A Study to Evaluate the Effect of Long-term Treatment With BELVIQ (Lorcaserin HCl) on the Incidence of Major Adverse Cardiovascular Events and Conversion to Type 2 Diabetes Mellitus in Obese and Overweight Subjects With Cardiovascular Disease or Multiple Cardiovascular Risk Factors

Obesity Clinical Trial

— CAMELLIA-TIMI  

Official title:

A Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Effect of Long-term Treatment With BELVIQ (Lorcaserin HCl) on the Incidence of Major Adverse Cardiovascular Events and Conversion to Type 2 Diabetes Mellitus in Obese and Overweight Subjects With Cardiovascular Disease or Multiple Cardiovascular Risk Factors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02019264
• Other study ID #: APD356-G000-401
• Secondary ID: 2013-000324-34
• Status: Completed
• Phase: Phase 4
• Start date: January 24, 2014
• Est. completion date: May 14, 2018

Study information

• Verified date: November 2017
• Source: Eisai Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in overweight and obese subjects with cardiovascular (CV) disease and/or multiple CV risk factors.

Description:

Approximately 12,000 subjects will be randomized to two treatment groups in a ratio of 1:1, stratified by the presence of established CV disease (approximately 80%) or CV risk factors without established CV disease (approximately 20%). Subjects will receive lorcaserin HCl 10 mg BID or placebo BID. The study will consist of 2 phases: Prerandomization and Randomization. The Prerandomization Phase will last up to 30 days and consist of one visit during which subjects will be screened for eligibility. The Randomization Phase will consist of two periods: Treatment and Follow-up. The Treatment Period will last for approximately 5 years with approximately 18 visits and Follow-up period is 30 (+ or - 10 days) from the end of treatment visit.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 14673
• Est. completion date: May 14, 2018
• Est. primary completion date: May 14, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

Inclusion Criteria

1. BMI greater than or equal (>=) to 27 kilogram per meter square (kg/m^2)

2. Subjects able and willing to comply with a reduced-calorie diet and an increased physical activity program

3. Age >= to 40 years with established CV disease as defined by one of the following:

1. History of documented MI or ischemic stroke

2. History of peripheral artery disease

3. History of revascularization (coronary, carotid, or peripheral artery)

4. Significant unrevascularized coronary arterial stenosis

OR

Age >= to 55 years for women or >= to 50 years for men who have type 2 diabetes mellitus (T2DM) without established CV disease plus at least one of the following CV risk factors:

1. Hypertension, or currently receiving therapy for documented hypertension

2. Dyslipidemia, or currently taking prescription lipid-lowering therapy for documented dyslipidemia

3. Estimated glomerular filtration rate >= to 30 to less than equal (<=) to 60 mililitre per minute per 1.73 meter square (mL/min/1.73 m^) per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation

4. High high sensitivity C-reactive protein (hsCRP)

5. Urinary albumin-to-creatinine ratio (ACR) >= 30 ug/mg

Subjects with T2DM may have a pre-existing or new diagnosis of T2DM. A new diagnosis of T2DM (ie, discovered at Screening) should be based on the 2013 American Diabetes Association (ADA) guidelines.

All T2DM subjects must have an HbA[1c] less (<) than 10% at Screening. If subjects are being treated, or upon diagnosis need to be treated with antidiabetic agents, the T2DM treatment regimen must be stable for at least 3 months prior to randomization.

Exclusion Criteria

1. Moderate or greater symptoms of congestive cardiac failure (New York Heart Association [NYHA] class III or IV)

2. Known left ventricular (LV) ejection fraction < than 20%

3. Moderate or greater symptoms of pulmonary hypertension (PH)

4. Known severe valvular disease

5. Moderate renal impairment, severe renal impairment (estimated glomerular filtration rate < 30 mL/min/1.73 m^ per the CKD-EPI equation based on ideal body weight), or end stage renal disease (ESRD)

6. Severe hepatic impairment

7. Use of other products intended for weight loss including prescription drugs, over-the-counter (OTC) drugs, and herbal preparations

8. Use of more than one other serotonergic drug

9. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months prior to Screening including, but not limited to: pergolide, ergotamine, methysergide, cabergoline

10. History or evidence of clinically significant disease (e.g., malignancy, cardiac, respiratory, gastrointestinal, renal or psychiatric disease)

11. Use of lorcaserin HCl prior to Screening or hypersensitivity to lorcaserin HCl or any of the excipients

12. Planned bariatric surgery

13. Females must not be breastfeeding or pregnant

Related Conditions & MeSH terms

• Cardiovascular Disease
• Cardiovascular Diseases
• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• High Cardiovascular Risk
• Obesity
• Overweight
• Type 2 Diabetes

Intervention

Drug:
• Lorcaserin hydrochloride
APD356 10 mg twice daily
• Placebo
Placebo twice daily

