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

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

Official Title
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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

Conditions
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Thrombosis

Intervention / Treatment
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* Drug: Apixaban
* Drug: Vitamin K Antagonist (VKA)
* Drug: Low Molecular Weight Heparin (LMWH)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 28 Days
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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 |