• Determine the safety and efficacy of rilonacept vs. placebo to reduce CRP levels in CAD patients with elevated CRP despite concurrent treatement with a statin. [ Time Frame: Baseline, 2 wks following completion of tx and 6 wks following completion of tx. ] [ Designated as safety issue: Yes ]
  

• Study the effects of rilonacept admin on endothelial progenitor stem cells using cell culture, flow cytometry and mRNA gene expression techiques. [ Time Frame: Baseline, 2 wks following completion of tx and 6 wks following completion of tx. ] [ Designated as safety issue: No ]
  

Drug: Rilonacept
N/A
Procedure: Treadmill Exercise Test
N/A

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. In vitro 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.

• INCLUSION CRITERIA:
• Male and non-pregnant, non-lactating female subjects, over 18 years of age at Screening Visit 1.
• Diagnosis of atherosclerotic CAD by coronary angiography
• High sensitivity C-reactive protein (hsCRP) between 2.0 and 10.0 g/L, inclusive, at Screening Visits 1 and 2, with percent change in CRP from Visit 1 to Visit 2 of less than 50% to +100%.
• Taking a HMG-CoA reductase inhibitor (and, if applicable, other agents to treat dyslipidemia) at a stable dose(s) for at least 60 days prior to Screening Visit 1 and agreeing to continue on that dose(s) at least until Week 12 (Visit 8) of the study.
• If taking aspirin (and/or other anti-platelet anti-thrombotic medication, if applicable), use at a stable dose for at least 30 days prior to Screening Visit 1 and agreeing to continue on that dose at least until Week 12 of the study.
• For men and women of childbearing potential, willingness to utilize adequate contraception and not become pregnant (or have their partner[s] become pregnant) during the full course of the study. [A woman will not be considered of childbearing potential, if she is post-menopausal for greater than 2 years or surgically sterile (bilateral tubal ligation, bilateral oophorectomy or hysterectomy). The following methods of birth control are adequate contraception and must be used throughout the study and for 2 months after the last dose of study medication: condom or diaphragm plus either contraceptive sponge, foam or jelly; IUD; contraceptives (oral, transdermal patch or parenteral) for 2 or more cycles prior to screening; vasectomy].
• Willing, at time of study enrollment, to return for all clinic visits specified in the protocol and complete all study-related procedures.

EXCLUSION CRITERIA:

• BMI (body mass index) greater than 49.9 kg/m2 at Screening Visit 1 (BMI is to be calculated to the nearest tenth BMI unit).
• Vascular intervention within 60 days prior to Screening Visit 1.
• Infection (or history of recurrent infections), use of systemic antibiotics, or clinically significant trauma (including surgery) within 30 days prior to Screening Visit 1.
• History or evidence of acute coronary syndrome (including new q-wave or new bundle branch block) or other significant acute vascular event within 60 days prior to Screening Visit 1.
• Acute or chronic inflammatory condition other than atherosclerosis (including, but not limited to, rheumatoid arthritis, systemic lupus erythematosis, polymyalgia rheumatica, autoimmune vasculitis, or myositis).
• Recently diagnosed diabetes mellitus (within 30 days prior to Screening Visit 1); or fasting glucose greater than 125 mg/dL and HbA1c greater than 6.5% at Screening Visit 1 in a subject without prior history of diabetes mellitus; or HbA1c greater than 7.0% at Screening Visit 1 in a subject without prior history of diabetes mellitus; or HbA1c greater than 8.5% at Screening Visit 1 in a subject with a prior history of diabetes mellitus.
• History of dyslipidemia with LDL-cholesterol greater than 250 mg/dL, or fasting triglycerides greater than 400 mg/dL during screening.
• Clinical evidence of congestive heart failure NYHA Class III-IV within 30 days prior to Screening Visit 1.
• History of hypersensitivity other than localized injection site reaction to any biologic agent.
• Use of a thiazolidinedione within 60 days prior to Screening Visit 1.
• Use of immunosuppressive or immunomodulatory medication (including, but not limited to glucocorticoids, methotrexate, leflunomide, mycophenolate, sulfasalazine, hydroxychloroquine, copaxone, cyclosporine, tacrolimus, sirolimus, azathioprine, cyclophosphamide, thalidomide) within 60 days prior to Screening Visit 1 (use of an inhaled glucocorticoid is permitted).
• Prior use of an immunomodulatory biologic drug within the last 6 months (including, but not limited to interferons, interleukins or interleukin antagonist, tumor necrosis factor antagonist, colony-stimulating factors, antibody-based drugs and immune globulins) except immunizations and biologics used as standard care in cardiac care settings.
• Received a live/live attenuated vaccine (smallpox vaccinia, measles, mumps, rubella, measles mumps-rubella [MMR] combination, oral polio [Sabin], intranasal influenza, yellow fever, chickenpox [varicella], oral typhoid) within 90 days prior to Screening Visit 1 or other immunization within 30 days prior to Screening Visit 1.
• Prior or planned organ transplant recipient.
• Severe respiratory disease, including, but not limited to, severe bronchiectasis, chronic obstructive pulmonary disease, bullous lung disease, uncontrolled asthma, or pulmonary fibrosis.
• A history of tuberculosis infection, history of a positive skin test for tuberculosis, or a chest radiograph at Screening Visit 1 consistent with prior tuberculosis infection, including, but not limited to apical scarring, apical fibrosis, or multiple calcified apical granulomata.
• Positive result (5 mm or more in duration at 48 to 72 hours post-placement) of the PPD 5 TU placed at Screening Visit 2 (all subjects, including those having received a BCG vaccination, will have a PPD 5 TU placed at Screening Visit 2).
• History or presence of malignancy (except for successfully treated basal cell carcinoma of the skin or in situ carcinoma of the cervix) within the past 5 years.
• HIV positive.
• Hepatitis B surface antigen or Hepatitis C antibody positive at Screening Visit 1.
• ALT, AST or alkaline phosphatase greater than twice the upper limit of the normal range, serum creatinine or total bilirubin greater than 1.5 times the upper limit of normal at Screening Visit 1.
• Hemoglobin less than 11.0 gm/dL, white blood cell (WBC) count less than 3,000/mm3, neutrophil count less than 2000/mm3 or platelet count less than 100,000/mm3 at Screening Visit 1.
• Participation in any clinical research study evaluating another investigational drug or therapy within 30 days prior to Screening Visit 1.
• History of substance abuse (drug or alcohol) or any other factor (e.g. serious psychiatric condition) that limits the subject's ability to comply with the study procedure.
• Elective surgery or vascular intervention planned to occur during the study.
• Any medical condition which, in the opinion of the Investigator, would interfere with participation in the study, interfere with interpretation of study outcome measures, or place the subject at risk.