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Cardiovascular Inflammation R...

Cardiovascular Inflammation Reduction Trial

Last Updated: 2020-07-24

Study Results

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

4786 participants

Study Classification

INTERVENTIONAL

Study Start Date

2013-04-30

Study Completion Date

2019-10-30

Brief Summary

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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).

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Detailed Description

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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

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Cardiovascular Disease

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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Methotrexate

Methotrexate: Tablet, Oral, Target dose 15-20mg weekly plus 1.0 mg folic acid 6 days/week

Group Type EXPERIMENTAL

Methotrexate

Intervention Type DRUG

Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week

Placebo

Placebo: Tablet, Oral weekly plus 1.0mg folic acid 6 days/week

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week

Interventions

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Methotrexate

Tablet, Oral, Target dose 15-20 mg weekly plus 1.0 mg folic acid 6 days/week

Intervention Type DRUG

Placebo

Tablet, Oral, weekly plus 1.0 mg folic acid 6 days/week

Intervention Type DRUG

Other Intervention Names

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Trexall, TEVA Inc (brand of methotrexate)

Eligibility Criteria

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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.

Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Responsible Party

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Paul Ridker

Director, Center for Cardiovascular Disease and Prevention, Brigham and Women's Hospital

Responsibility Role PRINCIPAL_INVESTIGATOR

Principal Investigators

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Paul Ridker, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

Brigham and Women's Hospital

Locations

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University of Alabama at Birmingham

Birmingham, Alabama, United States

Site Status

Appalachian Research Associates

Fort Payne, Alabama, United States

Site Status

Avant Research Associates, LLC

Guntersville, Alabama, United States

Site Status

Saadat Ansari MD LLC

Huntsville, Alabama, United States

Site Status

University of South Alabama: Division of Clinical Research

Mobile, Alabama, United States

Site Status

Heart Vascular of Northern Arizona

Cottonwood, Arizona, United States

Site Status

CardioVascular Associates of Mesa

Mesa, Arizona, United States

Site Status

Arizona Arthritis & Rheumatology Research

Phoenix, Arizona, United States

Site Status

Scottsdale Medical Imaging

Scottsdale, Arizona, United States

Site Status

The Heart Clinic

Scottsdale, Arizona, United States

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Pima Heart

Tucson, Arizona, United States

Site Status

Southern Arizona VA Health Care System

Tucson, Arizona, United States

Site Status

Arkansas Cardiology

Little Rock, Arkansas, United States

Site Status

Arkansas Heart Hospital

Little Rock, Arkansas, United States

Site Status

Oracle Clinical Research, Inc.

Anaheim, California, United States

Site Status

Medical Group of Culver City

Culver City, California, United States

Site Status

Touro University California- Solano County Affiliated Clinics

Fairfield, California, United States

Site Status

University Of California San Francisco

Fresno, California, United States

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VACCHCS

Fresno, California, United States

Site Status

UCSD Sulpizio Cardiovascular Center

La Jolla, California, United States

Site Status

University Of California San Diego

La Jolla, California, United States

Site Status

Desert Medical Care & Wellness

La Quinta, California, United States

Site Status

Kumar Medical Corporation

Lancaster, California, United States

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Loma Linda University Health

Loma Linda, California, United States

Site Status

VA Loma Linda Healthcare System

Loma Linda, California, United States

Site Status

Long Beach Center for Clinical Research

Long Beach, California, United States

Site Status

Cardiovascular Innovation and Research

Long Beach, California, United States

Site Status

Los Alamitos Cardiovascular

Los Alamitos, California, United States

Site Status

Faye Montegrande Md. Clinical Research

Los Angeles, California, United States

Site Status

Eastside Clinical Research Associates

Los Angeles, California, United States

Site Status

Salman Khan A. Medical Corporation

Los Angeles, California, United States

Site Status

University of Southern California

Los Angeles, California, United States

Site Status

West LA VA Medical Center

Los Angeles, California, United States

Site Status

VA Northern California Health Care

Mather, California, United States

Site Status

Valley Clinical Trials, Inc.

Northridge, California, United States

Site Status

Orange County Heart Institute & Research

Orange, California, United States

Site Status

University of CA Irvine Medical Center

Orange, California, United States

Site Status

Diverse Research Solutions

Oxnard, California, United States

Site Status

Huntington Memorial Hospital

Pasadena, California, United States

Site Status

Central Coast Cardiology

Salinas, California, United States

Site Status

Richard G. Friedman, MD

San Diego, California, United States

Site Status

Ritchken and First MDs

San Diego, California, United States

Site Status

Foundation for Cardiovascular Medicine

San Diego, California, United States

Site Status

San Diego Cardiac Center

San Diego, California, United States

Site Status

Veterans Affairs San Diego Healthcare System

San Diego, California, United States

Site Status

UCSF at Zuckerberg SF General Hospital

San Francisco, California, United States

Site Status

Coastal Heart Medical Group, Inc.

Santa Ana, California, United States

Site Status

Comprehensive Cardiovascular Care

Santa Maria, California, United States

Site Status

Pacific Heart and Vascular Medical Group

Stockton, California, United States

Site Status

Manoj D. Aswani M.D.

Thousand Oaks, California, United States

Site Status

Touro University California- Solano Public Health Affiliated Clinics

Vallejo, California, United States

Site Status

Munni R. Selagamsetty, Md, Pc

Colorado Springs, Colorado, United States

Site Status

Vijay - Aurora Denver Cardiology

Denver, Colorado, United States

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Colorado Health Medical Group Heart Center of the Rockies

Fort Collins, Colorado, United States

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Medical Center of the Rockies Research

Fort Collins, Colorado, United States

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Unrein - Rocky Vista University Health Center

Parker, Colorado, United States

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Connecticut Heart and Vascular Center

Bridgeport, Connecticut, United States

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Bridgeport Hospital

Bridgeport, Connecticut, United States

Site Status

Cardiology Physicians/Red Clay Research

Newark, Delaware, United States

Site Status

Boisey Barnes MD, PC

Washington D.C., District of Columbia, United States

Site Status

GWU Medical Faculty Associatin, Inc.

Washington D.C., District of Columbia, United States

Site Status

Pianko - Aventura Research Center, LLC

Aventura, Florida, United States

Site Status

North Ridge Heart Associates

Boca Raton, Florida, United States

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St. Francis Medical Institute

Clearwater, Florida, United States

Site Status

Gonzalez MD & Aswad MD Health Ser

Coral Gables, Florida, United States

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American Research Institute, Inc.

Cutler Bay, Florida, United States

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Daytona Heart Group

Daytona Beach, Florida, United States

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Daytona Heart Group

DeLand, Florida, United States

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Seidman Clinical Trials

Delray Beach, Florida, United States

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Steven Cohen MD

Delray Beach, Florida, United States

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Infinite Clinical Research

Doral, Florida, United States

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International Research Partners, LLC

Doral, Florida, United States

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Medical Research Institute at Doral, Inc.

Doral, Florida, United States

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Lake Internal Medicine Assocaties

Eustis, Florida, United States

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Invesclinic

Fort Lauderdale, Florida, United States

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Primary Care Associates

Fort Myers, Florida, United States

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Lee Physician Group

Fort Myers, Florida, United States

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The Cardiac and Vascular Institute

Gainesville, Florida, United States

Site Status