Cardiovascular Inflammation Reduction Trial (CIRT)
|Principal Investigator: DebraSimmons|
|Keywords: Cardiovascular events , Myocardial infarction , Heart attack , Type 2 diabetes , Metabolic syndrome||Department: Endocrinology/Diabetes Researc|
|IRB Number: 00065345||Co Investigator:|
|Specialty: Cardiology, Endocrinology and Metabolism, Endocrinology and Metabolism|
|Sub Specialties: Metabolic Syndrome, Diabetes|
2.0. SPECIFIC AIMS
Abundant laboratory and translational data demonstrate that inflammation plays a major role in all stages of the atherothrombotic process1,2. These observations have generated the hypothesis that targeted anti-inflammatory therapy can lower vascular event rates. To date, however, no clinical trial has directly addressed this critical biologic hypothesis3,4.
The primary scientific aim of CIRT is to directly test the inflammatory hypothesis of atherothrombosis. Specifically, CIRT will evaluate whether LDM will reduce rates of myocardial infarction, stroke, or cardiovascular death among patients with a recent history of coronary artery disease and either type 2 diabetes or metabolic syndrome, conditions associated with an enhanced pro-inflammatory response. LDM is an effective anti-inflammatory therapy widely used to treat rheumatoid arthritis that lowers plasma levels of interleukin-6 (IL-6), tumor necrosis factor (TNF), and C-reactive protein (CRP) but does not otherwise have beneficial effects on lipids or biomarkers of hemostasis and thrombosis. Thus, a randomized trial of LDM provides an innovative approach to target inflammation while minimizing confounding effects that might accrue from activation or inhibition of alternative vascular pathways. The wide use of LDM as a mainstay in current therapy for rheumatoid arthritis provides both guidelines for safety monitoring and strong evidence that off-target toxicity is unlikely to be uncovered during the course of this trial.
- To determine in a randomized, double-blind, placebo-controlled setting whether LDM given at a target dose of 15 to 20 mg po weekly will reduce rates of myocardial infarction, stroke, or cardiovascular death among patients with a prior history of coronary artery disease and either type 2 diabetes or metabolic syndrome.
2.2. Secondary Aims
- To determine in a randomized, double-blind, placebo-controlled setting whether LDM will reduce rates of all-cause mortality among patients with a prior history of coronary artery disease and either type 2 diabetes or metabolic syndrome.
- To determine in a randomized, double-blind, placebo-controlled setting whether LDM will reduce rates of the primary endpoint plus coronary revascularization.
- To determine in a randomized, double-blind, placebo-controlled setting whether LDM will reduce the rates of hospitalization for congestive heart failure.
- To determine in a randomized, double-blind, placebo-controlled setting whether LDM will reduce rates of the primary endpoint plus all-cause mortality plus coronary revascularization plus congestive heart failure.
- To determine in a randomized, double-blind, placebo-controlled setting the side effect profile of LDM in a non-rheumatologic population at risk for vascular events. By so doing, CIRT will evaluate the net clinical benefit or harm that might accrue from the hypothesized use of LDM as a novel method for the secondary prevention of myocardial infarction, stroke, and cardiovascular death.
- To determine in a randomized, double-blind, placebo-controlled setting whether LDM will reduce the rate of new onset type 2 diabetes among those with metabolic syndrome but not diabetes at study entry.
2.3. Tertiary Aims
In addition, we will determine in a randomized, double-blind, placebo-controlled setting whether LDM will
- reduce rates of the individual components of the primary endpoint
- reduce rates of the primary endpoint plus unstable angina requiring unplanned coronary revascularization
- reduce rates of coronary revascularization
- reduce rates of peripheral artery disease
- reduce rates of symptomatic deep vein thrombosis or pulmonary embolism, including those considered to be provoked and those considered to be idiopathic
- reduce rates of clinically significant aortic stenosis
- reduce rates of atrial fibrillation
- have positive or negative effects on standardized measures of quality of life and global health status
2.4.Proposed Exploratory and Mechanistic Studies
CIRT will include 7,000 patients with either myocardial infarction within the past five years or angiographically demonstrated multivessel coronary artery disease within the past five years who have either type 2 diabetes or metabolic syndrome. Clinical endpoints of interest that will be prospectively evaluated include incident age-related macular degeneration, sleep apnea, and nephropathy and retinopathy. In addition, a plasma and DNA bank will be established as part of the trial protocol. Thus, cohort accrual and biobanking also allows for the evaluation of several tertiary aims that relate to mechanisms of effect using measured plasma biomarkers of inflammation and glucose metabolism, as well as potential genetic determinants of LDM activity.
