Cardiovascular Inflammation Reduction Trial



Status:Active, not recruiting
Conditions:Peripheral Vascular Disease, Cardiology, Endocrine
Therapuetic Areas:Cardiology / Vascular Diseases, Endocrinology
Healthy:No
Age Range:18 - Any
Updated:4/17/2018
Start Date:April 2013
End Date:December 2019

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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

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).

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.

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 Cockroft-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.
We found this trial at
406
sites
111 Brewster St
Pawtucket, Rhode Island 02860
(401) 729-2000
Memorial Hospital of Rhode Island Memorial Hospital of Rhode Island is a 294-bed community teaching...
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1720 2nd Ave S
Birmingham, Alabama 35233
(205) 934-4011 
University of Alabama at Birmingham The University of Alabama at Birmingham (UAB) traces its roots...
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1720 2nd Ave S
Birmingham, Alabama 35233
(205) 934-4011 
University of Alabama at Birmingham The University of Alabama at Birmingham (UAB) traces its roots...
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75 Francis street
Boston, Massachusetts 02115
(617) 732-5500
Brigham and Women's Hosp Boston’s Brigham and Women’s Hospital (BWH) is an international leader in...
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3550 Jerome Avenue
Bronx, New York 10467
(718) 920-4321
Montefiore Medical Center As the academic medical center and University Hospital for Albert Einstein College...
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9500 Euclid Avenue
Cleveland, Ohio 44106
216.444.2200
Cleveland Clinic Cleveland Clinic is committed to principles as presented in the United Nations Global...
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5258 Linton Blvd # 205
Delray Beach, Florida 33484
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Gainesville, Florida 32610
(352) 392-3261
University of Florida The University of Florida (UF) is a major, public, comprehensive, land-grant, research...
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Los Angeles, California 90033
213) 740-2311
University of Southern California The University of Southern California is one of the world’s leading...
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3400 Spruce St
Philadelphia, Pennsylvania 19104
 (215) 662-4000
Hospital of the University of Pennsylvania The Hospital of the University of Pennsylvania (HUP) is...
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3181 Southwest Sam Jackson Park Road
Portland, Oregon 97239
503 494-8311
Oregon Health and Science University In 1887, the inaugural class of the University of Oregon...
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Abington, Pennsylvania 19001
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1 Akron General Ave
Akron, Ohio 44307
(330) 344-6000
Akron General Medical Center It
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47 New Scotland Ave
Albany, New York 12208
(518) 262-3125
Albany Medical College Albany Medical Center is northeastern New York's only academic health sciences center...
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Albany, New York 12208
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Albuquerque, New Mexico 87106
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Alpena, Michigan 49707
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Anaheim, California 92801
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Arlington Heights, Illinois 60005
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Asheville, North Carolina 28803
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Athens, Georgia 30606
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Atlanta, Georgia 30127
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1000 Johnson Ferry Rd NE
Atlanta, Georgia 30342
(404) 851-8000
Northside Hospital Northside Hospital-Atlanta (in Sandy Springs) opened in 1970. The original facility had 250...
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Auburn, Maine 04210
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Austin, Texas 78745
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Austin, Texas 78704
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Aventura, Florida 33180
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Baltimore, Maryland 21215
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Bangor, Maine 04401
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Biddeford, Maine 04005
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Big Spring, Texas 79720
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Boca Raton, Florida 33434
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Boston, Massachusetts 02135
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Boston, Massachusetts 02214
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One Joslin Place
Boston, Massachusetts 02215
617-309-2400
Joslin Diabetes Center Joslin Diabetes Center, located in Boston, Massachusetts, is the world's largest diabetes...
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Bridgeport, Connecticut 06606
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Bridgeport, Connecticut 06610
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Bronx, New York 10461
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Brooklyn, New York 11203
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1991 Sproul Road
Broomall, Pennsylvania 19008
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Buffalo, New York 14215
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Burke, Virginia 22015
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Burlington, Massachusetts 01805
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Camp Hill, Pennsylvania 17011
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Carrollton, Texas 75010
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2138 North Josey Lane
Carrollton, Texas 75006
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Chambersburg, Pennsylvania 17201
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Charlotte, North Carolina 28204
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Charlotte, North Carolina 28205
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2001 Vail Avenue
Charlotte, North Carolina 28215
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Charlotte Hall, Maryland 20622
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Chattanooga, Tennessee 37409
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5841 S Maryland Ave
Chicago, Illinois 60637
(773) 702-1000
University of Chicago Medical Center The University of Chicago Medicine has been at the forefront...
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Cincinnati, Ohio 45219
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Clearwater, Florida 33765
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Clinton, Maryland 20735
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Colorado Springs, Colorado 80910
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Columbia, South Carolina 29204
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Columbia, South Carolina 29223
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Columbus, Ohio 43235
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Cooperstown, New York 13326
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3900 West Flagler Street
Coral Gables, Florida 33134
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Cortlandt Manor, New York 10567
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Corvallis, Oregon 97330
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COttonwood, Arizona 86326
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Covington, Louisiana 70433
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Crowley, Louisiana 70526
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Culver City, California 90230
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Cumberland, Rhode Island 02864
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Cumming, Georgia 30041
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Cutler Bay, Florida 33157
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Dallas, Texas 75231
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Dalton, Georgia 30720
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Dayton, Ohio 45414
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Daytona Beach, Florida 32114
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Deland, Florida 32720
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Denver, Colorado 80218
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DeSoto, Texas 75115
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2799 W Grand Blvd
Detroit, Michigan 48202
(313) 916-2600
Henry Ford Hospital Founded in 1915 by auto pioneer Henry Ford and now one of...
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Doral, Florida 33126
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Doylestown, Pennsylvania 18901
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