Locations

Country	Name	City	State
Australia	New Royal Adelaide Hospital, Cardiology Department	Adelaide	South Australia
Australia	South Australian Medical Research Inst, Centre for Clinical Research	Adelaide
Australia	Adelaide Medical Research	Ashford	South Australia
Australia	Ballarat Health Services	Ballarat	Victoria
Australia	Core Research Group	Brisbane	Queensland
Australia	Princess Alexandra Hospital, Cardiology Research Department	Brisbane	Queensland
Australia	Coffs Harbour Health Campus	Coffs Harbour	New South Wales
Australia	Lyell McEwin Hospital, Department of Cardiology	Elizabeth Vale	South Australia
Australia	Heart and Vascular Institute	Fullarton	South Australia
Australia	Geelong Cardiology Research Unit, Barwon Health	Geelong	Victoria
Australia	Gosford Hospital, Cardiology Clinical Trials	Gosford	New South Wales
Australia	Austin Health - Heidelberg Repatriation Hospital, Department of Medicine, Boronia Centre	Heidelberg Heights	Victoria
Australia	Royal Brisbane and Women's Hospital, Endocrinology Department	Herston	Queensland
Australia	Joondalup Cardiovascular Trials Foundation Inc	Joondalup	Western Australia
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	HeartCare Partners Clinical Research Unit	Milton	Queensland
Australia	Fiona Stanley Hospital, Cardiology Research Department,CDO11	Murdoch	Western Australia
Australia	Avenue Cardiovascular Centre	Saint Kilda East	Victoria
Australia	AusTrials Pty Ltd	Sherwood	Queensland
Australia	Gold Coast Hospital, Cardiovascular Research Centre	Southport	Queensland
Australia	Illawarra Shoalhaven Local Health District, Clinical Trial and Research Unit	Wollongong	New South Wales
Australia	Wollongong Hospital	Wollongong	New South Wales
Australia	The Queen Elizabeth Hospital	Woodville South	South Australia
Bahamas	The Partners Clinical Research Centre	Nassau
Canada	LMC Diabetes & Endocrinology - Brampton	Brampton	Ontario
Canada	McMaster University	Brampton	Ontario
Canada	ViaCar Recherche Clinique	Brossard	Quebec
Canada	Aviva Clinical Trial Group In.	Burlington	Ontario
Canada	JBN Medical Diagnostic Services Inc.	Burlington	Ontario
Canada	LMC Clinical Research Inc. (Calgary)	Calgary	Alberta
Canada	Cambridge Cardiac Care Centre	Cambridge	Ontario
Canada	Joanne F. Liutkus Medicine Professional Corp.	Cambridge	Ontario
Canada	Saul Vizel Professional Medicine Corporation, Vizel Cardiac Research	Cambridge	Ontario
Canada	LMC Diabetes & Endocrinology (Etobicoke)	Etobicoke	Ontario
Canada	Q&T Research Outaouais Inc.	Gatineau	Quebec
Canada	ViaCar Recherche Clinique Inc.	Greenfield Park	Quebec
Canada	Nova Scotia Health Authority /QEII Health Sciences Centre	Halifax	Nova Scotia
Canada	Wharton Medical Clinic Clinical Trials Group Inc.	Hamilton	Ontario
Canada	Manna Research Inc	Levis	Quebec
Canada	Saint Josephs Health Care London	London	Ontario
Canada	LMC Diabetes & Endocrinoly	Markham	Ontario
Canada	Clinique Sante Cardio MC	Montreal	Quebec
Canada	New Market Cardiology Research Group	Newmarket	Ontario
Canada	Dr. Michael Heffernan	Oakville	Ontario
Canada	LMC Clinical Research Inc. (Oakville)	Oakville	Ontario
Canada	Dr. Cha	Oshawa	Ontario
Canada	University of Ottawa Heart Institute	Ottawa	Ontario
Canada	Kawartha Cardiology Clinical Trials	Peterborough	Ontario
Canada	Universitaire de Cardiologie et de Pneumologie de Quebec	Quebec City	Quebec
Canada	Centre hospitalier régional de Lanaudière	Saint-Charles-Borromee	Quebec
Canada	Recherche Clinique London	Sherbrooke	Quebec
Canada	CardioVasc HR, Inc.	St Jean sur Richelieu	Quebec
Canada	ViaCar Recherche Clinique Inc.	St-Lambert	Quebec
Canada	Dr Roger Labonte Professional Medicine Corp	Sudbury	Ontario
Canada	Dr. Dinkar Shukla Professional Medicine Corporation	Sudbury	Ontario
Canada	LMC Diabetes & Endocrinology (Thornhill)	Thornhill	Ontario
Canada	JJ DIG Research Ltd.	Toronto	Ontario
Canada	Keele Medical Place	Toronto	Ontario
Canada	LMC Clinical Research Inc. (Bayview)	Toronto	Ontario
Canada	St Michael's Hospital Health Centre	Toronto	Ontario
Canada	Gordon and Leslie Diamond Health Care Centre	Vancouver	British Columbia
Canada	LMC Clinical Research Inc. (Montreal)	Ville Saint-Laurent	Quebec
Chile	Hospital Regional Concepcion	Concepcion
Chile	Biomedica Research Group	Providencia	Santiago
Chile	Sociedad Medica Cardiologica El Llano	San Miguel	Santiago
Chile	Cardiocob	Santiago
Chile	Ccbr Cecim	Santiago
Chile	Servicios Medicos Godoy Ltda.	Santiago
Chile	CECMI Ltda.	Temuco
Chile	Centro Investigacion Clinica del Sur	Temuco
Mexico	Fundacion Cardiovascular de Aguascalientes	Aguascalientes
Mexico	Hospital Cardiologica Aguascalientes	Aguascalientes
Mexico	Mentrials S.A.de C.V.	Distrito Federal
Mexico	ICLE	Guadalajara	Jalisco
Mexico	Private Medical Practice	Guadalajara	Jalisco
Mexico	Cardiolink ClinTrials S.C.	Monterrey	Nuevo Leon
Mexico	Centro de Estudios Clinicos y Especialidades Medicas S.C.	Monterrey	Nuevo Leon
Mexico	IMED Clin Trials	Monterrey	Nuevo Leon
Mexico	Hospital de Angeles Xalapa	Xalapa	Veracruz
New Zealand	Auckland City Hospital	Auckland
New Zealand	Christchurch Hospital, Cardiology Research	Christchurch	Canterbury
New Zealand	Christchurch Hospital, Lipids	Christchurch	Canterbury
New Zealand	Dunedin Hospital	Dunedin	Otago
New Zealand	Hawkes Bay Regional Hospital	Hastings
New Zealand	Hutt Hospital, Cardiology Dept	Lower Hutt	Wellington
