Edoxaban in Peripheral Arterial Disease (ePAD)

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

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.

Study Overview

• Status: Completed
• Conditions: Peripheral Arterial Disease
• Intervention / Treatment: Drug: Aspirin; Drug: edoxaban; Drug: Clopidogrel

• Study Type: Interventional
• Enrollment (Actual): 203
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria
  • Innsbruck, Austria
  • Wien, Austria
• Belgium
  • Edegem, Belgium
    • Edgem
  • Ghent, Belgium
  • Leuven, Belgium
• Germany
  • Bad Krozingen, Germany
  • Leipzig, Germany
• Israel
  • Afula, Israel
  • Jerusalem, Israel
  • Tel Aviv, Israel
  • Tel Hashomer, Israel
• Netherlands
  • Rotterdam, Netherlands
  • Utrecht, Netherlands
• Switzerland
  • Bern, Switzerland
  • Zurich, Switzerland
• United States
  • Alabama
    • Birmingham, Alabama, United States
  • Arizona
    • Phoenix, Arizona, United States
  • California
    • Beverly Hills, California, United States
    • Los Angeles, California, United States
    • Orange, California, United States
  • Connecticut
    • New Haven, Connecticut, United States
  • Florida
    • Hollywood, Florida, United States
    • Jacksonville, Florida, United States
  • Illinois
    • Aurora, Illinois, United States
  • Iowa
    • Iowa City, Iowa, United States
  • Louisiana
    • New Orleans, Louisiana, United States
  • Maine
    • Lewiston, Maine, United States
  • Massachusetts
    • Boston, Massachusetts, United States
  • Michigan
    • Flint, Michigan, United States
    • Ypsilanti, Michigan, United States
  • New Jersey
    • Teaneck, New Jersey, United States
  • New York
    • New York, New York, United States
  • North Carolina
    • Raleigh, North Carolina, United States
    • Wilmington, North Carolina, United States
  • Ohio
    • Cleveland, Ohio, United States
    • Columbus, Ohio, United States
  • Pennsylvania
    • Camp Hill, Pennsylvania, United States
  • South Carolina
    • Columbia, South Carolina, United States
    • Greenville, South Carolina, United States
  • Texas
    • Austin, Texas, United States
    • San Antonio, Texas, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Gilbert"s 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

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: edoxaban/aspirin; 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: Aspirin; Drug: edoxaban
Active Comparator: clopidogrel/aspirin; 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: Aspirin; Drug: Clopidogrel; 75mg tablet; Other Names: Plavix

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.
• Collaborators: UMC Utrecht

Publications and helpful links

General Publications

• Moll F, Baumgartner I, Jaff M, Nwachuku C, Tangelder M, Ansel G, Adams G, Zeller T, Rundback J, Grosso M, Lin M, Mercur MF, Minar E; ePAD Investigators. Edoxaban Plus Aspirin vs Dual Antiplatelet Therapy in Endovascular Treatment of Patients With Peripheral Artery Disease: Results of the ePAD Trial. J Endovasc Ther. 2018 Apr;25(2):158-168. doi: 10.1177/1526602818760488.
• Tangelder MJ, Nwachuku CE, Jaff M, Baumgartner I, Duggal A, Adams G, Ansel G, Grosso M, Mercuri M, Shi M, Minar E, Moll FL. A review of antithrombotic therapy and the rationale and design of the randomized edoxaban in patients with peripheral artery disease (ePAD) trial adding edoxaban or clopidogrel to aspirin after femoropopliteal endovascular intervention. J Endovasc Ther. 2015 Apr;22(2):261-8. doi: 10.1177/1526602815574687.

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2013
• Primary Completion (Actual): December 3, 2014
• Study Completion (Actual): December 3, 2014

Study Registration Dates

• First Submitted: February 25, 2013
• First Submitted That Met QC Criteria: February 28, 2013
• First Posted (Estimate): March 1, 2013

Study Record Updates

• Last Update Posted (Actual): February 26, 2019
• Last Update Submitted That Met QC Criteria: February 8, 2019
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Peripheral Arterial Disease; Peripheral Vascular Diseases; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Aspirin; Clopidogrel; Edoxaban
• Other Study ID Numbers: DU176b-E-U210; 2012-003009-88 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR