Cardiovascular Inflammation Reduction Trial

Cardiovascular Disease Clinical Trial

— CIRT  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01594333
• Other study ID #: 2012P-000857
• Secondary ID: U01HL101422U01HL
• Status: Completed
• Phase: Phase 3
• Start date: April 2013
• Est. completion date: October 30, 2019

Study information

• Verified date: July 2020
• Source: Brigham and Women's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4786
• Est. completion date: October 30, 2019
• Est. primary completion date: April 15, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cardiovascular Disease
• Cardiovascular Diseases

Intervention

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

Locations

Country	Name	City	State
Canada	Bramalea Medical Centre	Brampton	Ontario
Canada	Brampton Research Associates	Brampton	Ontario
Canada	Viacar Recherche Clinique Inc.	Brossard	Quebec
Canada	Philippe R Beaudry Medicine Professional Corporation	Burlington	Ontario
Canada	Vizel Cardiac Research	Cambridge	Ontario
Canada	Dr. Linda Sinnaeve's Office	Chatham	Ontario
Canada	Ecogene-21	Chicoutimi	Quebec
Canada	Q&T Research Chicoutimi	Chicoutimi	Quebec
Canada	Scisco Clinical Research	Cornwall	Ontario
Canada	Viacar Recherche Clinique Inc.	Greenfield Park	Quebec
Canada	Dr. Peter Spadafora Health Center	Guelph	Ontario
Canada	Dr. William Liang	Hamilton	Ontario
Canada	John Stimac, MD	Hamilton	Ontario
Canada	KMH Cardiology & Diagnostics: Hamilton	Hamilton	Ontario
Canada	Source Unique Clinic	Hawkesbury	Ontario
Canada	Dr. Ronald Fowlis	Kitchener	Ontario
Canada	University Hospital	London	Ontario
Canada	KMH Cardiology & Diagnostics: Mississauga	Mississauga	Ontario
Canada	Malton Medical Research	Mississauga	Ontario
Canada	Sewa Ram Singal Medicine Professional Corporation	Mississauga	Ontario
Canada	CHUM Hotel-Dieu	Montreal	Quebec
Canada	Newmarket Cardiology Research Group	Newmarket	Ontario
Canada	Newmarket Cardiology Research Group	Newmarket	Ontario
Canada	Portage Medical Centre	Niagara Falls	Ontario
Canada	The Medical Arts Health Research Group	North Vancouver	British Columbia
Canada	Humber River Regional Hospital	North York	Ontario
Canada	Bakbak Medicine Professional Corporation	Oshawa	Ontario
Canada	Dr. James Y. Cha	Oshawa	Ontario
Canada	University Of Ottawa Heart Institute	Ottawa	Ontario
Canada	The Medical Arts Health Research Group	Penticton	British Columbia
Canada	Kawartha Cardiology Clinical Trials	Peterborough	Ontario
Canada	Steeple Hill Medical Centre	Pickering	Ontario
Canada	Recherche Clinique Sigma, Inc.	Quebec
Canada	ALPHA Recherche Clinique	Québec	Quebec
Canada	Iucpq	Quebec City	Quebec
Canada	CardioVasc HR	Saint-Jean-sur-Richelieu	Quebec
Canada	ViaCar Recherche Clinique Inc	Saint-Lambert	Quebec
Canada	Sarnia Institute Of Clinical Research	Sarnia	Ontario
Canada	Milliken Medical Centre	Scarborough	Ontario
Canada	Scarborough Cardiology Research	Scarborough	Ontario
Canada	Scarborough General Hospital Cardiology Research Associates	Scarborough	Ontario
Canada	Canadian Centre for Research on Diabetes	Smith Falls	Ontario
Canada	Lake Shore Cardiology	St. Catharines	Ontario
Canada	Viacar Recherche Clinique	St. Lambert	Quebec
Canada	Sardar Medical Clinic	St. Thomas	Ontario
Canada	Dr. G. Garrioch, Independent Practice	Sudbury	Ontario
Canada	Dr. R. Labonte Professional Med Corp	Sudbury	Ontario
Canada	G.S. Cardiac Lab Medicine Professional Corp	Sudbury	Ontario
Canada	Hopital Pierre-Le Gardeur	Terrebonne	Quebec
Canada	Dr. Laurence Gibbs Medicine Professional Corp.	Thedford	Ontario
Canada	Tillsonburg Medical Centre	Tillsonburg	Ontario
Canada	Humber River Hospital	Toronto	Ontario
Canada	Mount Sinai Hospital	Toronto	Ontario
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	Toronto General Hospital	Toronto	Ontario
Canada	Weston Road Medical Clinic	Toronto	Ontario
Canada	Dr. Nigel Jagan Medicine Professional Corporation	Whitby	Ontario
Canada	Dr. Nwadiaro Medicine Professional Corp	Windsor	Ontario
Canada	Winnipeg Clinic	Winnipeg	Manitoba
Puerto Rico	Instituto Sanacoop	Bayamón
Puerto Rico	San Juan Bautista School of Medicine	Caguas
Puerto Rico	Norma S. Severino-Pacheco, MD	Canovanas
Puerto Rico	Cardiometabolic Research Center	Ponce
Puerto Rico	Miguel Sosa-Padilla, MD	San Juan