New Zealand	North Shore Hospital-Cardiology Research	Milford	Auckland
New Zealand	Nelson Hospital, Cardiology Department	Nelson
New Zealand	Taranaki Base Hospital	New Plymouth	Taranaki
New Zealand	Middlemore Hospital	Papatoetoe	Auckland
New Zealand	Lakeland Clinical Trials, Rotorua	Rotorua
New Zealand	North Shore Hospital - Diabetes Clinic	Takapuna	Auckland
New Zealand	Tauranga Hospital	Tauranga
Poland	Indywidualna Specjalistyczna Praktyka Lekarska	Bezrzecze
Poland	NZOZ "Eskulap"	Biala Rawska
Poland	Podlaski Osrodek Kardiologii Janusz Korecki	Bialystok
Poland	10 Wojskowy Szpital Kliniczny z Poliklinika SPZOZ	Bydgoszcz
Poland	Centrum Medyczne KERmed	Bydgoszcz
Poland	Nzoz "Mada-Med"	Chorzów
Poland	DIABET Centrum Medyczne s. c.	Chrzanów
Poland	Gabinet Kardiologiczno-Internistyczny	Gdynia
Poland	ISPL w Dziedzinie Kardiologii lek.med. Krzysztof Cymerman	Gdynia
Poland	NZOZ SCBK ProCordis	Gdynia
Poland	Praktyka Lekarska dr n. med. Marek Bronisz	Inowroclaw
Poland	Piotr Mader Diabetic Clinic NZOZ PD-I	Kamieniec Zabkowicki
Poland	NZOZ Eskulap SC	Koluszki
Poland	Ewa Mirek-Bryniarska Specjalistyczna Praktyka Lekarska	Kraków
Poland	LANDA' Specjalistyczne Gabinety Lekarskie	Kraków
Poland	Medyczne Centrum Diabetologiczno Endokrynologiczno	Kraków
Poland	SP ZOZ w Lecznej	Leczna
Poland	Nzoz Cardiamed	Legnica
Poland	NZOZ ALL-MED Centrum Medyczne	Lódz
Poland	"CenterMed Lublin" Sp. z o.o.	Lublin
Poland	Indywidualna Praktyka Lekarska	Mragowo
Poland	Zechowicz MEDEUSZ-PLUS	Olsztyn
Poland	Specjalistyczna Przychodnia Lekarska MEDIKARD (SPL Medikard)	Plock
Poland	NZOZ NEURO-KARD "Ilkowski i Partnerzy"	Poznan
Poland	Praktyka Lekarska Ewa Krzyzagorska	Poznan
Poland	Specjalistyczny Gabinet Lekarski	Tarnów
Poland	Lecznice Citomed Sp. z o.o.	Torun
Poland	Praktyka Lekarska Pawlowicz Lidia	Torun
Poland	Centrum Badawcze Wspolczesnej Terapii	Warszawa
Poland	Centrum Medyczne AMED	Warszawa
Poland	SNZOZ Fundacji PROCLINICA	Warszawa
Poland	Centrum Zdrowia Wierzchoslawice	Wierzchoslawice
Poland	Specjalistyczne Gabinety Lekarskie "Medicor PLUS"	Wloclawek
Poland	Regionalna Poradnia Diabetologiczna	Wroclaw
United States	Albany College of Medicine, Division of Endocrinology	Albany	New York
United States	Capital Cardiology Associates	Albany	New York
United States	New Mexico Heart Institute, PA	Albuquerque	New Mexico
United States	Advanced Cardiovascular, LLC	Alexander City	Alabama
United States	Alexandria Clinical Research, LLC	Alexandria	Virginia
United States	Clinical Research Alliance	Alhambra	California
United States	Endeavor Medical Research PLC	Alpena	Michigan
United States	Blair Medical Associates	Altoona	Pennsylvania
United States	Clinical Research Associates of Central PA, LLC	Altoona	Pennsylvania
United States	Alaska Heart Institute	Anchorage	Alaska
United States	Community Clinical Research Center	Anderson	Indiana
United States	Medstar Cardiology Associates	Annapolis	Maryland
United States	Washington Center for Weight Management and Resear	Arlington	Virginia
United States	Northwest Heart Clinical Research, LLC	Arlington Heights	Illinois
United States	North Alabama Research Center, LLC	Athens	Alabama
United States	Atlanta Diabetes Associates, Endocrinology	Atlanta	Georgia
United States	Central Maine Medical Center	Auburn	Maine
United States	Central Texas Clinical Research, LLC	Austin	Texas
United States	Texas Diabetes & Endocrinology	Austin	Texas
United States	Aventura Heart Center	Aventura	Florida
United States	American Health Network of IN, LLC, Avon	Avon	Indiana
United States	Central Cardiology	Bakersfield	California
United States	Chesapeake Cardiovascular Associates, GBMC	Baltimore	Maryland
United States	Clinical Research, Inc	Baltimore	Maryland
United States	Medstar Union Memorial Heart Specialists	Baltimore	Maryland
United States	Medstar Union Memorial Hospital	Baltimore	Maryland
United States	Overlea Personal Physicians	Baltimore	Maryland
United States	Shahid Saeed MD, PC	Baltimore	Maryland
United States	Spectrum Clinical Research	Baltimore	Maryland
United States	Acadia Clinical Research, LLC	Bangor	Maine
United States	Eastern Maine Medical Center Northeast Cardiology Associates	Bangor	Maine
United States	Minneapolis Heart Institute Foundation	Baxter	Minnesota
United States	Cardiovascular Research Foundation of Southern Cal	Beverly Hills	California
United States	Southern Maine Health Care/Maine Medical Center Research Ins	Biddeford	Maine
United States	Billings Clinic Research Center	Billings	Montana
United States	Montana Health Research Institute, Inc.	Billings	Montana
United States	United Medical Associates, PC	Binghamton	New York
United States	UAB Medical Center	Birmingham	Alabama
United States	Premier Healthcare, LLC	Bloomington	Indiana
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	MGH Weight Center	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	Zasa Clinical Research	Boynton Beach	Florida
United States	Meridien Research	Bradenton	Florida
United States	NOVA Southeastern University	Bradenton	Florida
United States	Bay Area Cardiology	Brandon	Florida
United States	Bridgeport Hospital	Bridgeport	Connecticut
United States	Connecticut Clinical Research, LLC	Bridgeport	Connecticut
United States	Advanced Heart Care	Bridgewater	New Jersey
United States	Medicor Cardiology, PA	Bridgewater	New Jersey
