteria. CRNM bleeding events are adjudicated by a blinded, independent events adjudication committee (EAC). CRNM bleeding is defined as bleeding that satisfies one or both of the following criteria: overt bleeding for which blood product is administered and not directly attributable to the subject's underlying medical condition; bleeding that requires medical or surgical intervention to restore hemostasis, other than in an operating room	From first dose to 2 days after last dose (Up to approximately 12 months)
The Number of Participants With All Adjudicated Bleeding	The number of participants with all adjudicated bleeding events	From first dose to 2 days after last dose (Up to approximately 12 months)
The Number of Participants With Drug Discontinuation Due to Adverse Effects, Intolerability, or Bleeding	The number of participants with drug discontinuation due to adverse effects, intolerability, or bleeding.	From first dose to 2 days after last dose (Up to approximately 12 months)
The Number of Participant Deaths in the Study	The number of participant deaths in the study.	From first dose to 2 days after last dose (Up to approximately 12 months)
Maximum Observed Concentration (Cmax)		From first dose up to 6 months after first dose
Trough Observed Concentration (Cmin)		From first dose up to 6 months after first dose
Area Under the Concentration-Time Curve in One Dosing Interval (AUC (TAU))		From first dose up to 6 months after first dose
Time of Maximum Observed Concentration (Tmax)		From first dose up to 6 months after first dose
Anti-FXa Activity	Anti-FXa Activity was measured to assess participant plasma apixaban levels. 125 participants received at least one dose of apixaban and had anti-FXa samples collected that contributed measurements to at least one of the timepoints below.	From first dose up to 6 months after first dose
Chromogenic FX Assay (Apparent FX Level)	Chromogenic FX was measured to assess (apparent) FX levels in participants and inhibition of FXa by apixaban. 125 participants received at least one dose of apixaban and had chromogenic FX assay samples collected that contributed measurements to at least one of the timepoints below.	From first dose up to 6 months after first dose
The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL)	Subjects' quality of life was measured using the PedsQL instrument administered only to English-speaking children/parents. Only subjects who completed the questionnaires at both baseline and post-baseline visits were included in the analyses. PedsQL consists of 23 items scored on a 5-point Likert scale from 0 (never) to 4 (almost always) or for the child report for younger children ages 5-7, a 3-point Likert scale: 0 (Not at all), 2 (Sometimes), and 4 (A lot). Scores are reverse scored and transformed to a 0-100 scale as follows: 0=100, 1=75, 3=25, 4=0. Higher scores indicate a better HRQOL and/or lower problems.	from randomization up to 12 months after randomization
Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score	Subjects' quality of life was measured using the KIDCLOT instrument administered only to English-speaking children/parents. Only subjects who completed the questionnaires at both baseline and post-baseline visits were included in the analyses. KIDCLOT Parent inventory uses a 5 point Likert scale from 1 (N/A), 2 (Never), 3 (Rarely), 4 ( Now and then), 5 (Often). Child inventory uses a 4 point Likert scale 1 (N/A), 2 (Never), 3 (Now and then), 5 (Always). Values are scores as follows 1=0, 2=1, 3=2, 4=3, 5=4. Score interpretation is 0 to 100 percent IMPACT of anticoagulation on a child's life therefore, higher scores indicates a more negative effect.	from randomization up to 12 months after randomization

Collaborators and Investigators

• Sponsor: Bristol-Myers Squibb
• Collaborators: Pfizer; Pediatric Heart Network

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): January 19, 2017
• Primary Completion (Actual): October 18, 2021
• Study Completion (Actual): October 18, 2021

Study Registration Dates

• First Submitted: November 18, 2016
• First Submitted That Met QC Criteria: November 30, 2016
• First Posted (Estimate): December 5, 2016

Study Record Updates

• Last Update Posted (Actual): October 3, 2022
• Last Update Submitted That Met QC Criteria: September 29, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Heart Diseases; Thrombosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Protease Inhibitors; Micronutrients; Vitamins; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Antifibrinolytic Agents; Hemostatics; Coagulants; Vitamin K; Heparin; Apixaban; Enoxaparin; Heparin, Low-Molecular-Weight; Tinzaparin; Dalteparin; Warfarin
• Other Study ID Numbers: CV185-362; 2016-001247-39 (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