Zibotentan, an Endothelin Receptor Antagonist, Patients With Intermittent Claudication

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.

Inclusion Criteria:

- Age >40 years. Patients less than 40 years of age could well have a form or
"thromboangitis obliterans" often called Berger's Disease and the investigators wish
to enroll only subjects with atherosclerotic vascular disease.

- Currently taking all standard medications that are part of the "good medical care"
for patients with PAD including an anti-platlet agent, an angiotensin-converting
enzyme inhibitors or receptor blockers, beta-blockers if indicated for ischemic heart
disease, and cholesterol lowering therapy; unless documented contra-indications to
these therapies exist. Those patients not on these therapies will be referred back
with the suggestion that they be added and they can be re-approached for enrollment
at a later date.

- Exercise induced thigh, calf, buttock pain and absence of Rutherford Class IV, V, or
VI.3

- A resting ABI of <0.9 but >0.4 and the presence of both superficial femoral artery
stenosis (70% or greater) disease and below the knee disease with a significant
stenosis in at least one of the run-off vessels.

- Absence of critical inflow (iliac or common femoral) disease. The profunda femoral
artery is the major source of collateral blood vessels. The investigators initial
approach will be to try and enroll as homogenous of a patient population as possible
to allow us to focus on the primary endpoint of the study (the change in muscle
perfusion to the ischemic limb over time).

- Ability to undergo magnetic resonance imaging and provide informed written consent.

Exclusion Criteria:

- Serious known concomitant disease with life expectancy of less than one year

- Prior amputation or history of critical limb ischemia

- Creatinine clearance (CrCl) >45 to permit safe administration of the gadolinium
contrast agent.

- Recent myocardial infarction, unstable angina, stroke or transient ischemic attack
within 3 months.

- American Heart Association Class III or IV congestive heart failure or known left
ventricular ejection fraction less than 40%.

- Known history of anemia