United States	Clinical Research Works, Bristol	Bristol	Connecticut
United States	PMG Research of Bristol, LLC	Bristol	Tennessee
United States	James J. Peters VA Medical Center, Bronx, NY	Bronx	New York
United States	Meridien Research, Brooksville	Brooksville	Florida
United States	Buffalo Heart Group	Buffalo	New York
United States	Burke Internal Medicine and Research	Burke	Virginia
United States	Kernodle Clinic	Burlington	North Carolina
United States	Cadillac Clinical Research, LLC	Cadillac	Michigan
United States	Capital Area Research, LLC	Camp Hill	Pennsylvania
United States	Aultman Hospital	Canton	Ohio
United States	Capitol Interventional Cardiology	Carmichael	California
United States	Texas Health Physicians Group	Carrollton	Texas
United States	Clinical Trials of America Inc.	Cary	North Carolina
United States	Connect Clinical Research Center, LCC	Chandler	Arizona
United States	Metrolina Internal Medicine	Charlotte	North Carolina
United States	PMG Research of Charlotte, LLC	Charlotte	North Carolina
United States	Chattanooga Research and Medicine (CHARM)	Chattanooga	Tennessee
United States	WR-ClinSearch, LLC	Chattanooga	Tennessee
United States	Diabetes & Endocrinology Specialists, Inc.	Chesterfield	Missouri
United States	Cedar-Crosse Research Center	Chicago	Illinois
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	University of Chicago	Chicago	Illinois
United States	San Diego Costal Endocrinology Group AMC	Chula Vista	California
United States	Sentral Clinical Research	Cincinnati	Ohio
United States	The Lindner Research Center	Cincinnati	Ohio
United States	Clearwater Cardiovascular and Interventional Cons.	Clearwater	Florida
United States	UCH-MHS Cardiac Research	Colorado Springs	Colorado
United States	John Muir Physician Network Clinical Research Cent	Concord	California
United States	Rockdale Medical-Research Associates	Conyers	Georgia
United States	Clinical Research of South Florida	Coral Gables	Florida
United States	Holy Cross Medical Group	Coral Springs	Florida
United States	Adriana Pop-Moody MD Clinic, PA	Corpus Christi	Texas
United States	Partners in Clinical Research	Cumberland	Rhode Island
United States	Atlanta Heart Specialists	Cumming	Georgia
United States	Baylor Research Institute	Dallas	Texas
United States	Research Institute of Dallas	Dallas	Texas
United States	Texas Health Physicians Group	Dallas	Texas
United States	Texas Health Physicians Group, Dallas	Dallas	Texas
United States	Cardiology Consultants of Danville, Inc.	Danville	Virginia
United States	Danville Internal Medicine, Inc	Danville	Virginia
United States	Geisinger Health Clinic	Danville	Pennsylvania
United States	Geisinger Health System	Danville	Pennsylvania
United States	Cardiology Research Associates	Daytona Beach	Florida
United States	International Medical Research	Daytona Beach	Florida
United States	Delaware Research Group, LLC	Delaware	Ohio
United States	Creekside Endocrine Associates PC	Denver	Colorado
United States	Asclepius Medical Research	Doral	Florida
United States	Doylestown Health Cardiology a Division of Doylestown Health	Doylestown	Pennsylvania
United States	Essentia Institute of Rural Health	Duluth	Minnesota
United States	Altoona Center for Clinical Research	Duncansville	Pennsylvania
United States	MNCOME Clinic	Eagan	Minnesota
United States	UmiMed Center LLC	East Brunswick	New Jersey
United States	Radiant Research, Inc.	Edina	Minnesota
United States	Cardiovascular Associates of the Delaware Valley	Elmer	New Jersey
United States	Consultants in Cardiovascular Medicine	Elmhurst	Illinois
United States	Medical Group of Encino	Encino	California
United States	Regional Clinical Research, Inc.	Endwell	New York
United States	Liberty Family Practice	Erie	Pennsylvania
United States	Deaconess Clinic, Inc.	Evansville	Indiana
United States	New England Center for Clinical Research, IMCA	Fall River	Massachusetts
United States	Seven Corners Medical Research Center	Falls Church	Virginia
United States	Virginia Heart	Falls Church	Virginia
United States	Lillestol Research LLC	Fargo	North Dakota
United States	Endocrine Clinical Research LLC	Feasterville	Pennsylvania
United States	Larry D. Stonesifer, MD, Inc PS	Federal Way	Washington
United States	Fleming Island Center for Clinical Research	Fleming Island	Florida
United States	Integrative Research Associates, Inc.	Fort Lauderdale	Florida
United States	M & O Clinical Research, LLC	Fort Lauderdale	Florida
United States	Primary Care Associates	Fort Myers	Florida
United States	Odilon Alvarado, M.D.	Fort Worth	Texas
United States	Tand R Clinic, PA	Fort Worth	Texas
United States	Texas Health Physicians Group Fort Worth	Fort Worth	Texas
United States	American Health Network of IN, LLC, Franklin	Franklin	Indiana
United States	Florida Research Network, LLC	Gainesville	Florida
United States	San Gabriel Clinical Research, LLC	Georgetown	Texas
United States	Maryland Heart Associates, LLC	Glen Burnie	Maryland
United States	Arrowhead Health Centers	Glendale	Arizona
United States	Phoenix Heart, PLLC	Glendale	Arizona
United States	New West Physicians, PC	Golden	Colorado
United States	Internal Medical Associates of Grand Island, PC	Grand Island	Nebraska
United States	Long Island Gastrointestinal Research Group LLP	Great Neck	New York
United States	Cardiology Associates of Bellin Health	Green Bay	Wisconsin
