Cardiovascular Inflammation Reduction Trial - Inflammation Imaging Study
Condition: Vascular Inflammation; Atherosclerotic Cardiovascular Disease
MeSH terms: Cardiovascular Diseases; Atherosclerosis; Inflammation
Intervention: Low dose methotrexate; Placebo
Intervention description: Study participants will additionally receive 1 mg daily oral folate.
Intervention MeSH terms: Methotrexate
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 123.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Atherosclerotic cardiovascular disease; Inflammation reduction

Summary:

      Vascular inflammation, a central feature of atherosclerosis, participates in the initiation,
      perpetuation and instability of plaques. Multiple clinical trials of cholesterol lowering
      therapy with statins have demonstrated that reductions in atherosclerotic cardiovascular
      disease (CVD) events are associated with reductions in both LDL cholesterol (LDL-C) and the
      systemic inflammatory mediator C-reactive protein (CRP). The Cardiovascular Inflammation
      Reduction Trial (CIRT) investigates if an anti-inflammatory agent commonly used in rheumatoid
      arthritis (low dose methotrexate (LDM)) can reduce CV morbidity and mortality among patients
      with a prior myocardial infarction or angiographically demonstrated multivessel coronary
      artery disease (GCO#13-1467).

      In this ancillary CIRT imaging study, the investigators propose to use this well validated
      approach by non-invasive serial FDG-PET/CT imaging in a subset of patients enrolled in the
      main CIRT trial to directly visualize vascular inflammation. Once the subjects are enrolled
      in the main CIRT trial, baseline imaging will be done and follow up imaging will be done
      approximately 8 months after the baseline imaging.

      18FDG-PET imaging data will be acquired, analyzed centrally and results incorporated into the
      main CIRT database. The investigators hypothesize that LDM treatment will result in a
      significant decrease in plaque inflammation as measured by 18-FDG-PET/CT after 8 months as
      compared to placebo.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age > 18 years at screening

          -  Documented MI in the past or past evidence of multivessel coronary artery disease by
             angiography must have completed any planned coronary revascularization procedures
             associated with the qualifying event, and must be clinically stable for at least 60 d
             before screening; the qualifying prior MI must be documented either by hospital
             records or by evidence on current electrocardiogram of Q waves in 2 contiguous leads
             and/or an imaging test demonstrating wall motion abnormality or scar; the qualifying
             documentation of multivessel coronary disease must include 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.

          -  History of type 2 diabetes or metabolic syndrome at the time of study enrollment

          -  Willing to participate as evidence by signing the study informed consent

        Exclusion Criteria:

          1. Prior history of chronic infectious disease, including tuberculosis, severe fungal
             disease, or known HIV positive

          2. Chronic hepatitis B or C infection

          3. Interstitial pneumonitis, bronchiectasis, or pulmonary fibrosis. Chest x-ray evidence
             in the past 12 months of interstitial pneumonitis, bronchiectasis, or pulmonary
             fibrosis.

          4. Prior history of non basal cell malignancy or myeloproliferative or
             lymphoproliferative disease within the past 5 years

          5. White blood cell count <3,500/mm3, hematocrit <32%, or platelet count <75000/mm3

          6. Liver transaminase levels (AST/ALT) greater than the upper limit of normal or albumin
             less than the lower limit of normal

          7. Creatinine clearance (CrCl) <40 mL/min as estimated by the Cockcroft-Gault equation

          8. History of alcohol abuse or unwillingness to limit alcohol consumption to <4 drinks
             per week

          9. Women of child bearing potential, even if currently using contraception, and women
             intending to breastfeed

         10. Men who plan to father children during the study period or who are unwilling to use
             contraception

         11. Requirement for use of drugs that alter folate metabolism
             (trimethoprim/sulfamethoxazoyl) or reduce tubular excretion (probenecid) or known
             allergies to antibiotics making avoidance of trimethoprim impossible

         12. Current indication for methotrexate therapy

         13. Chronic use of oral steroid therapy or other immunosuppressive or biologic response
             modifiers

         14. Known chronic pericardial effusion, pleural effusion, or ascites

         15. New York Heart Association class IV congestive heart failure

         16. Life expectancy of <3 years

        The study population for the ancillary study will be the same as the main trial with the
        following additional exclusion criteria

          1. Subjects with a history of multiple imaging studies associated with radiation exposure

          2. Insulin-dependent diabetics

          3. If subject is Type 2 diabetic, hemoglobin A1c greater than 8% as determined by patient
             medical record review in the one year prior to the date of consent to this study.

          4. BMI greater than 37 kg/m2 or weight greater than 350 pounds