Rilonacept to Improve Artery Function in Patients With Atherosclerosis

Phase 2

Completed

Conditions: Coronary Artery Disease
Inflammation
Atherosclerosis
Endothelial Dysfunction

Interventions: Drug: Placebo
Drug: Rilonacept

Registration Number: NCT00417417

Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Brief Summary: This study will determine whether an experimental drug called Rilonacept can improve artery function in patients with atherosclerosis, a disease in which fatty deposits in arteries cause the vessels to stiffen, impeding blood flow. Atherosclerosis is believed to be caused in part by inflammation. Rilonacept blocks production of a protein called CRP, which, in high levels in the blood is associated with increased inflammation. Patients with coronary artery disease who have elevated blood levels of CRP are at increased risk of heart attack, heart failure and sudden death compared with people who have lower levels of the protein.

Patients 18 years of age and older with atherosclerotic coronary artery disease with a CRP level between 2 and 10 mg/L may be eligible for this study.

Patients are randomly assigned to receive four doses of either Rilonacept or placebo, given at 2-week intervals as injections under the skin. In addition to treatment, patients undergo the following procedures during eight visits to the NIH Clinical Center:

* Visit 1 (screening visit): Medical history, measurement of vital signs (temperature, blood pressure, heart rate and breathing rate), electrocardiogram (EKG) and blood tests.

* Visit 2: Blood tests, chest X-ray, treadmill exercise testing, tuberculin skin test, brachial artery flow-mediated dilation. Brachial artery flow-mediated dilation is used to measure how well the brachial artery (artery inside the elbow) dilates. An ultrasound device placed just above the elbow measures the size of the brachial artery and the flow of blood through it before and after a pressure cuff is inflated around the forearm.

* Visit 3: Injection of study drug.

* Visits 4, 5, and 6: Review of any changes in health or medical treatment, measurement of vital signs, blood tests, EKG, injection of study drug.

* Visit 7: Review of any changes in health or medical treatment, measurement of vital signs, blood tests, EKG, treadmill exercise testing, brachial artery flow-mediated dilation.

* Visit 8: Review of any changes in health or medical treatment, measurement of vital signs, blood tests, EKG, treadmill exercise testing, brachial artery flow-mediated dilation.

Detailed Description: Rilonacept (Interleukin-1 Trap) has been developed as an antagonist of the cytokine IL-1 in the treatment of rheumatoid arthritis and other inflammatory diseases. IL-1 causes leukocyte accumulation by inducing adhesion receptors on vascular endothelium and stimulating chemokine production. It also stimulates the synthesis of other cytokines, including IL-6, which in turn stimulates synthesis of C-reactive protein (CRP) in the liver. Based on numerous clinical studies, CRP has emerged as a risk marker for the development and clinical expression of atherosclerotic cardiovascular disease, leading to published recommendations for measurement of CRP in screening population subsets for cardiovascular risk. Endothelial function, as evidenced by stimulated nitric oxide release, has also been recognized as a marker of cardiovascular disease risk. Thus, patients with coronary artery disease (CAD) or its risk factors have impaired nitric oxide release from the endothelium compared with healthy subjects. Recent studies have shown that CRP levels were significantly higher in CAD patients compared with healthy subjects, with an inverse correlation between forearm blood flow responses to acetylcholine as a measure of endothelial function and CRP. Endothelial progenitor cells (EPCs) are primitive bone marrow-derived cells that have a capacity to home to sites of vascular injury and differentiate into vascular cell types, and are reduced in number and differentiation capacity in CAD patients relative to healthy subjects. Studies suggest that CRP inhibits viability and endothelial differentiation capacity of EPCs and may account for reduced numbers of EPCs and endothelial dysfunction in CAD patients. The objective of the present study is to demonstrate the potential of an investigational biological agent, rilonacept, as adjunctive treatment for CAD by examining effects of this agent on CRP levels, endothelial progenitor cell mobilization and endothelial function in a randomized, double-blind, placebo-controlled phase I/II clinical trial.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 10

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Normal saline subcutaneously at each treatment visit.
Rilonacept	Rilonacept	Rilonacept 320 mg subcutaneous at each treatment visit

Primary Outcome Measures

Name	Time	Method
C-Reactive Protein (CRP)	2 wks following last drug administration	C-reactive protein levels in subjects randomized to rilonacept versus placebo injections.

Secondary Outcome Measures