United States	Prevea Clinic, Inc	Green Bay	Wisconsin
United States	George E. Platt, M.D.	Green Cove Springs	Florida
United States	Marin Endocrine Care & Research, Inc.	Greenbrae	California
United States	Wellmont CVA Heart Institute	Greeneville	Tennessee
United States	American Health Network of IN, LLC, Greenfield	Greenfield	Indiana
United States	Bland Clinic, PA	Greensboro	North Carolina
United States	Mountain View Clinical Research	Greer	South Carolina
United States	Radiant Research, Inc.	Greer	South Carolina
United States	Coast Cardiovascular Consultants PLLC	Gulfport	Mississippi
United States	Clinical Investigation Specialists, Inc. in Gurnee	Gurnee	Illinois
United States	Advocare Heights Primary Care	Haddon Heights	New Jersey
United States	Cardiovascular Associates of the Delaware Valley P	Haddon Heights	New Jersey
United States	Klein & Associates, MD, PA	Hagerstown	Maryland
United States	Pentucket Medical Associates	Haverhill	Massachusetts
United States	Clinical Research Advantage / Rita Chuang, M.D.	Henderson	Nevada
United States	Eastern Research, Inc.	Hialeah	Florida
United States	Clinical Trials of America Inc. Hickory	Hickory	North Carolina
United States	Clinical Trials of America, Inc.	Hickory	North Carolina
United States	Peters Medical Research	High Point	North Carolina
United States	Larry K. Levinson, D.O., P.A.	Hollywood	Florida
United States	Research Physicians Network Alliance	Hollywood	Florida
United States	Angiocardiac Care of Texas PA	Houston	Texas
United States	Endocrine and Psychiatry Center	Houston	Texas
United States	Oxford Clinical Research, LLC	Houston	Texas
United States	West Houston Area Clinical Trial Consultants, LLC	Houston	Texas
United States	Pasco Cardiology Center	Hudson	Florida
United States	California Heart Specialists	Huntington Beach	California
United States	Del Rosario Medical Clinic, Inc.	Huntington Park	California
United States	MedStar Health Research Institute	Hyattsville	Maryland
United States	Joseph Lamantia, DO	Indiana	Pennsylvania
United States	American Health Network - Thomas Moretto, MD	Indianapolis	Indiana
United States	Nature Coast Clinical Research	Inverness	Florida
United States	The University of Iowa, College of Public Health	Iowa City	Iowa
United States	Texas Health Physicians Group	Irving	Texas
United States	Kore Cardiovascular Research	Jackson	Tennessee
United States	Research Associates of Jackson	Jackson	Tennessee
United States	The Jackson Clinic, PA	Jackson	Tennessee
United States	Jacksonville Center for Clinical Research	Jacksonville	Florida
United States	University of Florida- Jacksonville	Jacksonville	Florida
United States	Westside Center for Clinical Research	Jacksonville	Florida
United States	The Clinical Trial Center, LLC	Jenkintown	Pennsylvania
United States	Lycoming Internal Medicine, Inc.	Jersey Shore	Pennsylvania
United States	Wellmont CVA Heart Institute	Johnson City	Tennessee
United States	Berkley Hills Clinicals	Johnstown	Pennsylvania
United States	Ilumina Clinical Associates, Johnstown	Johnstown	Pennsylvania
United States	Joseph Lamantia, DO	Johnstown	Pennsylvania
United States	NEA Baptist Clinic	Jonesboro	Arkansas
United States	Westside Family Medical Center, PC	Kalamazoo	Michigan
United States	Glacier View Cardiology PC	Kalispell	Montana
United States	Clinical Investigation Specialists, Inc.	Kenosha	Wisconsin
United States	Holston Medical Group	Kingsport	Tennessee
United States	Wellmont CVA Heart Institute	Kingsport	Tennessee
United States	Texas Cardiology Associates of Houston	Kingwood	Texas
United States	Diabetes and Endocrine Associates	La Mesa	California
United States	La Mesa Cardiac Center	La Mesa	California
United States	Alliance Research Centers	Laguna Hills	California
United States	Meridien Research	Lakeland	Florida
United States	Comprehensive Cardiology Consultants	Langhorne	Pennsylvania
United States	Detweiler Family Medicine and Associates PC	Lansdale	Pennsylvania
United States	Green & Seidner Family Practice Associates	Lansdale	Pennsylvania
United States	Cardiology Consultants of East Michigan	Lapeer	Michigan
United States	Clinical Research Advantage, Inc.	Las Vegas	Nevada
United States	Clinical Research of South Nevada	Las Vegas	Nevada
United States	Clinical Trials of America, Inc.	Lenoir	North Carolina
United States	Jalil Aziz Khan M.D., P.A.	Lewisville	Texas
United States	NJ Heart	Linden	New Jersey
United States	Arkansas Cardiology Clinic	Little Rock	Arkansas
United States	Central Arkansas Veterans Healthcare System	Little Rock	Arkansas
United States	Preferred Research Partners	Little Rock	Arkansas
United States	Torrance Clinical Research Institute, Inc.	Lomita	California
United States	Long Beach Center for Clinical Research	Long Beach	California
United States	Beverly Hills Cardiology	Los Angeles	California
United States	Metabolic Clinic and Research Center	Los Angeles	California
United States	VA Greater Los Angeles Health Care System	Los Angeles	California
United States	L-MARC Research Center	Louisville	Kentucky
United States	Norton Heart Specialists	Louisville	Kentucky
United States	Norton Heart Specialists	Louisville	Kentucky
United States	University of Colorado Health	Loveland	Colorado
United States	Lutherville Personal Physicians	Lutherville	Maryland
