Cardiovascular Inflammation Reduction Trial (CIRT)

• Rate of all-cause mortality [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
• Rate of the primary endpoint plus coronary revascularization [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
• Rate of hospitalization for congestive heart failure [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
• Rate of primary endpoint plus all-cause mortality plus coronary revascularization plus congestive heart failure [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
• Rate of new onset type 2 diabetes among those with metabolic syndrome but not diabetes at study entry [ Time Frame: Up to six years ] [ Designated as safety issue: No ]

• Rate of all-cause mortality [ Time Frame: Four years ] [ Designated as safety issue: No ]
• Rate of hospitalization for congestive heart failure [ Time Frame: Four years ] [ Designated as safety issue: No ]
• Rate of incident venous thromboembolism [ Time Frame: Four years ] [ Designated as safety issue: No ]
• Rate of atrial fibrillation [ Time Frame: Four years ] [ Designated as safety issue: No ]
• Rate of percutaneous or surgical coronary revascularization [ Time Frame: Four years ] [ Designated as safety issue: No ]
• Rate of incident diabetes among those without diabetes at randomization [ Time Frame: Four years ] [ Designated as safety issue: No ]

• Rate of the primary endpoint plus unstable angina requiring unplanned coronary revascularization [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
• Rate of coronary revascularization [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
• Rate of peripheral artery disease [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
• Rate of symptomatic deep vein thrombosis or pulmonary embolism, including those considered to be provoked and those considered to be idiopathic [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
• Rate of clinically significant aortic stenosis [ Time Frame: Up to six years ] [ Designated as safety issue: No ]
• Rate of atrial fibrillation [ Time Frame: Up to six years ] [ Designated as safety issue: No ]

The Cardiovascular Inflammation Reduction Trial (CIRT) is a randomized clinical trial investigating whether taking low-dose methotrexate reduces heart attacks, strokes, or death in people with type 2 diabetes or metabolic syndrome that have had a heart attack. This trial is funded by the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH).

While inflammation contributes crucially to atherothrombosis, it is unknown whether inhibition of inflammation per se will lower vascular event rates. The primary aim of the Cardiovascular Inflammation Reduction Trial (CIRT) is to directly test the inflammatory hypothesis of atherothrombosis by evaluating whether or not low-dose methotrexate (LDM) will reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable post-myocardial infarction patients with type 2 diabetes or metabolic syndrome, conditions associated with an enhanced pro-inflammatory response. CIRT is a randomized, double-blind, placebo-controlled, multi-center, event-driven trial that will randomize 7,000 men and women from the United States and Canada. Following a five- to six-week open-label run-in (maximum 8 weeks), eligible participants who have suffered documented myocardial infarction in the past five years will be randomly allocated over a three to four year period to usual care plus placebo or usual care plus LDM. The target methotrexate dose among those allocated to active therapy is 15 to 20 mg po per week, a dose within the range of that commonly used for the treatment of rheumatoid arthritis. All study participants will additionally receive 1.0 mg oral folate to be taken daily six days per week. LDM complications will be minimized through education programs for all investigators and coordinators, through enhanced communication with study participants, by limiting enrollment to those with no evidence of malignancy, hepatitis, renal dysfunction, chronic infection, pulmonary disease, or other risk factors for toxicity; by conducting an initial 5- to 6-week active-therapy run-in (maximum 8 weeks) designed to eliminate individuals who are either intolerant of or unable to adhere to treatment before randomization; and through regular monitoring of liver function and hematologic indices using a centralized methodology designed to ensure participant safety, allow for dose adjustments while maintaining the study blind, and provide an efficient method to address issues of compliance and follow-up on a cost-effective centralized basis. The primary trial endpoint is the rate of recurrent myocardial infarction, stroke, or cardiovascular death. Secondary and tertiary endpoints include all-cause mortality, coronary revascularization, incident congestive heart failure, incident peripheral artery disease, incident venous thrombosis, clinically significant aortic stenosis, incident atrial fibrillation, incident diabetes among those with metabolic syndrome but not diabetes at study entry, and hemoglobin A1c (HbA1c) control among those with diabetes at study entry. The trial is event driven such that in the absence of extreme effects, the trial will conclude after accrual of at least 530 primary endpoints, an effect estimated to provide 90 percent power to detect a 25 percent relative risk reduction. The potential clinical impact of CIRT is broad as it has sufficient power to directly address core issues in the inflammatory hypothesis of atherothrombosis, and thus, if successful, will open major new directions for cardiovascular treatment.

• Drug: Methotrexate
  Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week
  Other Name: Trexall, TEVA Inc (brand of methotrexate)
• Drug: Placebo
  Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week

• Experimental: Methotrexate
  Intervention: Drug: Methotrexate
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

• Age ≥ 18 years at screening
• Documented myocardial infarction within the past five years, completed any planned coronary revascularization procedures associated with the qualifying event, and have been clinically stable for at least 60 days prior to screening; the qualifying prior myocardial infarction 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
• History of type 2 diabetes or metabolic syndrome at time of study enrollment
• Willingness to participate as evidenced by signing the study informed consent

Exclusion Criteria:

• 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. 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.