Peripheral artery disease (PAD) is a major complication of atherosclerosis that affects >8 million people in the United States alone. Intermittent claudication (IC), defined as leg pain with walking that is relieved with rest, is the most frequent clinical manifestation of PAD. The number of patients with, and the health care costs of, PAD will increase as the prevalence of PAD is associated with advancing age, diabetes, and smoking. Our application will test the "reuse" of zibotentan (ZD4054), an orally active, endothelin type A antagonist in patients with IC. The study will seek to confirm the safety and tolerability of 10mg of ZD4054 in patients with intermittent claudication (Rutherford II or III and, in parallel, establish the capacity of ZD4054 to change calf muscle perfusion, as assessed by contrast-enhanced magnetic resonance imaging, functional treadmill performance, and quality of life indicators. The study will be a 1:1 randomized, double-blind, placebo-controlled trial of 44 subjects with intermittent claudication with randomization stratified based on the entr calf muscle perfusion. We will use magnetic resonance imaging to quantify changes in blood flow to the ischemic limb over time and compare drug to placebo. Based on the prior experience and the known tolerability of ZD4054, the experience of the investigative team with a mechanistically appropriate end-point measure that is part of other NIH funded projects, we will be proceed directly to this Phase II trial. The primary endpoint of the study will be the change in absolute perfusion in the index calf muscle from baseline to follow-up, after 12 weeks on the 10 mg dose or placebo. Additional outcome measures will be: a) ability of patients with PAD to tolerate 10 mg dose of ZD4054 vs. placebo;b) freedom from unexpected serious adverse events;c) change in peak walking time from baseline to 12 weeks between 10 mg of ZD4054 and placebo groups;d) change in ABI from baseline to 12 weeks between 10 mg of ZD4054 and placebo groups, and;d) change in quality of life measure between 10 mg of ZD4054 and placebo groups.

Public Health Relevance

Peripheral artery disease (PAD) is a major complication of atherosclerosis when blockages in the arteries to leg cause a problem termed intermittent claudication (IC) which is leg pain with walking that is relieved with rest. Ths is the most frequent clinical manifestation of PAD and it effects millions of Americans. The number of patients with, and the health care costs of, PAD will increase as the prevalence of PAD is associated with advancing age, diabetes, and smoking. Zibotentan (ZD4054) is an endothelin receptor A (ETA) blocker that has been shown to be safe in several patient population. Here we will test the ability of this medication to allow better blood flow to the legsof patients with PAD. In patients with IC, we will test the ability of ZD4054 to improve leg blood flow and improve the ability of patients with leg pain to walk further and feel better.

Agency
National Institute of Health (NIH)
Institute
National Center for Advancing Translational Sciences (NCATS)
Type
Exploratory/Developmental Cooperative Agreement Phase II (UH3)
Project #
5UH3TR000959-02
Application #
8685367
Study Section
Special Emphasis Panel (ZTR1-CI-2 (01))
Program Officer
Colvis, Christine
Project Start
2013-06-18
Project End
2015-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$587,704
Indirect Cost
$198,387
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904