United States	Meriter hospital Inc., DBA: UnityPoint Health-Meriter Heart	Madison	Wisconsin
United States	Burke Internal Medicine and Research	Manassas	Virginia
United States	INOVA Health Care Services	Manassas	Virginia
United States	Manassas Clinical Research Center	Manassas	Virginia
United States	Urban Family Practice Associates/Clinical Research Advantage	Marietta	Georgia
United States	Awasty Research Network, LLC	Marion	Ohio
United States	Marquette General Heart and Vascular Institute	Marquette	Michigan
United States	Marshfield Clinic	Marshfield	Wisconsin
United States	Community Health Care	Massillon	Ohio
United States	The Endocrine Clinic	Memphis	Tennessee
United States	ActivMed Practices	Methuen	Massachusetts
United States	Cardiovascular Research Center of South Florida	Miami	Florida
United States	Life Spring Research Foundation	Miami	Florida
United States	Pharmax Research Clinic, Inc	Miami	Florida
United States	South Florida Research Group LLC	Miami	Florida
United States	United Clinical Research Corp.	Miami	Florida
United States	Midland Clinical Research Center	Midland	Texas
United States	MidMichigan Medical Center	Midland	Michigan
United States	Rutgers New Jersey Medical School	Mine Hill	New Jersey
United States	Long Island Heart Associates	Mineola	New York
United States	Minneapolis Heart Institute	Minneapolis	Minnesota
United States	South Florida Research Solutions	Miramar	Florida
United States	Clinical Interventions Research Institute	Mission Viejo	California
United States	Coastal Clinical Research, Inc.	Mobile	Alabama
United States	Mobile Heart Specialists, PC	Mobile	Alabama
United States	Diabetes & Endocrinology Consultants	Morehead City	North Carolina
United States	Burke Primary Care	Morganton	North Carolina
United States	American Health Network of IN, LLC	Muncie	Indiana
United States	Medical Consultants PC	Muncie	Indiana
United States	Cardiology Associates of Northwest Indiana, P.C	Munster	Indiana
United States	Brigid Freyne MD Inc	Murrieta	California
United States	Southwest Florida Research	Naples	Florida
United States	Cardiology Wellness Center	Nashville	Tennessee
United States	Partners Community Physicians Organization	Natick	Massachusetts
United States	Partners Community Physicians Organization	Needham	Massachusetts
United States	North Shore Diabetes and Endocrine Associates	New Hyde Park	New York
United States	Weill Cornell Medical College	New York	New York
United States	Red Clay Research	Newark	Delaware
United States	Capital Area Research LLC	Newport	Pennsylvania
United States	Clinical Research Associates of Tidewater	Norfolk	Virginia
United States	Health Research of Hampton Roads - Norfolk, Inc.	Norfolk	Virginia
United States	DiGiovanna Institute for Medical Education	North Massapequa	New York
United States	Valley Clinical Trials Inc	Northridge	California
United States	Cardiology Associates of Fairfield County, Norwalk	Norwalk	Connecticut
United States	Ocala Research Institute, Inc	Ocala	Florida
United States	Carr Cardiology	Oceanside	California
United States	Permian Research Foundation	Odessa	Texas
United States	Advanced Research Institute	Ogden	Utah
United States	Integris Cardiovascular Physicians LLC	Oklahoma City	Oklahoma
United States	Memorial Clinical Research	Oklahoma City	Oklahoma
United States	South Oklahoma Heart Research, LLC	Oklahoma City	Oklahoma
United States	Oviedo Medical Research	Oviedo	Florida
United States	Research Integrity LLC	Owensboro	Kentucky
United States	MD Medical Research	Oxon Hill	Maryland
United States	Cardiology Partners Clinical Research Institute	Palm Beach Gardens	Florida
United States	Palm Beach Gardens Research Center	Palm Beach Gardens	Florida
United States	Research Physicians Network Alliance, Pembrok	Pembroke Pines	Florida
United States	South Florida Research Solutions	Pembroke Pines	Florida
United States	Cardiology Consultants	Pensacola	Florida
United States	Nisus Research at McLaren Northern Michigan Hospital	Petoskey	Michigan
United States	Endocrine Metabolic Associates	Philadelphia	Pennsylvania
United States	Pinehurst Medical Clinic, Inc.	Pinehurst	North Carolina
United States	Clinical Investigations of Texas, LLC	Plano	Texas
United States	Medical Clinic of North Texas	Plano	Texas
United States	Clinical Research of Central Florida	Plant City	Florida
United States	Columbia Primary Care, LLC d/b/a Heart and Health Institute	Plantation	Florida
United States	St Johns Center for Clinical Research	Ponte Vedra	Florida
United States	Saint Joseph Mercy Oakland Hospital	Pontiac	Michigan
United States	Charlotte Heart Group Research Center	Port Charlotte	Florida
United States	Progressive Medical Research	Port Orange	Florida
United States	InterMed, PA	Portland	Maine
United States	Pottstown Medical Specialists, Inc. (PMSI)	Pottstown	Pennsylvania
United States	Hudson Valley Heart Center	Poughkeepsie	New York
United States	Wake Research Associates, LLC	Raleigh	North Carolina
United States	Northern California Clinical Research Center	Redding	California
United States	Clinical Research Partners	Richmond	Virginia
United States	National Clinical Research-Richmond, Inc	Richmond	Virginia
United States	Virginia Cardiovascular Specialists	Richmond	Virginia
United States	Remedica LLC	Rochester	Michigan
United States	Rochester Clinical Research, Inc.	Rochester	New York
