Comparison of Two Doses of Edoxaban Using Different Tests (Assays) and Clinical Outcomes

Study Overview
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Brief Summary
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Atrial fibrillation is when the heart's two upper chambers (called atria) beat chaotically and irregularly, out of coordination with the two lower chambers (called ventricles) of the heart. This can lead to blood clots forming in the heart chamber. Patients with atrial fibrillation will be treated with either 60 mg or 75 mg of edoxaban for up to 12 months, with a 2-4 week follow-up, after which their participation is complete. Blood samples will be collected before the first dose of study drug (Day 0), and on Days 30, 90 and 360 (at pre dose, 1-2 hours post dose and 4-8 hours post-dose).

Official Title
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Evaluation of Edoxaban in Anticoagulant Naïve Patients With Nonvalvular Atrial Fibrillation (NVAF) and High Creatinine Clearance

Conditions
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Atrial Fibrillation

Intervention / Treatment
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* Drug: Edoxaban


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meets protocol-specified criteria for qualification Is able to follow the protocol specified contraception methods Is willing and able to comply with any restrictions related to food, drink and medications Voluntarily consents to participate and provides written informed consent prior to any protocol-specific procedures Exclusion Criteria: Has history or current use of over-the-counter medications, dietary supplements, or drugs (including nicotine and alcohol) outside protocol-specified parameters Has signs, symptoms or history of any condition that, per protocol or in the opinion of the investigator, might compromise: the safety or well-being of the participant or study staff the safety or well-being of the participant's offspring (such as through pregnancy or breast-feeding) the analysis of results

Ages Eligible for Study
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Minimum Age: 18 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Edoxaban 75 mg<br>Edoxaban 60 mg + edoxaban 15 mg orally, once daily, at the same time (preferably morning) for up to 12 months, with a 2-4 week follow-up period. If needed when the patient completes or discontinues the study, an open-label transition dose of 30 mg and 15 mg edoxaban tablets will be provided. | Drug: Edoxaban<br>* Edoxaban will be provided in blister packs with active and placebo tablets maintaining the blind, i.e., one 60 mg active tablet and a 15 mg placebo or one 60 mg active tablet and a 15 mg active tablet. Transition doses of 30 mg + 15 mg edoxaban are provided in 14-tablet blister packs.<br>|
| Active Comparator: Edoxaban 60 mg<br>Edoxaban 60 mg + placebo 15 mg orally, once daily, at the same time (preferably morning) for up to 12 months, with a 2-4 week follow-up period. If needed when the patient completes or discontinues the study, an open-label transition dose of 30 mg and 15 mg edoxaban tablets will be provided. | Drug: Edoxaban<br>* Edoxaban will be provided in blister packs with active and placebo tablets maintaining the blind, i.e., one 60 mg active tablet and a 15 mg placebo or one 60 mg active tablet and a 15 mg active tablet. Transition doses of 30 mg + 15 mg edoxaban are provided in 14-tablet blister packs.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics: Average Concentration of Edoxaban at Steady State (Cav) | In pharmacokinetics, steady state means the overall intake of a drug is about equal to its elimination | After initiation of dosing on Days 30, 90, and 360 (at pre dose, 1-2 hours post dose and 4-8 hours post-dose) | 
| Pharmacokinetics: Minimum Concentration of Edoxaban in Plasma (Cmin) | Cmin is a term used in pharmacokinetics that usually refers to the minimum blood plasma concentration that a drug achieves after the drug has been administered and prior to the administration of a second dose | After initiation of dosing on Days 30, 90, and 360 (at pre dose, 1-2 hours post dose and 4-8 hours post-dose) | 
| Pharmacodynamics: Mean exposure using validated assays | Exposure analysis performed with validated Liquid Chromatography/Tandem Mass Spectrometry/Mass Spectrometry (LC/MS/MS) assay with lithium heparin plasma. Categories: Edoxaban and its metabolite (D21-2393) | Pre-dose and after initiation of dosing on Days 30, 90, and 360 (at pre dose, 1-2 hours post dose and 4-8 hours post-dose) | 
| Pharmacodynamics: Mean exposure with anti-Factor Xa (FXa) assay | Exposure analysis performed with anti-FXa assay, using sodium citrate plasma samples Categories: Edoxaban and D21-2393 | Pre-dose and after initiation of dosing on Days 30, 90, and 360 (at pre dose, 1-2 hours post dose and 4-8 hours post-dose) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: Number of participants with composite event 1 | Composite event 1 includes ischemic or hemorrhagic stroke/transient ischemic attack (TIA) and systemic embolic events (SEE) | within 3 years | 
| Efficacy: Number of participants with composite event 2 | Composite event 2 includes stroke/TIA, SEE, myocardial infarction, cardiovascular death, and major bleeding | within 3 years | 
| Safety: Number of participants with major bleeding (including intracranial) | Major bleeding is defined per the International Society on Thrombosis and Haemostasis (ISTH) definition | within 3 years | 
| Safety: Number of participants with clinically relevant bleeding | Clinically relevant bleeding is a combination of major bleeding and clinically relevant non-major (CRNM) bleeding | within 3 years | 
| Safety: Number of participants with any bleeding | Count of participants who experienced any bleeding event | within 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nonvalvular Atrial Fibrillation, High Creatinine Clearance, Developmental Phase III, Anticoagulant Naïve