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A Randomized, Double-blind, Placebo-controlled, Event-driven Trial of Weekly Low-dose Methotrexate (LDM) in the Prevention of Cardiovascular Events Among Stable Coronary Artery Disease Patients With Type 2 Diabetes or Metabolic Syndrome

Description

Brief 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).


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.

Phase

Phase 3 - a treatment has shown activity against a particular disease, where it is either added to existing treatment or compared to the standard treatment.

Inclusion and Exclusion 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

  • 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.

Sites

  • California

    • Axis Clinical Trials, Los Angeles, California, 90017
    • Huntington Memorial Hospital, Pasadena, California, 91105
    • Axis Clinical Trials, Los Angeles, California, 90036
    • Ram Dandillaya MD, Inc., Beverly Hills, California, 90211
    • Shervin Eshaghian M.D., Inc. (Beverly Hills Cardiology), Los Angeles, California, 90067
    • Medical Group of Culver City, Culver City, California, 90230
    • West LA VA Medical Center, Los Angeles, California, 90049
    • Long Beach Center for Clinical Research, Long Beach, California, 90807
    • Torrance Clinical Research Inc, Lomita, California, 90717
    • Anthony Mills M.D., Inc., Los Angeles, California, 90096
    • Los Alamitos Cardiovascular, Los Alamitos, California, 90720
    • Valley Clinical Trials, Inc., Northridge, California, 91325
    • Orange County Heart Institute & Research, Orange, California, 92868
    • University of CA Irvine Medical Center, Orange, California, 92868
    • Coastal Heart Medical Group, Inc., Santa Ana, California, 92704
    • Manoj D. Aswani M.D., Thousand Oaks, California, 91360
    • Kumar Medical Corporation, Lancaster, California, 93534
    • Spectrum Clinical Research Institute, Inc., Moreno Valley, California, 92553
    • Shiva Heart Center, Wildomar, California, 92595
    • Foundation for Cardiovascular Medicine, San Diego, California, 92121
    • Veterans Affairs San Diego Healthcare System, San Diego, California, 92161
    • UCSD Sulpizio Cardiovascular Center, La Jolla, California, 92037
    • Ritchken and First MDs, San Diego, California, 92117
    • Eisenhower Desert Cardiology Center, Rancho Mirage, California, 92270
    • San Diego Cardiac Center, San Diego, California, 92123
    • Richard G. Friedman, MD, San Diego, California, 92103
    • Central Cardiology Medical Clinic, Bakersfield, California, 93308
    • Albert Sharf, MD, National City, California, 91950
    • Comprehensive Cardiovascular Care, Santa Maria, California, 93454
    • Arroya Medical Group, Pismo Beach, California, 93449
    • Central Coast Cardiology, Salinas, California, 93901
    • Central Coast Cardiology, Monterey, California, 93940
    • Pacific Heart and Vascular Medical Group, Stockton, California, 95210
    • Touro University California- Solano County Affiliated Clinics, Fairfield, California, 94533
    • Touro University California- Solano Public Health Affiliated Clinics, Vallejo, California, 94592

  • Nevada

    • Internal Medicine Clinic, Las Vegas, Nevada, 89102
    • Impact Clinical Trials, Las Vegas, Nevada, 89106
    • Accent Clinical Trials, Las Vegas, Nevada, 89106
    • Sierra Nevada Health Care System, Reno, Nevada, 89502
    • Renown Inst for Heart & Vasc Health, Reno, Nevada, 89503

  • Arizona

    • Heart Vascular of Northern Arizona, COttonwood, Arizona, 86326
    • Arizona Arthritis & Rheumatology Associates, PC, Phoenix, Arizona, 85032
    • Maricopa Integrated Health System, Phoenix, Arizona, 85008
    • The Heart Clinic, Scottsdale, Arizona, 85258
    • Scottsdale Medical Imaging, Scottsdale, Arizona, 85258
    • CardioVascular Associates of Mesa, Mesa, Arizona, 85206
    • U of Arizona Medical Center South Campus, Tucson, Arizona, 85713
    • Pima Heart, Tucson, Arizona, 85718
    • University of Arizona Sarver Heart Center, Tucson, Arizona, 85724