Puerto Rico	Yolanda Sierra Quinones, MD	Toa Baja
United States	Center for Clinical Res. Abington Health	Abington	Pennsylvania
United States	Akron General Medical Center	Akron	Ohio
United States	Albany Medical College	Albany	New York
United States	Albany Stratton VA Medical Center	Albany	New York
United States	Presbyterian Heart Group	Albuquerque	New Mexico
United States	Endeavor Medical Research	Alpena	Michigan
United States	Oracle Clinical Research, Inc.	Anaheim	California
United States	Northwest Heart Clinical Research	Arlington Heights	Illinois
United States	Clinical Study Center of Asheville	Asheville	North Carolina
United States	Athens Regional Medical Center	Athens	Georgia
United States	Ohio University Heritage College of Osteopathic Medicine	Athens	Ohio
United States	Atlanta Veterans Affairs Medical Center	Atlanta	Georgia
United States	Laureate Medical Group at Northside	Atlanta	Georgia
United States	Northside Hospital	Atlanta	Georgia
United States	Synergy Therapeutic Partners	Atlanta	Georgia
United States	Maine Research Associates	Auburn	Maine
United States	Avant Research Associates LLC	Austin	Texas
United States	Texas Heart and Vascular Research, LLC	Austin	Texas
United States	Pianko - Aventura Research Center, LLC	Aventura	Florida
United States	Sinai Center for Thrombosis Research	Baltimore	Maryland
United States	Paul A. Shapero, M.D.	Bangor	Maine
United States	Southeast TX Clinical Research Center	Beaumont	Texas
United States	St. Luke's University Hospital	Bethlehem	Pennsylvania
United States	Southern Maine Health Care	Biddeford	Maine
United States	Cornerstone Family Medicine	Big Spring	Texas
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	North Ridge Heart Associates	Boca Raton	Florida
United States	St. Luke's Idaho Cardiology Associates	Boise	Idaho
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Joslin Diabetes Center	Boston	Massachusetts
United States	MGH Cardiology	Boston	Massachusetts
United States	St. Elizabeth's Medical Center	Boston	Massachusetts
United States	Bridgeport Hospital	Bridgeport	Connecticut
United States	Connecticut Heart and Vascular Center	Bridgeport	Connecticut
United States	Center for Advanced Medicine and Research LLC	Bridgeton	Missouri
United States	Renu-Ca Research Institute, Lower Bucks Hospital	Bristol	Pennsylvania
United States	Montefiore Medical Center	Bronx	New York
United States	Novel Research of New York, LLC	Bronx	New York
United States	Brown - SUNY Downstate Medical Center	Brooklyn	New York
United States	Main Line Health Center, Broomall	Broomall	Pennsylvania
United States	Buffalo Heart Group	Buffalo	New York
United States	Burke Internal Medicine & Research	Burke	Virginia
United States	Lahey Hospital and Medical Center	Burlington	Massachusetts
United States	Spirit Physician Services, Inc	Camp Hill	Pennsylvania
United States	Diabetes and Endocrinology Associates of Stark Cit	Canton	Ohio
United States	IMD Medical Center	Carrollton	Texas
United States	Texas Health Physicians Group	Carrollton	Texas
United States	The Chambersburg Hospital	Chambersburg	Pennsylvania
United States	Carolinas Research Center	Charlotte	North Carolina
United States	Gaffney Health Services	Charlotte	North Carolina
United States	Metrolina Internal Medicine	Charlotte	North Carolina
United States	St. Mary's Medical Center	Charlotte Hall	Maryland
United States	New Phase Research & Development	Chattanooga	Tennessee
United States	Massachusetts General Hospital - Chelsea Health Care Center	Chelsea	Massachusetts
United States	Advocate Med Group-Heart & Vascular Of Illinois	Chicago	Illinois
United States	University of Chicago Medical Center	Chicago	Illinois
United States	The Lindner Research Center	Cincinnati	Ohio
United States	St. Francis Medical Institute	Clearwater	Florida
United States	Cleveland Clinic	Cleveland	Ohio
United States	Calvert Memorial Hospital	Clinton	Maryland
United States	Munni R. Selagamsetty, Md, Pc	Colorado Springs	Colorado
United States	Amistad Research Center, LLC	Columbia	South Carolina
United States	Clinical Research Center University of Missouri	Columbia	Missouri
United States	South Carolina Heart Center	Columbia	South Carolina
United States	Optimed Research, LTD	Columbus	Ohio
