- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01890135
Zibotentan, an Endothelin Receptor Antagonist, Patients With Intermittent Claudication
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).
Study Overview
Status
Intervention / Treatment
Detailed 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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
Virginia
-
Charlottesville, Virginia, United States, 22908
- University of Virginia Health System
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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 Plan
How is the study designed?
Design Details
- Primary Purpose: BASIC_SCIENCE
- Allocation: RANDOMIZED
- Interventional Model: PARALLEL
- Masking: QUADRUPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
ACTIVE_COMPARATOR: endothelin receptor antogonist
10 mg of zibotentan
|
10 mg
randomized double blind
Other Names:
|
PLACEBO_COMPARATOR: placebo
matched placebo
|
10 mg
randomized double blind
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Change in exercise-induced calf muscle perfusion by magnetic resonance imaging
Time Frame: Baseline and 12 weeks
|
Baseline and 12 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in peak walking time
Time Frame: Baseline and 12 weeks
|
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
|
Change in quality of life measures
Time Frame: Baseline and 12 weeks
|
Quality of life measures specific to peripheral arterial disease will be assessed by questionnaire.
|
Baseline and 12 weeks
|
Safety
Time Frame: Baseline and Day 30
|
Confirmation of lack of change in edema or heart failure by history and physical examination
|
Baseline and Day 30
|
Other Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Change in ankle-brachial blood pressure index (ABI
Time Frame: Baseline and 12 weeks
|
Baseline and 12 weeks
|
Change in hematocrit
Time Frame: baseline and day 30
|
baseline and day 30
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Brian H Annex, MD, University of Virginia
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ESTIMATE)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 17030
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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