Rilonacept to Improve Artery Function in Patients With Atherosclerosis
Condition: Coronary Artery Disease; Atherosclerosis; Inflammation; Endothelial Dysfunction
MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Atherosclerosis; Inflammation
Intervention: Rilonacept; Placebo
Intervention description: Lyophilized rilonacept will be supplied by Regeneron Pharmaceuticals at 160 mg/vial and reconstituted with 2.3 mL of sterile water for injection by the Clinical Center Pharmacy Intravenous Admixture Unit. The formulation contains 80 mg/mL rilonacept, histidine, citrate, PEG 3350, polysorbate 20, glycine, arginine, and sucrose (pH 6.5). Matching placebo in the identical formulation will also be supplied, and also reconstituted with 2.3 mL of sterile water for injection. Each administration of study drug will consist of two syringes containing 2.0 mL in each syringe (320 mg total drug).; Normal saline subcutaneously at each treatment visit.
Intervention MeSH terms: Rilonacept
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 10.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Endothelium; Inflammation; Nitric Oxide; Rilonacept; Cytokines; Coronary Artery Disease; CAD; Atherosclerosis

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Male and non-pregnant female subjects over 18 years of age

          -  Diagnosis of atherosclerotic CAD by coronary angiography

          -  High sensitivity C-reactive protein (hsCRP) between 2.0 and 10.0 g/L, inclusive with
             percent change in CRP from Visit 1 to Visit 2 of less than 50% to +100%.

          -  Taking a HMG-CoA reductase inhibitor -For men and women of childbearing potential,
             willingness to utilize adequate contraception

          -  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 -Vascular
             intervention within 60 days prior to Screening Visit 1.

          -  Infection, 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 within 60 days prior to Screening Visit
             1.

          -  Acute or chronic inflammatory condition other than atherosclerosis

          -  Recently diagnosed diabetes mellitus

          -  Clinical evidence of congestive heart failure NYHA Class III-IV

          -  History of hypersensitivity other than localized injection site reaction to any
             biologic agent.

          -  Use of a thiazolidinedione

          -  Use of immunosuppressive or immunomodulatory medication (use of an inhaled
             glucocorticoid is permitted).

          -  Prior use of an immunomodulatory biologic drug within the last 6 months except
             immunizations and biologics used as standard care in cardiac care settings.

          -  Received a live/live attenuated vaccine 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

          -  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

          -  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

          -  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

          -  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

          -  Elective surgery or vascular intervention planned to occur during the study.

          -  Any medical condition which would interfere with participation in the study, interfere
             with interpretation of study outcome measures, or place the subject at risk.