A Study to Compare the Effects of Coreg CR and Coreg IR on Heart Function in Subjects With Stable Chronic Heart Failure

Condition(s) targeted: Congestive Heart Failure

Intervention: carvedilol controlled release (Drug); carvedilol immediate release (Drug)

Phase: Phase 3

Status: Active, not recruiting

Sponsored by: CTI-1, LLC

Official(s) and/or principal investigator(s):
Barry Greenberg, MD, Study Chair, Affiliation: Unaffiliated

The purpose of this study is to determine if Coreg CR is as effective as Coreg IR in improving heart function in subjects with stable chronic heart failure.

Official title: A Multicenter,Randomized, Double Blind, Double Dummy, Parallel Group Study to Compare Effects of Coreg CR and Coreg IR on Left Ventricular End Systolic Volume Index in Subjects With Stable Chronic Heart Failure

Study design: Treatment, Randomized, Double Blind (Subject, Investigator), Parallel Assignment, Efficacy Study

Primary outcome: Change from baseline in Left Ventricular End Systolic Volume Index (LVESVI) characterized by 2-D echocardiography

Secondary outcome:

Change from baseline in left ventricular ejection fraction

Change from baseline in left ventricular remodeling (IVST, PWT, LVM, ESV, EDV, EDVI, ESD, EDD, deceleration time, and E:A ratio)

Change from baseline in BNP levels

Incidence of hospitalizations from exacerbation of heart failure

Hospitalizations from all causes

Drug dose tolerability

Safety and tolerability of Coreg CR

Drug compliance

Detailed description: Results of clinical trials have shown beta-blockers improve symptoms and left ventricular function, reduce hospitalizations and death in heart failure, and prolong survival [MERIT-HF, CIBIS-II, Packer, 1996]. Clinical guidelines mandate use of beta-blockers in treatment of subjects with heart failure.

Carvedilol (Coreg IR) is a multiple action adrenergic receptor blocker with alpha 1, beta 1 and beta 2 receptor blockade properties. The beta-adrenergic properties are non-selective for beta 1 and beta 2 adrenergic receptors. Coreg IR, administered twice daily, is marketed in the United States for long term treatment of mild-moderate hypertension, mild to severe heart failure and subjects surviving an acute myocardial infarction with left ventricular dysfunction with or without symptomatic heart failure.

Coreg IR significantly reduces all cause mortality and the need for cardiovascular hospitalization [Packer, 1996a; Packer, 1996b; Colucci, 1996; Cohn, 1997; Olsen, 1995; Sharpe 1997]. The effect of Coreg is dose dependent [Bristow, 1996]. In subjects treated long term after an acute myocardial infarction (MI) complicated by left ventricular systolic dysfunction, Coreg IR reduced the frequency of all-cause and cardiovascular mortality, and recurrent non-fatal MIs. These beneficial effects are additional to those of evidence-based treatments for acute MI, including ACE inhibitors [Dargie, 2001].

Left Ventricular End Systolic Volume Index (LVESVI) is an important measure of ventricular function and remodeling in the evaluation of heart failure. In controlled clinical trials, Coreg IR, administered twice daily, has reduced LVESVI in subjects with ischemic heart failure. An echocardiography substudy of the Australia-New Zealand Trial [Doughty, 1997], evaluated left ventricular remodeling in 123 subjects with ischemic heart failure with an LVEF < 45 randomized to carvedilol or placebo. The LVESVI was reduced by 6. 2 + 1. 6 ml/m2 after 6 months and 8. 7 + 2. 6 ml/m2 after 12 months of carvedilol therapy compared to the placebo treated subjects. Metra et al [Metra, 2000] observed the favorable effects of carvedilol compared with metoprolol on LVEF, LV stroke volume, and pulmonary artery pressure despite similar effects on cardiovascular outcome. Both groups also showed significant decreases in LV systolic volume. Doughty et al [Doughty, 2004] observed the favorable effects of carvedilol on LV remodeling, with improved LV end-systolic volume and ejection fraction, after 6 months of treatment.

Carvedilol phosphate CR (Coreg CR) is an approved, modified release, once-daily formulation of carvedilol that is hoped to provide an advance in patient care through improved compliance with prescribed dose.

The clinical experience with various formulations of Coreg CR is limited to eight single dose studies in healthy subjects and one repeated dose study in subjects with hypertension. In total 230, adult subjects have received at least one dose of Coreg IR or one of several CR formulations across nine studies. The subjects ranged in age from 18 to 63 years; 62% were male and 69% were white. The various formulations of Coreg CR capsules were safe and well tolerated in single dose pharmacokinetic studies in doses ranging from 6. 25 to 60 mg in healthy subjects. The most common adverse events were headache, dizziness and orthostatic hypotension and are all known adverse events following administration of Coreg IR [GSK Study 386, 388, 399, 400, 402, 907].