United States	Advanced CardioVascular Consultants, SC	Rock Island	Illinois
United States	Brevard Cardiovascular Research Associates Inc	Rockledge	Florida
United States	Endocrine & Metabolic Consultants	Rockville	Maryland
United States	PMG Research of Rocky Mount	Rocky Mount	North Carolina
United States	Endocrine Research Solutions, Inc.	Roswell	Georgia
United States	Texas Diabetes	Round Rock	Texas
United States	Clearwater Cardiovascular and Interventional Cons.	Safety Harbor	Florida
United States	Michigan CardioVascular Institute	Saginaw	Michigan
United States	Regions Hospital	Saint Paul	Minnesota
United States	Bayfront Health St. Petersburg, Research	Saint Petersburg	Florida
United States	Meridien Research - St. Petersburg	Saint Petersburg	Florida
United States	Professional Health Care of Pinellas, INC	Saint Petersburg	Florida
United States	PMG Research of Salisbury	Salisbury	North Carolina
United States	Jean Brown Research	Salt Lake City	Utah
United States	Cardiology Clinic of San Antonio	San Antonio	Texas
United States	Physician PrimeCare Research Institute, PLLC	San Antonio	Texas
United States	Radiant Research San Antonio	San Antonio	Texas
United States	Ritchken and First MD's	San Diego	California
United States	Sharp Rees-Stealy Medical Group, Inc.	San Diego	California
United States	University of California San Diego	San Diego	California
United States	West Coast Research LLC	San Ramon	California
United States	Sanford Cardiology	Sanford	North Carolina
United States	Coastal Multi-Specialty Research	Santa Ana	California
United States	Intercoastal Medical Group	Sarasota	Florida
United States	Geisinger Clinic	Scranton	Pennsylvania
United States	Seattle Women's	Seattle	Washington
United States	Cardiovascular Associates Delaware Valley Sewell	Sewell	New Jersey
United States	Cardio Metabolic Institute	Somerset	New Jersey
United States	Northwell Health Physician Partners Cardiology	Southampton	New York
United States	American Center for Clinical Trials	Southfield	Michigan
United States	Palmetto Research Center, LLC	Spartanburg	South Carolina
United States	Rowan Research Inc.	Spokane	Washington
United States	Apex Medical Research Inc.	Springfield	Ohio
United States	Springfield Medical Center	Springfield	Florida
United States	Cardiology Associates of Fairfield County, P.C.	Stamford	Connecticut
United States	Stamford Therapeutics Consortium	Stamford	Connecticut
United States	Piedmont Healthcare	Statesville	North Carolina
United States	Advanced Clinical Research Group	Stuart	Florida
United States	Herman Clinical Research LLC	Suwanee	Georgia
United States	MultiCare Research Institute	Tacoma	Washington
United States	Universal Research Group	Tacoma	Washington
United States	Healthpoint Medical Group, Inc	Tampa	Florida
United States	Meridien Research - Tampa	Tampa	Florida
United States	Stedman Clinical Trials	Tampa	Florida
United States	Westlake Medical Research	Thousand Oaks	California
United States	Martin Diagnostic Clinic	Tomball	Texas
United States	Harbor - UCLA Medical Center	Torrance	California
United States	Lutherville Personal Physicians	Towson	Maryland
United States	Overlea Personal Physicians	Towson	Maryland
United States	Medical Research Associates, Inc.	Traverse City	Michigan
United States	Interventional Cardiac Consultants	Trinity	Florida
United States	Capital Cardiology Associates	Troy	New York
United States	Cardiology Associates of Fairfield County, P.C.	Trumbull	Connecticut
United States	Connecticut Heart and Vascular Center	Trumbull	Connecticut
United States	Atlanta Heart Specialists	Tucker	Georgia
United States	Eclipse Clinical Research	Tucson	Arizona
United States	Oklahoma Heart Institute	Tulsa	Oklahoma
United States	Vital Prospects Clinical Research Institute PC	Tulsa	Oklahoma
United States	Cardiology Associates Research, LLC	Tupelo	Mississippi
United States	Cardiovascular Associates of East Texas	Tyler	Texas
United States	Lovelace Scientific Research	Venice	Florida
United States	Ronald Chochinov, MD	Ventura	California
United States	Ventura Cardiology Consultants	Ventura	California
United States	Indian River Medical Center-Cardiology	Vero Beach	Florida
United States	BodyAesthetic Research Center	Washington	Missouri
United States	Chase Medical Research, LLC	Waterbury	Connecticut
United States	Brown Clinic, PLLP	Watertown	South Dakota
United States	Aspirus Research Institute	Wausau	Wisconsin
United States	Bay Area Total Health Medical Group	Webster	Texas
United States	Cardiology Partners Clinical Research Institute	Wellington	Florida
United States	Wenatchee Valley Hospital & Clinics	Wenatchee	Washington
United States	Infosphere Clinical Research	West Hills	California
United States	Cleveland Clinic Foundation	West Palm Beach	Florida
United States	Metabolic Research Institute	West Palm Beach	Florida
United States	Great Lakes Medical Research	Westfield	New York
United States	Professional Research Network of Kansas, LLC	Wichita	Kansas
United States	Alfieri Cardiology	Wilmington	Delaware
United States	PMG Research of Wilmington	Wilmington	North Carolina
United States	Selma Medical Associates	Winchester	Virginia
United States	PMG Research of Winston-Salem, LLC	Winston-Salem	North Carolina
United States	Clinical Research of Central Florida	Winter Haven	Florida
United States	Michigan Heart	Ypsilanti	Michigan

