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

Phase 2

Completed

Conditions: Thrombosis

Interventions: Drug: Vitamin K Antagonist (VKA)
Drug: Apixaban
Drug: Low Molecular Weight Heparin (LMWH)

Registration Number: NCT02981472

Lead Sponsor: Bristol-Myers Squibb

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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 192

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
LMWH/VKA	Low Molecular Weight Heparin (LMWH)	-
LMWH/VKA	Vitamin K Antagonist (VKA)	-
Apixaban	Apixaban	-

Primary Outcome Measures

Name	Time	Method
Composite of Adjudicated Major or Clinically Relevant Non-Major (CRNM) Bleeding Events	From first dose to 2 days after last dose (Up to approximately 12 months)	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.

Secondary Outcome Measures

Name	Time	Method
The Number of Participants With Thrombotic Events and Thromboembolic Event-Related Death	From randomization to 2 days after last dose (Up to approximately 12 months)	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)
The Number of Participants With All Adjudicated Bleeding	From first dose to 2 days after last dose (Up to approximately 12 months)	The number of participants with all adjudicated bleeding events
Time of Maximum Observed Concentration (Tmax)	From first dose up to 6 months after first dose
The Number of Participants With Adjudicated CRNM Bleeding	From first dose to 2 days after last dose (Up to approximately 12 months)	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
The Number of Participant Deaths in the Study	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 Participants With Adjudicated Major Bleeding	From first dose to 2 days after last dose (Up to approximately 12 months)	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
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
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 participants with drug discontinuation due to adverse effects, intolerability, or bleeding.
Anti-FXa Activity	From first dose up to 6 months after first dose	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.
Chromogenic FX Assay (Apparent FX Level)	From first dose up to 6 months after first dose	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.
The Child and Parent Reports of Pediatric Quality of Life Inventory (PedsQL)	from randomization up to 12 months after randomization	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.
Kids Informed Decrease Complications Learning on Thrombosis (KIDCLOT) IMPACT Score	from randomization up to 12 months after randomization	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.

Trial Locations

Locations (42): Local Institution - 0026
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Rome, Roma, Italy
Children'S Hospital Colorado
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Aurora, Colorado, United States
Local Institution - 0013
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Ann Arbor, Michigan, United States
Local Institution - 0006
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Cincinnati, Ohio, United States
Local Institution - 0008
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Indianapolis, Indiana, United States
Local Institution - 0027
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Milano, Italy
Childrens Mercy Hospital
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Kansas City, Missouri, United States
Local Institution - 0022
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Curitiba, Parana, Brazil
Local Institution - 0003
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Muenchen, Germany
Primary Children's Hospital
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Salt Lake City, Utah, United States
Local Institution - 0004
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Hamburg, Germany
Instituto de Pesquisa PENSI
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Sao Paulo, Brazil
Local Institution - 0002
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Freiburg, Germany
Local Institution - 0048
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Madrid, Spain
Local Institution
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Manchester, United Kingdom
Local Institution - 0028
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Bologna, Italy
Local Institution - 0020
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Campinas, Sao Paulo, Brazil
Local Institution - 0049
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Barcelona, Spain
Local Institution - 0009
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Boston, Massachusetts, United States
Childrens Hospital Of Philadelphia
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Philadelphia, Pennsylvania, United States
Local Institution - 0011
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Houston, Texas, United States
Local Institution - 0044
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Leon, Guanajuato, Mexico
Childrens Healthcare Of Atlanta
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Atlanta, Georgia, United States
Local Institution - 0055
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Seattle, Washington, United States
Instituto De Cardiologia Do Rio Grande Do Sul
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Porto Alegre, Rio Grande Do Sul, Brazil
Local Institution - 0015
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Toronto, Ontario, Canada
Local Institution - 0018
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Mexico City, Distrito Federal, Mexico
Universidade Federal De Sao Paulo
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Sao Paulo, Brazil
University Of California San Diego
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La Jolla, California, United States
Local Institution - 0012
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Charleston, South Carolina, United States
Local Institution - 0030
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Parkville, Victoria, Australia
Local Institution - 0031
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HUS, Finland
Local Institution - 0016
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Mexico City, Distrito Federal, Mexico
Local Institution - 0001
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Vienna, Austria
Local Institution - 0047
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Petach Tikva, Israel
Local Institution - 0046
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Tel Hashomer, Israel
Local Institution - 0019
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Mexico City, Distrito Federal, Mexico
Local Institution - 0062
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Ekaterinburg, Russian Federation
Local Institution - 0040
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Leicester, Leicestershire, United Kingdom
Phoenix Children'S Hospital
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Phoenix, Arizona, United States
Local Institution - 0057
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Novosibirsk, Russian Federation
Local Institution - 0042
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Bristol, Somerset, United Kingdom