Zibotentan, an Endothelin Receptor Antagonist, Patients With Intermittent Claudication

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).

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01890135
• Other study ID #: 17030
• Status: Completed
• Phase: Phase 2
• First received: June 18, 2013
• Last updated: August 1, 2016
• Start date: June 2013
• Est. completion date: June 2016

Study information

• Verified date: August 2016
• Source: University of Virginia
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: June 2016
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 40 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Intermittent Claudication
• Peripheral Arterial Disease
• Peripheral Vascular Diseases

Intervention

Drug:
• Zibotentan (ZD4054)
10 mg
• placebo
randomized double blind

Locations

Country	Name	City	State
United States	University Of Virginia Health System	Charlottesville	Virginia

Sponsors (2)

Lead Sponsor	Collaborator
University of Virginia	National Institutes of Health (NIH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change in ankle-brachial blood pressure index (ABI		Baseline and 12 weeks	No
Other	Change in hematocrit		baseline and day 30	Yes
Primary	Change in exercise-induced calf muscle perfusion by magnetic resonance imaging		Baseline and 12 weeks	No
Secondary	Change in peak walking time	Peak walking time (PWT) will be measured using the Gardner treadmill protocol which is designed for patients with peripheral arterial disease.	Baseline and 12 weeks	No
Secondary	Change in quality of life measures	Quality of life measures specific to peripheral arterial disease will be assessed by questionnaire.	Baseline and 12 weeks	No
Secondary	Safety	Confirmation of lack of change in edema or heart failure by history and physical examination	Baseline and Day 30	Yes