Sponsors (2)

Lead Sponsor	Collaborator
Eisai Inc.	Thrombolysis In Myocardial Infarction (TIMI) Academic Research Organization

Countries where clinical trial is conducted

United States,  Australia,  Bahamas,  Canada,  Chile,  Mexico,  New Zealand,  Poland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time From Randomization to First Occurrence of Major Adverse Cardiovascular Events (MACE) at Interim Analysis	The MACE events involved myocardial infarction (MI), stroke, or cardiovascular (CV) death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.	Baseline up to Month 42
Primary	Time From Randomization to First Occurrence of MACE+	The MACE+ events involved MI, stroke, or CV death or hospitalization for unstable angina or heart failure (HF), or any coronary revascularization. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.	Baseline up to end of study (Month 56)
Secondary	Time From Randomization to Conversion to Type 2 Diabetes Mellitus (T2DM) for Participants With Prediabetes at Baseline	Time from randomization to conversion to T2DM was defined as first occurrence of any component of the 2013 American Diabetes Association (ADA) Diagnostic Criteria (ADA, 2013) in participants with prediabetes at baseline. The diagnostic criteria were met if a participant had unequivocal hyperglycemia (random plasma glucose greater than or equal to (>=) 200 milligram per deciliter (mg/dL) (11.1 millimole per liter [mmol/L]) with classic symptoms of hyperglycemia or hyperglycemic crisis) or any of the following criteria were observed and subsequently confirmed on repeat laboratory testing such as: glycosylated hemoglobin (HbA1c) >=to 6.5%; fasting plasma glucose (FPG) >=126 mg/dL (7.0 mmol/L); 2-hour plasma glucose >=200 mg/dL (11.1 mmol/L) by an oral glucose tolerance test (OGTT). The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.	Baseline up to end of study (Month 56)
Secondary	Time From Randomization to First Occurrence of the Individual Components of MACE+	The MACE+ events involved MI, stroke, or CV death or hospitalization for unstable angina or HF, or any coronary revascularization. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.	Baseline up to end of study (Month 56)
Secondary	Time From Randomization to Event of All-cause Mortality	The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.	Baseline up to end of study (Month 56)
Secondary	Time From Randomization to Conversion to Normal Glucose Homeostasis in Participants With Prediabetes at Baseline	Normal glucose homeostasis was defined as HbA1c less than or equal to (<=) 5.6% and FPG < 100 mg/dL without any antidiabetic treatment. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.	Baseline up to end of study (Month 56)
Secondary	Time From Randomization to Conversion to T2DM for Participants Without Any Type of Diabetes at Baseline	The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.	Baseline up to end of study (Month 56)
Secondary	Change From Baseline in HbA1c at Month 6 in Participants With T2DM at Baseline		Baseline, and Month 6
Secondary	Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in All Participants	New onset/worsening of existing renal impairment was first occurrence of any events: microalbuminuria and macroalbuminuria (albumin-to-creatinine ratio [ACR] >=30mcg/mg and ACR>=300 mcg/mg in spot urine), worsening albuminuria (microalbuminuria at Baseline developed macroalbuminuria, ACR increased >=30% from Baseline during treatment), newly developed chronic kidney disease (CKD) (eGFR >=90 milliliter per minute per 1.73 [mL/min/1.73]body surface area (BSA) and without kidney damage at Baseline changed to CKD Stage 1/higher as per National Kidney Foundation [NKF] Guidelines [2002]) or worsening of CKD (CKD Stage 1/higher as per NKF Guidelines [2002] worsened to higher CKD stages during treatment), or doubling of serum creatinine (creatinine value at least 2 times Baseline value and >=1.5 mg/dL during treatment.), or any of the following: end-stage renal disease, renal transplant, renal death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.	Baseline up to end of study (Month 56)
Secondary	Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in Participants With Prediabetes at Baseline	New onset/worsening of existing renal impairment was first occurrence of any events: microalbuminuria and macroalbuminuria (ACR >=30mcg/mg and ACR >=300 mcg/mg in spot urine), worsening albuminuria (microalbuminuria at baseline developed macroalbuminuria, ACR increased >=30% from baseline during treatment), CKD (eGFR >=90 mL/min/1.73 BSA and without kidney damage at baseline changed to CKD Stage 1/higher as per NKF Guidelines [2002]) or worsening of CKD (CKD Stage 1/higher as per NKF Guidelines [2002] worsened to higher CKD stages during treatment), or doubling of serum creatinine (creatinine value at least 2 times baseline value and >=1.5 mg/dL during treatment.), or any of the following: end-stage renal disease, renal transplant, renal death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.	Baseline up to end of study (Month 56)
Secondary	Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in Participants With T2DM at Baseline	New onset/worsening of existing renal impairment was first occurrence of any events: microalbuminuria and macroalbuminuria (ACR >=30 mcg/mg and ACR >=300 mcg/mg in spot urine), worsening albuminuria (microalbuminuria at baseline developed macroalbuminuria, ACR increased >=30% from baseline during treatment), CKD (eGFR >=90 mL/min/1.73 BSA and without kidney damage at baseline changed to CKD Stage 1/higher as per NKF Guidelines [2002]) or worsening of CKD (CKD Stage 1/higher as per NKF Guidelines [2002] worsened to higher CKD stages during treatment), or doubling of serum creatinine (creatinine value at least 2 times baseline value and >=1.5 mg/dL during treatment.), or any of the following: end-stage renal disease, renal transplant, renal death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.	Baseline up to end of study (Month 56)
Secondary	Time From Randomization to Event of Improvement in Renal Function in Participants With T2DM at Baseline	Improvement in renal function was defined as first occurrence of regression of albuminuria or regression of CKD. Regression of albuminuria was defined as when participants with macroalbuminuria at baseline developed microalbuminuria or nonalbuminuria (ACR <30 mcg/mg in spot urine), or participants with microalbuminuria at baseline became nonalbuminuric, and ACR value decreased >= 30% from previous assessment during treatment. Regression of CKD defined as when participants with CKD Stage 1 or higher at baseline improved to normal or lower stages by NKF guidelines (eGFR >=90 with albuminuria at baseline improved to eGFR >=90 without albuminuria, or eGFR 60 to 89 at baseline became eGFR >=90 with or without albuminuria, or eGFR between 30 to 59 at baseline improved to >60 mL/min/1.73 BSA) during treatment. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.	Baseline up to end of study (Month 56)
Secondary	Percentage of Participants Who Met FDA-Defined Valvulopathy in Echocardiographically Determined Heart Valve Changes		Months 6 and 12
Secondary	Percentage of Participants With FDA-Defined Valvulopathy at Baseline Who Demonstrated Worsened FDA-Defined Valvulopathy		Months 6 and 12
Secondary	Change From Baseline in Echocardiographically-Determined Pulmonary Arterial Systolic Pressure		Baseline, Month 12