United States	Bassett Healthcare Network	Cooperstown	New York
United States	Gonzalez MD & Aswad MD Health Ser	Coral Gables	Florida
United States	NYU Hudson Valley Cardiology	Cortlandt Manor	New York
United States	Samaritan Health Services	Corvallis	Oregon
United States	Heart Vascular of Northern Arizona	Cottonwood	Arizona
United States	Dorothy H. Banish, MD, APMC Study Group	Covington	Louisiana
United States	Avant Research Associates, LLC	Crowley	Louisiana
United States	Medical Group of Culver City	Culver City	California
United States	Partners in Clinical Research	Cumberland	Rhode Island
United States	Atlanta Heart Specialists, LLC	Cumming	Georgia
United States	American Research Institute, Inc.	Cutler Bay	Florida
United States	Cardiovascular Research Institute of Dallas	Dallas	Texas
United States	North Texas Health Center	Dallas	Texas
United States	The Heart Center of Dallas	Dallas	Texas
United States	Heart and Rhythm Specialists	Dalton	Georgia
United States	Dayton Heart Center	Dayton	Ohio
United States	Dayton Veteran Affairs Medical Center	Dayton	Ohio
United States	Daytona Heart Group	Daytona Beach	Florida
United States	Daytona Heart Group	DeLand	Florida
United States	Seidman Clinical Trials	Delray Beach	Florida
United States	Steven Cohen MD	Delray Beach	Florida
United States	Vijay - Aurora Denver Cardiology	Denver	Colorado
United States	Global Medical Research	DeSoto	Texas
United States	Henry Ford Hospital	Detroit	Michigan
United States	John D. Dingell Veterans Affairs Medical Center	Detroit	Michigan
United States	Trace Research Group at Wayne State University	Detroit	Michigan
United States	Infinite Clinical Research	Doral	Florida
United States	International Research Partners, LLC	Doral	Florida
United States	Medical Research Institute at Doral, Inc.	Doral	Florida
United States	Central Bucks Cardiology	Doylestown	Pennsylvania
United States	Altoona Center for Clinical Research	Duncansville	Pennsylvania
United States	Albert F. Johary MD, PC	Dunwoody	Georgia
United States	Cardiospecialists, LTD	Dyer	Indiana
United States	Eastern Carolina Cardiovascular, PA	Elizabeth City	North Carolina
United States	Heart Specialists of Lancaster County	Ephrata	Pennsylvania
United States	Saint Vincent Consultants in Cardiovascular Diseases, LLC	Erie	Pennsylvania
United States	Lake Internal Medicine Assocaties	Eustis	Florida
United States	Martin - Martin Family Practice and Research	Evansville	Indiana
United States	Touro University California- Solano County Affiliated Clinics	Fairfield	California
United States	Seven Corners Medical Research Center	Falls Church	Virginia
United States	Parkway Medical Group	Fayetteville	Tennessee
United States	Feasterville Family Healthcare Center	Feasterville	Pennsylvania
United States	Quantum Research LLC	Festus	Missouri
United States	Family Health at Mount Olive	Flanders	New Jersey
United States	Apex Medical Research MI, Inc.	Flint	Michigan
United States	Flint Clinical Research	Flint	Michigan
United States	NYHQ	Flushing	New York
United States	Colorado Health Medical Group Heart Center of the Rockies	Fort Collins	Colorado
United States	Medical Center of the Rockies Research	Fort Collins	Colorado
United States	Invesclinic	Fort Lauderdale	Florida
United States	Lee Physician Group	Fort Myers	Florida
United States	Primary Care Associates	Fort Myers	Florida
United States	Appalachian Research Associates	Fort Payne	Alabama
United States	Texas Health Physicians Group	Fort Worth	Texas
United States	The Medical Group of Texas	Fort Worth	Texas
United States	University Of California San Francisco	Fresno	California
United States	VACCHCS	Fresno	California
United States	The Cardiac and Vascular Institute	Gainesville	Florida
United States	University of Florida	Gainesville	Florida
United States	Garden City Hospital	Garden City	Michigan
United States	Stern Cardiovascular Foundation, Inc.	Germantown	Tennessee
United States	Christiana Care Health System	Glen Mills	Pennsylvania
United States	Genesys Regional Medical Center	Grand Blanc	Michigan
United States	Altru Health System Rehab Center	Grand Forks	North Dakota
United States	Great Falls Clinic Clinical Research Deptartment	Great Falls	Montana
United States	Cardiology Associates of Bellin Health	Green Bay	Wisconsin
