Cardiovascular Inflammation Reduction Trial "CIRT"

Recruiting

Phase 3 Results N/A

Trial Description

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).

Detailed Description

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 myocardial infarction, stroke, and cardiovascular death among stable coronary artery disease 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 either suffered documented myocardial infarction in the past or have angiographically demonstrated multivessel coronary artery disease in the past 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 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.

Conditions

Interventions

  • Placebo Drug
    Intervention Desc: Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week
    ARM 1: Kind: Experimental
    Label: Placebo
  • Methotrexate Drug
    Other Names: Trexall, TEVA Inc (brand of methotrexate)
    Intervention Desc: Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week
    ARM 1: Kind: Experimental
    Label: Methotrexate

Trial Design

  • Allocation: Randomized
  • Masking: Double Blind (Subject, Caregiver, Investigator)
  • Purpose: Treatment
  • Endpoint: Safety/Efficacy Study
  • Intervention: Parallel Assignment

Outcomes

Type Measure Time Frame Safety Issue
Primary Rate of recurrent major cardiovascular events Four years No
Secondary Rate of all-cause mortality Four years No
Secondary Rate of hospitalization for congestive heart failure Four years No
Secondary Rate of incident venous thromboembolism Four years No
Secondary Rate of atrial fibrillation Four years No
Secondary Rate of percutaneous or surgical coronary revascularization Four years No
Secondary Rate of incident diabetes among those without diabetes at randomization Four years No
Secondary Incident peripheral artery disease Four years No
Secondary Clinically worsening aortic stenosis Four years No
Secondary Rate of the primary endpoint plus coronary revascularization Up to six years No
Secondary Rate of primary endpoint plus all-cause mortality plus coronary revascularization plus congestive heart failure Up to six years No
Secondary Rate of new onset type 2 diabetes among those with metabolic syndrome but not diabetes at study entry Up to six years No
Primary Rate of major cardiovascular events Up to six years No

Sponsors