- To evaluate the effect of LDM as compared to placebo on a series of inflammatory biomarkers such as IL-6, TNF, CRP, interleukin-1 (IL-1), and interleukin-1 receptor antagonist (IL1ra), and to ascertain whether any effects on these biomarkers mediate observed benefits or risks of LDM on clinical outcomes in the trial.
- To evaluate whether genetic polymorphisms associated with vascular risk, inflammation, thrombosis, or LDM metabolism modify any benefits or risks of LDM on clinical outcomes observed in the trial.
- Among subjects with baseline diabetes, to evaluate the effect of LDM as compared to placebo on indices of diabetic progression and glycemic control such as need for diabetes treatment intensification, proportion of subjects achieving optimal glycemic control (HbA1c<7.0%), and change in HbA1c overall and by study visit.
4.2 Study Population
CIRT will randomize 7,000 men and women, age 18 years and over, who have either suffered a documented myocardial infarction within the past or have multivessel coronary disease by angiography in the past, have completed any planned coronary revascularization procedures associated with the qualifying event, have been on a stable secondary prevention regimen for a minimum of 60 days, and have either a clinical diagnosis of type 2 diabetes or metabolic syndrome.
For purposes of this trial, the formal 2004 AHA/NHLBI definition of metabolic syndrome will be used and requires evidence that any 3 of the following 5 diagnostic criteria are present: waist circumference ≥102 cm in men or≥ 88 cm in women; triglycerides ≥ 150 mg/dl (1.7 mmol/L) or on drug treatment for elevated triglycerides (fibrates, nicotinic acid, or omega 3 fatty acids ); HDL-C < 40 mg/dL in men or < 50 mg/dL in women or on drug treatment for reduced HDL-C (fibrates or nicotinic acid); systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥ 85 mm Hg or on drug treatment for hypertension; and elevated fasting glucose ≥ 100 mg/dL or on drug treatment for elevated glucose.
4.3 Inclusion Criteria
- Age ≥ 18 years at screening;
- Documented past history of myocardial infarction OR past evidence of multivessel coronary artery disease by angiography
in the past 5 years.
- To qualify on the basis of a past history myocardial infarction, the event must be documented either by hospital records or by evidence on current ECG of Q waves in two contiguous leads and/or an imaging test demonstrating wall motion abnormality or scar. The patient must also have completed any planned coronary revascularization procedures associated with the qualifying event, and be clinically stable for at least 60 days prior to screening.
- To qualify on the basis of multivessel coronary disease, there must be past angiographic evidence of atherosclerosis in at least 2 major epicardial vessels defined either as the presence of a stent, a coronary bypass graft, or an angiographic lesion of 60% or greater. Left main coronary artery disease that has been revascularized with a stent or bypass graft will qualify as multivessel disease, as will the presence of a 50% or greater isolated left main stenosis. The patient must also have completed any planned coronary revascularization procedures associated with the qualifying event, and be clinically stable for at least 60 days prior to screening.
- History of type 2 diabetes or metabolic syndrome at time of study enrollment;
- Willingness to participate as evidenced by signing the study informed consent.
- Prior history of chronic infectious disease, tuberculosis, or severe fungal disease; chronic hepatitis B or C infection; renal insufficiency; interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis; known chronic pericardial effusion, pleural effusion, or ascites; chronic liver disease; myeloproliferative disorders in the past 5 years; non-basal cell malignancy or treated lymphoproliferative disease within the past 5 years; known HIV positive; life expectancy of < 3 years;
- Chronic inflammatory condition such as lupus or rheumatoid arthritis, ulcerative colitis or Crohn’s disease
- White blood cell count < 4,000/ul, hematocrit < 32 percent, or platelet count < 75,000/ul
- Liver transaminase levels (AST or ALT) >upper limit of normal (ULN) or albumin < the lower limit of normal (LLN);
- Creatinine clearance < 40 ml/min as estimated with the Cockroft-Gault equation;
- History of alcohol abuse or unwillingness to limit alcohol consumption to less than 4 drinks per week
- Women of child bearing potential, even if they are currently using contraception, and women intending to breastfeed.
- Men who plan to father children during the study period or who are unwilling to use effective forms of contraception.
- Requirement for use of drugs that alter folate metabolism (trimethoprim/sulfamethoxazol) or reduce tubular excretion (probenecid) or known allergies to antibiotics making avoidance of trimethoprim impossible;
- Current indication for methotrexate therapy;
- Chronic use of oral steroid therapy or other immunosuppressive or biologic response modifiers (see Exclusionary Medication List in Manual of Operations). Eligible study participants will be encouraged to have up to date pneumococcal and influenza vaccinations as recommended based on their age and underlying medical conditions.
- Chest X-ray evidence in the past 12 months of interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis. For participants who do not have a chest X-ray in the prior 12 months, a chest X-ray will be obtained at baseline as part of the study protocol.
- New York Heart Association Class IV congestive heart failure.