United States	Eastern Cardiology	Greenville	North Carolina
United States	Gulfside Clinical Research, LLC	Gulfport	Mississippi
United States	Avant Research Associates, LLC	Guntersville	Alabama
United States	T&R Clinic, P.A.	Haltom City	Texas
United States	North Oaks Cardiology	Hammond	Louisiana
United States	Hampton Family Practice Research	Hampton	Virginia
United States	Tidewater Physicians Multispecialty Group	Hampton	Virginia
United States	National Clinical LLC	Hamtramck	Michigan
United States	Pinnacle Health Cardiovascular Institute	Harrisburg	Pennsylvania
United States	Pentucket Medical Associates, Inc.	Haverhill	Massachusetts
United States	Best Quality Research, Inc.	Hialeah	Florida
United States	Elite Cardiac Research Center LLC	Hialeah	Florida
United States	Healing Touch C&C Research	Hialeah	Florida
United States	Luzmed Clinical Research Institute	Hialeah	Florida
United States	Nova Clinical Research Clinic	Hialeah	Florida
United States	Qway Research	Hialeah	Florida
United States	State of the Art Research	Hialeah	Florida
United States	Viviana Perez MD Research & Cosmetics	Hialeah	Florida
United States	Cardiocare	Hillsborough	New Jersey
United States	South Florida Research Solutions, LLC	Hollywood	Florida
United States	John Gutleber Medical Research Office	Homestead	Florida
United States	VA Pacific Islands Health Care System	Honolulu	Hawaii
United States	Michele P. Sartori, MD	Houston	Texas
United States	Saadat Ansari MD LLC	Huntsville	Alabama
United States	Clinical Research Prime	Idaho Falls	Idaho
United States	Midwest Cardiology Associates	Independence	Missouri
United States	Charlotte Hearts	Indian Land	South Carolina
United States	Community Hospital South	Indianapolis	Indiana
United States	Indiana Heart Physicians	Indianapolis	Indiana
United States	Krannert Institute Of Cardiology	Indianapolis	Indiana
United States	Miller - SC Internal Medicine Associates.: Irmo	Irmo	South Carolina
United States	Kore Cardiovascular Research Institutue	Jackson	Tennessee
United States	University of MS Medical Center	Jackson	Mississippi
United States	Jamaica Hospital Medical Center	Jamaica	New York
United States	Freeman Health System	Joplin	Missouri
United States	Cardiovascular Medical Associates of Palm Beach	Jupiter	Florida
United States	VA Medical Center Kansas City	Kansas City	Missouri
United States	Grand Medical Care	Katy	Texas
United States	Team Research Of Central Texas	Killeen	Texas
United States	Houston Heart and Vascular Associates	Kingwood	Texas
United States	Hope Clinical Research	Kissimmee	Florida
United States	SIH Research, LLC	Kissimmee	Florida
United States	Cardiovascular Research of Knoxville	Knoxville	Tennessee
United States	New Phase Research & Development	Knoxville	Tennessee
United States	UCSD Sulpizio Cardiovascular Center	La Jolla	California
United States	University Of California San Diego	La Jolla	California
United States	Desert Medical Care & Wellness	La Quinta	California
United States	Barrett Clinic, P.C.	La Vista	Nebraska
United States	Colonnade Medical Group	Lancaster	Ohio
United States	Kumar Medical Corporation	Lancaster	California
United States	George Isajiw, MD	Lansdowne	Pennsylvania
United States	Internal Medicine Clinic	Las Vegas	Nevada
United States	Red Rock Clinical Research, LLC	Las Vegas	Nevada
United States	Utah Cardiology, P.C.	Layton	Utah
United States	VA Central Western Massachusetts Healthca	Leeds	Massachusetts
United States	Northside Clinical Research	Lenoir	North Carolina
United States	University of Kentucky	Lexington	Kentucky
United States	Ocean State Clinical Research Prtnr	Lincoln	Rhode Island
United States	New Jersey Heart	Linden	New Jersey
United States	Unity Clinical Research	Lindsay	Oklahoma
United States	Arkansas Cardiology	Little Rock	Arkansas
United States	Arkansas Heart Hospital	Little Rock	Arkansas
United States	Loma Linda University Health	Loma Linda	California
United States	VA Loma Linda Healthcare System	Loma Linda	California
United States	Cardiovascular Innovation and Research	Long Beach	California
United States	Long Beach Center for Clinical Research	Long Beach	California
United States	Los Alamitos Cardiovascular	Los Alamitos	California
United States	Eastside Clinical Research Associates	Los Angeles	California
