Peripheral Arterial Disease Clinical Trial
Official title:
A Phase II Clinical Trail to Assess the Safety and Effects of ZD4054 (Zibotentan) on Exercise Induced Calf Muscle Perfusion in Patients With Intermittent Claudication (Rutherford II or III).
Peripheral artery disease (PAD) is a major complication of atherosclerosis when blockages in the arteries to leg reduce blood flow and one of the resulting problems is termed intermittent claudication (IC). IC is leg pain with walking that is relieved with rest and IC 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 undergone extensive human testing and has been shown to be safe in several patient population. There is ample evidence to suggest that an ETA blocker could improve blood flow to the legs in patients with PAD. In a study that will be funded by the National Institute of Health, the investigators will test the ability of this medication to allow better blood flow to the legs of patients with PAD. In patients with IC, the investigators will test the ability of ZD4054 to improve leg blood flow using a non-invasive imaging technique. In parallel the study will test for the ability of patients with leg pain to walk further and feel better.
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.
In a proposal that was just funded by the National Institute of Health (NIH) National Center
for Advancing TRanslational Sciences (NCATS) the investigators pose to test the "reuse" of
zibotentan (ZD4054, an Asta-Zeneca compound), an orally active, endothelin receptor A (ETA)
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 entry calf muscle
perfusion. The investigators will use magnetic resonance imaging to quantify changes in
blood flow to the ischemic limb from baseline to week 12 between those randomized to drug
vs. 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, the investigators will 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 ankle-brachial blood pressure index (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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Basic Science
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