Cardiovascular Inflammation Reduction Trial
Condition: Cardiovascular Disease
MeSH terms: Cardiovascular Diseases
Intervention: Methotrexate; Placebo
Intervention description: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week; Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
Intervention MeSH terms: Methotrexate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 4786.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Myocardial Infarction; Stroke; Cardiovascular death; Type 2 Diabetes; Metabolic Syndrome; Cardiovascular Inflammation; Atherothrombosis

Summary:

      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 or multiple
      coronary blockages. This trial is funded by the National Heart, Lung, and Blood Institute
      (NHLBI)/National Institutes of Health (NIH).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age ≥ 18 years at screening

          -  Documented past history of myocardial infarction OR past evidence of multivessel
             coronary artery disease by angiography.

               -  To qualify on the basis of past history of 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

        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 < 3,500/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 Cockcroft-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.