  • Utah

    • Utah Diabetes Center, Salt Lake City, Utah, 84108

  • Oregon

    • Southern Oregon Cardiology, LLC, Medford, Oregon, 97504
    • Samaritan Health Services, Corvallis, Oregon, 97330

  • New Mexico

    • Presbyterian Heart Group, Albequerque, New Mexico, 87106

  • Idaho

    • Saint Alphonsus Regional Medical Center, Boise, Idaho, 83706
    • St. Luke's Idaho Cardiology Associates, Boise, Idaho, 83712

  • Washington

    • Northwest Medical Associates, P.S., Vancouver, Washington, 98684
    • Kootenai Heart Clinics, LLC, Spokane, Washington, 99204

  • Colorado

    • Medical Center of the Rockies Research, Fort Collins, Colorado, 80528

  • Montana

    • Great Falls Clinic Clinical Research Deptartment, Great Falls, Montana, 59420

  • Texas

    • Heart Center, Palo Pinto General Hospital, Mineral Wells, Texas, 76067
    • San Antonio Endovascular & Heart Institute, San Antonio, Texas, 78268
    • Texas Health Physicians Group, Fort Worth, Texas, 76107
    • Methodist Hospital San Antonio TX, Live Oak, Texas, 78233
    • The Medical Group of Texas, Fort Worth, Texas, 76104
    • T&R Clinic, P.A., Haltom City, Texas, 76117
    • Southlake Clinical Trials, Southlake, Texas, 76092
    • Texas Heart and Vascular Research, LLC, Austin, Texas, 78745
    • Texas Health Physicians Group, Carrollton, Texas, 75010
    • The Heart Center of Dallas, Dallas, Texas, 75235
    • Medical Clinic of North Texas, Plano, Texas, 75023
    • Dallas VA Medical Center, Dallas, Texas, 75216
    • North Texas Health Center, Dallas, Texas, 75231
    • Valley Central Research Inc, Mission, Texas, 78572
    • Valley Heart Consultants, McAllen, Texas, 78503
    • Northwest Houston Clinical Research, Tomball, Texas, 77375
    • Amcare Clinical Research, Inc., Houston, Texas, 77090
    • Cardiology Consultants of Houston, Houston, Texas, 77030
    • Michele P. Sartori, MD, Houston, Texas, 77030
    • Grace Research, LLC, Marshall, Texas, 75670
    • Southeast TX Clinical Research Center, Beaumont, Texas, 77702

  • Oklahoma

    • COR Clinical Research, LLC, Oklahoma City, Oklahoma, 73103
    • Oklahoma State University Center for Health Sciences, Tulsa, Oklahoma, 74127

  • Kansas

    • Professional Research Network of KS, Wichitia, Kansas, 67203

  • Nebraska

    • University of Nebraska Medical Center, Omaha, Nebraska, 68198
    • Heart Consultants, Omaha, Nebraska, 68114

  • Missouri

    • Freeman Health System, Joplin, Missouri, 64804
    • Saint Luke's Lipid & Diabetes Research, Kansas City, Missouri, 64111
    • The Kansas City Free Health Clinic, Kansas City, Missouri, 64111
    • Truman Medical Center, Kansas City, Missouri, 64108
    • Midwest Heart and Vascular Specialists, Kansas City, Missouri, 64132
    • VA Medical Center Kansas City, Kansas City, Missouri, 64128
    • Midwest Cardiology Associates, Independence, Missouri, 64057
    • Mercy Medical Research Institute, Springfield, Missouri, 65807
    • CoxHealth: Wheeler Heart & Vascular Center, Springfield, Missouri, 65807
    • Lake Regional Cardiovascular Institute, Osage Beach, Missouri, 65065
    • Clinical Research Center University of Missouri, Columbia, Missouri, 65212
    • Quantum Research LLC, Festus, Missouri, 63028
    • Consult and Research Associates, St. Louis, Missouri, 63122
    • SLUCare Cardiology, St. Louis, Missouri, 63110

  • Louisiana

    • Veterans Affairs Medical Center Shreveport, Shreveport, Louisiana, 71101
    • Grace Research, LLC, Bossier City, Louisiana, 71111
    • Otis Barnum D.O.P.C., Natchitoches, Louisiana, 71457
    • Southern Clinical Research, Zachary, Louisiana, 70791
    • North Oaks Cardiology, Hammond, Louisiana, 70403
    • Dorothy H. Banish, MD, APMC Study Group, Covington, Louisiana, 70433
    • American Clinical Research, LLC, Marrero, Louisiana, 70072
    • Tulane University Office of Health Research, New Orleans, Louisiana, 70112