United States	Faye Montegrande Md. Clinical Research	Los Angeles	California
United States	Salman Khan A. Medical Corporation	Los Angeles	California
United States	University of Southern California	Los Angeles	California
United States	West LA VA Medical Center	Los Angeles	California
United States	Bays - L-MARC Research Center	Louisville	Kentucky
United States	Robley Rex VAMC	Louisville	Kentucky
United States	Stoddard - University of Louisville	Louisville	Kentucky
United States	Dean Foundation	Madison	Wisconsin
United States	University Of Wisconsin	Madison	Wisconsin
United States	Manassas Clinical Research Center	Manassas	Virginia
United States	Virginia Cardiovascular Associates	Manassas	Virginia
United States	American Clinical Research, LLC	Marrero	Louisiana
United States	Grace Research, LLC	Marshall	Texas
United States	Marshfield Clinic	Marshfield	Wisconsin
United States	VA Northern California Health Care	Mather	California
United States	Valley Heart Consultants	McAllen	Texas
United States	Tucker Cardiology Associates, P.C.	Mechanicsville	Virginia
United States	Southern Oregon Cardiology, LLC	Medford	Oregon
United States	Ramanathan - VAMC Memphis	Memphis	Tennessee
United States	CardioVascular Associates of Mesa	Mesa	Arizona
United States	D De La Vega MD Research Group	Miami	Florida
United States	GAD Research Center	Miami	Florida
United States	Innovation Research Institute, Inc.	Miami	Florida
United States	LG Diagnostics, Inc.	Miami	Florida
United States	Medical Research Center of Florida	Miami	Florida
United States	Paradise Clinical Research, LLC	Miami	Florida
United States	Sanitas Research	Miami	Florida
United States	Segui - Med Care Research	Miami	Florida
United States	South Florida Research Group, LLC	Miami	Florida
United States	St. Paul Medical Research Center, Inc.	Miami	Florida
United States	Team Medical Research	Miami	Florida
United States	Vista Health Research, LLC	Miami	Florida
United States	Lakes Research, LLC	Miami Lakes	Florida
United States	Veritas Research Corp.	Miami Lakes	Florida
United States	Ocean Blue Medical Research Center	Miami Springs	Florida
United States	Middletown Cardiovascular Associates	Middletown	Ohio
United States	South Shore Internal Medicine	Milton	Massachusetts
United States	Aurora St. Luke's Medical Center	Milwaukee	Wisconsin
United States	Columbia St. Mary's	Milwaukee	Wisconsin
United States	Long Island Heart Associates	Mineola	New York
United States	Winthrop University Hospital	Mineola	New York
United States	Heart Center, Palo Pinto General Hospital	Mineral Wells	Texas
United States	Valley Central Research Inc	Mission	Texas
United States	Cone - Montana Medical Research	Missoula	Montana
United States	University of South Alabama: Division of Clinical Research	Mobile	Alabama
United States	Lake Shore Clinical Research, LLC.	Mooresville	North Carolina
United States	Carteret Medical Group	Morehead City	North Carolina
United States	Cardiology Associates of Carolinas, PA	Morganton	North Carolina
United States	Bucks County Clinical Research	Morrisville	Pennsylvania
United States	Medical Consultants, PC	Muncie	Indiana
United States	Southwest Florida Research, LLC	Naples	Florida
United States	Lahey Cardiology	Nashua	New Hampshire
United States	Clinical Research Center Meharry Medical College	Nashville	Tennessee
United States	Otis Barnum D.O.P.C.	Natchitoches	Louisiana
United States	Jersey Shore University Medical Center	Neptune	New Jersey
United States	Eastern Nephrology Associates, PLLC	New Bern	North Carolina
United States	Cardiovascular Institute	New Brunswick	New Jersey
United States	Long Island Jewish Medical Center	New Hyde Park	New York
United States	Queens Long Island Medical Group	New Hyde Park	New York
United States	Tulane University Office of Health Research	New Orleans	Louisiana
United States	Chinatown Cardiology, PC	New York	New York
United States	Mount Sinai School of Medicine	New York	New York
United States	Weill Cornell Medical College and NY Presbyterian	New York	New York
United States	Cardiology Physicians/Red Clay Research	Newark	Delaware
United States	TPMG Clinical Research	Newport News	Virginia
United States	Sentara Norfolk General Hospital	Norfolk	Virginia
United States	Illinois Heart & Lung Research Center, SC	Normal	Illinois
