Edoxaban in Peripheral Arterial Disease

Study Overview
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Brief Summary
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This study is a randomized, open-label, blinded endpoint, parallel-group, active-control, multi-center, proof-of-concept study in subjects with Peripheral Arterial Disease (PAD), designed to assess the safety and potential efficacy of adding edoxaban to aspirin following femoropopliteal endovascular intervention, with or without stent placement, relative to current treatment practice with clopidogrel and aspirin.

Official Title
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A Randomized, Open-Label, Parallel-Group, Multi-Center Study Of Adding Edoxaban Or Clopidogrel To Aspirin To Maintain Patency In Subjects With Peripheral Arterial Disease Following Femoropopliteal Endovascular Intervention

Conditions
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Peripheral Arterial Disease

Intervention / Treatment
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* Drug: edoxaban
* Drug: Clopidogrel
* Drug: Aspirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects older than the minimum legal adult age (country specific); Rutherford stages 2-5 provided there are no ulcerations on the heel and/or exposed tendon and/or bone; Superficial femoral above knee-popliteal ( 3 cm proximal to the medial femoral condyle) lesion and ≥ 50% stenosis or occlusion; At least one run-off vessel to the foot with or without additional endovascular intervention; Successful intervention, defined as angiographic confirmation of ≤ 30% residual stenosis and absence of flow limiting dissection; Adequate hemostasis at the vascular access site within 24 hours of intervention; A subject is also eligible if they have undergone additional successful endovascular intervention(s) during the index intervention; Able to provide signed informed consent. Exclusion Criteria: Calculated Creatinine Clearance < 30 ml/min; Femoral or popliteal aneurysm; Adjunctive use of thrombolytics; Any extravasation or distal embolization not successfully treated; Uncontrolled hypertension as judged by the investigator (e.g., systolic blood pressure > 170 mmHg or diastolic blood pressure > 100 mmHg despite antihypertensives); Aspirin intolerance; Clopidogrel intolerance; Contraindication for anticoagulants or antiplatelets and any other contraindication listed in the local labeling of aspirin and/or clopidogrel; Active bleeding or known high risk for bleeding or history of intracranial, or spontaneous intraocular, spinal retroperitoneal or intra-articular bleeding; overt gastrointestinal (GI) bleeding or active ulcer within the previous year; Subjects receiving dual antiplatelet or anticoagulant therapy at the time of randomization; subjects receiving pre-interventional loading dose of clopidogrel or other P2Y12 receptor antagonists; Treatment with cilostazol within 24 hours of randomization; Subjects receiving prohibited concomitant medications [fibrinolytics, chronic use of non steroidal anti-inflammatory drugs (NSAIDS) > 4 days per week, and oral or parenteral non-aspirin NSAIDs and strong P-gp inhibitors]; Prior stroke or myocardial infarction (MI) or acute coronary syndrome within 3 months; Chronic liver disease [alanine transaminase (ALT) and/or aspartate transaminase (AST) ≥ 2 × upper limit of normal; total bilirubin (TBL) ≥ 1.5 × upper limit of normal]; however, subjects whose elevated TBL is due to known Gilberts syndrome may be included in the study; Prior history of a positive test for Hepatitis B antigen or Hepatitis C antibody; Subjects who received any investigational drug or device within 30 days prior to randomization, or plan to receive such investigational therapy during the study period; Subjects previously randomized to an edoxaban (DU-176b) study; Women of childbearing potential without proper contraceptive measures (i.e. a method of contraception with a failure rate < 1 % during the course of the study including the observational period) and women who are pregnant or breast feeding; Subjects with the following diagnoses or situations: Active malignancy except for adequately treated non-melanoma skin cancer or other non-invasive or in-situ neoplasm (e.g., cervical cancer in situ); Concurrent treatment with cancer therapy (drugs, radiation, and/or surgery); Other significant active concurrent medical illness or infection; Life expectancy < 12 months; Subjects who are unlikely to comply with the protocol (e.g., uncooperative attitude, inability to return for subsequent visits, and/or otherwise considered by the Investigator to be unlikely to complete the study); Subjects with any condition that, in the opinion of the Investigator, would place the subject at increased risk of harm if he/she participated in the study; History of heparin-induced thrombocytopenia

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: edoxaban/aspirin<br>Open label edoxaban will be provided. Subjects randomized to this treatment arm will receive edoxaban 60 mg once daily (QD) (two 30 mg tablets) for a total of approximately 3 months on a background of aspirin 100 mg QD. | Drug: edoxaban<br> <br> Drug: Aspirin<br> <br> |
| Active Comparator: clopidogrel/aspirin<br>Open label clopidogrel will be provided. Subjects randomized to this treatment arm will receive clopidogrel 75 mg QD (one 75 mg tablet) for a total of approximately 3 months on a background of aspirin 100 mg QD. A loading dose of clopidogrel 300 mg (four 75mg tablets) will be given to subjects as the first dose as early as possible after adequate hemostasis (i.e., within 4 hours of hemostasis). | Drug: Clopidogrel<br>* 75mg tablet<br>* Other names: Plavix;Drug: Aspirin<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinically Relevant Bleeding During Treatment | Percentage of participants with clinically relevant bleeding, defined as major bleeding or clinical relevant non-major bleeding, in the on-treatment period based on International Society of Thrombosis and Haemostasis (ISTH) | at 3 months | 
| Percentage of Participants With First Re-stenosis / Re-occlusion | Percentage of participants with re-stenosis/re-occlusion during treatment within 6 months - only the first occurrence of re-stenosis / re-occlusion was counted for each participant | within 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Major, Clinically Relevant Non-major (CRNM), and Minor Bleeding During Treatment | The percentage of participants with major, clinically relevant non-major, and minor bleeding occurring during treatment, within 3 months | within 3 months | 
| Safety Assessments | Number of participants with serious adverse events (SAEs) within 6 months Note: Based on changes to the database structure, clinically significant changes in physical or laboratory parameters are recorded as adverse events (AEs). Details of non-serious adverse events are reported at the 5% reporting threshold in the AE module, as is all-cause mortality. | within 6 months | 
| Number of Adjudicated Major Adverse Cardiovascular Events During the Overall Study Period | Number of Adjudicated Major Adverse Cardiovascular Events (MACE) which is a composite of non-fatal myocardial infarction (MI), non-fatal stroke and cardiovascular death | within 6 months | 
| Number of Participants With Amputations | Number of participants with amputations within 6 months | within 6 months |