  • Iowa

    • Iowa Heart Center, West Des Moines, Iowa, 50266

  • Arkansas

    • Michael A. Frais, Cardiologist, P.A., Hot Springs, Arkansas, 71913
    • Arkansas Heart Hospital, Little Rock, Arkansas, 72211
    • Arkansas Cardiology, Little Rock, Arkansas, 72205

  • Minnesota

    • Centra Care Heart & Vascular Center at St. Cloud Hospital, St. Cloud, Minnesota, 56303
    • United Heart and Vascular Clinic, Saint Paul, Minnesota, 55102

  • Mississippi

    • David M. Headley M.D. PA Planters Clinic, Port Gibson, Mississippi, 39150
    • Stern Cardiovascular Foundation, Inc., Southaven, Mississippi, 38671
    • University of MS Medical Center, Jackson, Mississippi, 39216
    • Hattiesburg Clinic, Hattiesburg, Mississippi, 39402
    • Gulfside Clinical Research, LLC, Gulfport, Mississippi, 39501

  • Tennessee

    • Stern Cardiovascular Foundation, Inc., Germantown, Tennessee, 38138
    • Kore Cardiovascular Research Institutue, Jackson, Tennessee, 38305
    • Clinical Research Center Meharry Medical College, Nashville, Tennessee, 37208
    • Parkway Medical Group, Fayetteville, Tennessee, 37334

  • Wisconsin

    • Marshfield Clinic, Marshfield, Wisconsin, 54449
    • Dean Foundation, Madison, Wisconsin, 53715
    • Cardiology Associates of Bellin Health, Green Bay, Wisconsin, 54115

  • Illinois

    • Illinois Heart & Lung Research Center, SC, Normal, Illinois, 61761
    • Northwest Heart Clinical Research, Arlington Heights, Illinois, 60005
    • Tien C. Cheng, Gurnee, Illinois, 60031
    • Captain James A. Lovell Federal Health, North Chicago, Illinois, 60064
    • Advocate Med Group-Heart & Vascular Of Illinois, Chicago, Illinois, 60657
    • University of Chicago Medical Center, Chicago, Illinois, 60637

  • Indiana

    • Cardiospecialists, LTD, Dyer, Indiana, 46311
    • The Heart Center of Lake County, Merriville, Indiana, 46410
    • Community Hospital South, Indianapolis, Indiana, 46227
    • Indiana Heart Physicians, Indianapolis, Indiana, 46237
    • Medical Consultants, PC, Muncie, Indiana, 47303

  • Kentucky

    • Research Integrity LLC, Owensboro, Kentucky, 42303
    • Krishnan Challappa M.D. PSC, Elizabethtown, Kentucky, 42701
    • University of Kentucky, Lexington, Kentucky, 40536

  • Alabama

    • University of South Alabama: Division of Clinical Research, Mobile, Alabama, 36617
    • Adamsville Family Medicine, Adamsville, Alabama, 35005
    • University of Alabama Birmingham, Birmingham, Alabama, 35294
    • Saadat Ansari MD LLC, Huntsville, Alabama, 35801

  • Georgia

    • Heart and Rhythm Specialists, Dalton, Georgia, 30720
    • Atlanta Vanguard Medical Associates, Smyrna, Georgia, 30082
    • Synergy Therapeutic Partners, Atlanta, Georgia, 30308
    • Laureate Medical Group at Northside, Atlanta, Georgia, 30308
    • Albert F. Johary MD, PC, Dunwoody, Georgia, 30338
    • Atlanta Veterans Affairs Medical Center, Atlanta, Georgia, 30033
    • Atlanta Heart Specialists, LLC, Tucker, Georgia, 30084

  • Ohio

    • The Lindner Research Center, Cincinnati, Ohio, 45219
    • Middletown Cardiovascular Associates, Middletown, Ohio, 45044
    • Dayton Veteran Affairs Medical Center, Dayton, Ohio, 45428
    • Dayton Heart Center, Dayton, Ohio, 45414
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