United States	Palisade Medical Center	North Bergen	New Jersey
United States	Captain James A. Lovell Federal Health	North Chicago	Illinois
United States	DiGiovanna Institute for Medical Education and Research	North Massapequa	New York
United States	North Hills Medical Research, Inc	North Richland Hills	Texas
United States	Valley Clinical Trials, Inc.	Northridge	California
United States	Cardiovascular Health Clinic	Oklahoma City	Oklahoma
United States	COR Clinical Research, LLC	Oklahoma City	Oklahoma
United States	Thadani - VA Medical Center Oklahoma City, OK	Oklahoma City	Oklahoma
United States	Today Clinical Research	Oklahoma City	Oklahoma
United States	Specialty Physicians of Illinois, LLC	Olympia Fields	Illinois
United States	Alegent Creighton Health	Omaha	Nebraska
United States	Heart Consultants	Omaha	Nebraska
United States	University of Nebraska Medical Center	Omaha	Nebraska
United States	Orange County Heart Institute & Research	Orange	California
United States	University of CA Irvine Medical Center	Orange	California
United States	Orlando Healthy Heart Institute	Orlando	Florida
United States	Lake Regional Cardiovascular Institute	Osage Beach	Missouri
United States	Stahl - Midwest Heart & Vascular Specialists	Overland Park	Kansas
United States	Research Integrity LLC	Owensboro	Kentucky
United States	Diverse Research Solutions	Oxnard	California
United States	Grace Research, LLC	Palestine	Texas
United States	Palm Beach Gardens Research Center, LLC	Palm Beach Gardens	Florida
United States	Unrein - Rocky Vista University Health Center	Parker	Colorado
United States	Huntington Memorial Hospital	Pasadena	California
United States	Inlet Cardiopulmonary & Associates	Pawleys Island	South Carolina
United States	Memorial Hospital of Rhode Island	Pawtucket	Rhode Island
United States	Lahey Medical Center	Peabody	Massachusetts
United States	Broward Research Center	Pembroke Pines	Florida
United States	Pioneer Clinical Research	Pembroke Pines	Florida
United States	Sandoval - Broward Research Center	Pembroke Pines	Florida
United States	Drexel University College of Medicine	Philadelphia	Pennsylvania
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Arizona Arthritis & Rheumatology Research	Phoenix	Arizona
United States	Champlain Valley Physician Hospital	Plattsburgh	New York
United States	Avant Research Associates, LLC	Port Arthur	Texas
United States	David M. Headley M.D. PA Planters Clinic	Port Gibson	Mississippi
United States	Frandsen Family Medicine DBA Sound Medi	Port Orchard	Washington
United States	InterMed, PA	Portland	Maine
United States	Oregon Health & Science University	Portland	Oregon
United States	Shah Associates, MD, LLC	Prince Frederick	Maryland
United States	Ocean State Research Institute, Inc	Providence	Rhode Island
United States	The Miriam Hospital	Providence	Rhode Island
United States	Renown Inst for Heart & Vasc Health	Reno	Nevada
United States	Sierra Nevada Health Care System	Reno	Nevada
United States	The Valley Hospital	Ridgewood	New Jersey
United States	Infinite Clinical Trials	Riverdale	Georgia
United States	Roanoke Heart Institute PLC	Roanoke	Virginia
United States	Mercer Bucks Cardiology	Robbinsville	New Jersey
United States	Academic Cardiology Associates PC	Rochester Hills	Michigan
United States	Advanced CardioVascular Consultants	Rock Island	Illinois
United States	Boice Willis Clinic	Rocky Mount	North Carolina
United States	Beaumont Health Center	Royal Oak	Michigan
United States	Covenant Medical Center, Inc.	Saginaw	Michigan
United States	Mid-Michigan Heart & Vascular Center	Saginaw	Michigan
United States	Centra Care Heart & Vascular Center at St. Cloud Hospital	Saint Cloud	Minnesota
United States	Clinical Investigators LLC	Saint Louis	Missouri
United States	Consult and Research Associates	Saint Louis	Missouri
United States	SLUCare Cardiology	Saint Louis	Missouri
United States	VA St. Louis Health Care System (VASTLHCS)	Saint Louis	Missouri
United States	Washington University	Saint Louis	Missouri
United States	United Heart and Vascular Clinic	Saint Paul	Minnesota
United States	Center for Advanced Medicine and Research	Saint Peters	Missouri
United States	Bay Area Heart Center: 49th Street	Saint Petersburg	Florida
United States	Bay Area Heart Center: 7th Avenue	Saint Petersburg	Florida
United States	North Shore Cardiovascular Associates	Salem	Massachusetts
United States	Central Coast Cardiology	Salinas	California
United States	Peninsula Cardiology Associates	Salisbury	Maryland
United States	Utah Diabetes Center	Salt Lake City	Utah
United States	Element Research Group	San Antonio	Texas
United States	San Antonio Endovascular & Heart Institute	San Antonio	Texas
United States	Santoscoy - Health Texas Research Institute	San Antonio	Texas
United States	Schnitzler Cardiovascular Consultants	San Antonio	Texas
United States	Foundation for Cardiovascular Medicine	San Diego	California
United States	Richard G. Friedman, MD	San Diego	California
United States	Ritchken and First MDs	San Diego	California
United States	San Diego Cardiac Center	San Diego	California
United States	Veterans Affairs San Diego Healthcare System	San Diego	California
United States	UCSF at Zuckerberg SF General Hospital	San Francisco	California
United States	Sanford Cardiology	Sanford	North Carolina
United States	Coastal Heart Medical Group, Inc.	Santa Ana	California
United States	Comprehensive Cardiovascular Care	Santa Maria	California
United States	Cardiology Associates of Schenectady	Schenectady	New York
United States	Scottsdale Medical Imaging	Scottsdale	Arizona
United States	The Heart Clinic	Scottsdale	Arizona
United States	Lehigh Valley Health Services	Sellersville	Pennsylvania
United States	Veterans Affairs Medical Center Shreveport	Shreveport	Louisiana
United States	Atlanta Vanguard Medical Associates	Smyrna	Georgia
United States	Cardio Metabolic Institute	Somerset	New Jersey
United States	Maine Medical Partners Maine Health Cardiology	South Portland	Maine
United States	Stern Cardiovascular Foundation, Inc.	Southaven	Mississippi
United States	Fusion Clinical Research of Spartanburg	Spartanburg	South Carolina
United States	Palmetto Research Center, LLC	Spartanburg	South Carolina
United States	Kootenai Heart Clinics, LLC	Spokane	Washington
United States	Northside Internal Medicine	Spokane	Washington
United States	Premier Clinical Research	Spokane	Washington
United States	CoxHealth: Wheeler Heart & Vascular Center	Springfield	Missouri
United States	Mercy Medical Research Institute	Springfield	Missouri
United States	Pacific Heart and Vascular Medical Group	Stockton	California
United States	Acacia Medical Research Institute	Sugar Land	Texas
United States	Health Plus Clinical Research	Sugar Land	Texas
United States	Herman Clinical Research, LLC	Suwanee	Georgia
United States	Lenus Research & Medical Group	Sweetwater	Florida
United States	DBC Research	Tamarac	Florida
United States	Holy Name Medical Center, Inc.	Teaneck	New Jersey
United States	Manoj D. Aswani M.D.	Thousand Oaks	California
United States	Comprehensive Heart Care, Inc.	Toledo	Ohio
United States	Lone Star Heart and Vascular Center	Tomball	Texas
United States	Northwest Houston Clinical Research	Tomball	Texas
United States	IRC Clinics	Towson	Maryland
United States	Atlanta Heart Specialists, LLC	Tucker	Georgia
United States	Pima Heart	Tucson	Arizona
United States	Southern Arizona VA Health Care System	Tucson	Arizona
United States	Oklahoma State University Center for Health Sciences	Tulsa	Oklahoma
United States	Pish Medical Associates, Inc.	Uniontown	Pennsylvania
United States	Touro University California- Solano Public Health Affiliated Clinics	Vallejo	California
United States	Northwest Medical Associates, P.S.	Vancouver	Washington
United States	Cardiology Associates of Vidalia, P.C.	Vidalia	Georgia
United States	Hillcrest Family Health Center	Waco	Texas
United States	Boisey Barnes MD, PC	Washington	District of Columbia
United States	GWU Medical Faculty Associatin, Inc.	Washington	District of Columbia
United States	Total Cardiology Care, LLC	Wayne	New Jersey
United States	Asclepes Research Centers	Weeki Wachee	Florida
United States	Gupta - Premier Heart and Vascular Center	Wesley Chapel	Florida
United States	Iowa Heart Center	West Des Moines	Iowa
United States	Maine Centers for Healthcare	Westbrook	Maine
United States	Mount Carmel Clinical Cardiovascular Care	Westerville	Ohio
United States	Premier Physicians	Westlake	Ohio
United States	Westwood Cardiology Associates	Westwood	New Jersey
United States	VA Medical Center, White River Junction	White River Junction	Vermont
United States	Lehigh Valley Family Practice	Whitehall	Pennsylvania
United States	Professional Research Network of KS	Wichita	Kansas
United States	Robert J. Dole VAMC	Wichita	Kansas
United States	Wilkes-Barre VA Medical Center	Wilkes-Barre	Pennsylvania
United States	Natalie A. Doyle, MD, PA	Wilson	North Carolina
United States	Cardinal Internal Medicine Associates	Woodbridge	Virginia
United States	Wooster Heart Group	Wooster	Ohio
United States	Reliant Medical Group	Worcester	Massachusetts
United States	Tidewater Physicians Multispecialty Group	Yorktown	Virginia

Sponsors (2)

Lead Sponsor	Collaborator
Brigham and Women's Hospital	National Heart, Lung, and Blood Institute (NHLBI)

Countries where clinical trial is conducted

United States,  Canada,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Number of Subjects With Hospitalization for Unstable Angina That Led to Unplanned Coronary Revascularization	The first occurrence of hospitalization for unstable angina that led to unplanned coronary revascularization	From randomization to the trial end (April 2, 2018) up to 5 years
Other	Number of Subjects With Coronary Revascularization	The first occurrence of coronary revascularization	From randomization to trial end (April 2, 2018) up to 5 years
Other	Number of Subjects With Peripheral Artery Disease	The first occurrence of new or worsening of peripheral artery disease	From randomization to the trial end (April 2, 2018) - up to 5 years
Other	Number of Subjects With Deep Vein Thrombosis or Pulmonary Embolism	The first occurrence of symptomatic deep vein thrombosis or pulmonary embolism	From randomization to the trial end (April 2, 2018) - up to 5 years
Other	Number of Subjects With Aortic Stenosis	The first occurrence of clinically significant aortic stenosis	From randomization to the trial end (April 2, 2018) - up to 5 years
Other	Number of Subjects With Atrial Fibrillation	The first occurrence of new or worsening of atrial fibrillation	From randomization to the trial end (April 2, 2018) - up to 5 years
Primary	Number of Subjects With Major Adverse Cardiovascular Events	The first occurrence of Major Adverse Cardiovascular Event which is defined as the occurrence of one or more of the following: Cardiovascular Death, Non-Fatal Myocardial Infarction or Non-Fatal Stroke.	From randomization to trial end (April 2, 2018) up to a maximum of 5 years
Primary	Number of Subjects With Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina That Led to Urgent Coronary Revascularization	The first occurrence of Major Adverse Cardiovascular Event or Hospitalization for Unstable Angina that led to Urgent Coronary Revascularization.	From randomization to trial end (April 2, 2018) - up to a maximum of 5 years
Secondary	Number of Subjects With All-cause Mortality	Subjects who died from any cause.	From randomization to the trial end (April 2, 2018) up to a maximum of 5 years
Secondary	Number of Subjects With Major Adverse Cardiovascular Event or Any Coronary Revascularization	The first occurrence of Major Adverse Cardiovascular Event or Any Coronary Revascularization.	From randomization to the trial end (April 2, 2018) - up to a maximum of 5 years
Secondary	Number of Subjects With Hospitalization for Congestive Heart Failure	The first occurrence of Hospitalization for Congestive Heart Failure	From randomization to trial end (April 2, 2018) up to a maximum of 5 years
Secondary	Number of Subjects With Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality	The first occurrence of Major Adverse Cardiovascular Event, Coronary Revascularization, Hospitalization for Congestive Heart Failure or All Cause Mortality.	From randomization to trial end (April 2, 2018) up to a maximum of 5 years
Secondary	Number of Subjects With New Onset Type 2 Diabetes	New onset type 2 diabetes among those without diabetes at baseline. Baseline diabetes is defined as any of the following prior to randomization: clinician report of diabetes, use of antidiabetic medication, hbA1c >=6.5 or fasting plasma glucose >=126.	From randomization to the trial end (April 2, 2018) - up to 5 years