This study will be the first controlled clinical study investigating the efficacy of treatment with Coreg CR formulation [Coreg CR filled with 7. 5 mg of carvedilol phosphate immediate release (IRp) microparticles, 22. 5 mg of carvedilol phosphate Micropump IIa MR microparticles, and 30 mg of carvedilol phosphate Micropump IIc MR microparticles] compared to Coreg IR evaluating LVESVI in subjects with stable chronic heart failure.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Male or non-pregnant female

- At least 18 years of age at the time informed consent is signed

- Stable, chronic, mild to severe heart failure as defined as subjects with symptoms of

heart failure who do not require IV diuretics, inotropes, or vasodilators or those that require support with a left ventricular assist device

- Angiotensin converting enzyme inhibitors or angiotensin receptor blockers should be

prescribed to all patients with HF due to LV systolic dysfunction with reduced LVEF unless contraindicated or intolerant to use

- At screening, subject has an LVEF < 40 as measured by 2-D echocardiography

- Willing to provide written informed consent

Exclusion Criteria:

- On beta-blocker therapy for greater than 42 days prior to consent

- Acute ischemic coronary event or coronary revascularization (PTCA, CABG, thrombolysis)

within 1 week of screening echocardiography

- Scheduled or expected to be scheduled coronary revascularization within 4 weeks

- Unstable angina (angina characterized by sudden changes in the severity or length of

angina attacks or a decrease in level of exertion that precipitates an episode

- Uncorrected primary obstructive or severe regurgitant valvular disease, nondilated

(restrictive) or hypertrophic cardiomyopathies

- Uncontrolled ventricular arrhythmias (symptomatic or sustained ventricular arrhythmias

not controlled with antiarrhythmic therapy or an implantable defibrillator)

- Current treatment of calcium channel blockers except for long acting dihydropyridines

- Current treatment on any Class I or III antiarrhythmic, except amiodarone

- History of sick sinus syndrome unless a pacemaker is in place

- Second or third degree heart block unless a pacemaker is in place

- Current clinical evidence of obstructive pulmonary disease (e. g., asthma or

bronchitis) requiring inhaled or oral bronchodilator or steroid therapy; or having a history of bronchospastic disease not undergoing active therapy in whom, in the investigator's opinion, treatment with study medication could provoke bronchospasm

- Expected biventricular pacemaker placement within 8 months of enrollment

- Resting systolic blood pressure <90 mmHg (based on the average of 3 readings

- Resting heart rate <50 beats per minute (bpm) (based on the average of 3 readings)

- Current decompensated heart failure

- Elevated liver enzymes (i. e., ALT or AST levels greater than 3 times upper limit of

normal)

- History of drug sensitivity or allergic reaction to alpha or beta-blockers

- Contraindication or intolerance to beta-blockers

- Pregnant or lactating women and women planning to become pregnant. NOTE: Female

subjects must be post-menopausal (i. e., no menstrual period for a minimum of 6 months prior to screening), surgically sterilized, using a double barrier method contraceptive, or using Depo-Provera or implanted contraceptives for at least one month prior to screening and agree to continue to use the same contraceptive method throughout the study.

- Use of an investigational drug within 30 days of enrollment

- Participation in an investigational device trial within 30 days of enrollment

- Known drug or alcohol abuse 1 year prior to enrollment

- In the opinion of the investigator the subject is known to be noncompliant with

prescribed medication regimen

- Has any systemic disease, including cancer, with reduced life expectancy (<12 months)

- Has a history of psychological illness/condition that interferes with ability to

understand or complete requirements of the study.

Cardiology Associates, Mobile, Alabama 36608, United States

Mobile Heart Specialists, Mobile, Alabama 36608, United States

South West Heart, Tucson, Arizona 85715, United States

Mayo Clinic Arizona, Phoenix, Arizona 85054, United States

William Bowden, DO Private Practice, Healdsburg, California 95448, United States

Sutter Memorial Hospital, Sacramento, California 95819, United States

Merced Heart Associates, Merced, California 95340, United States

Southern California Cardiology Medical Group, Inc., San Diego, California 92120, United States

Rancho Los Amigos USC, Downey, California 90242, United States

Heart and Vascular Clinic of Northern Colorado, P.C., Fort Collins, Colorado 80528, United States

Bay Area Cardiology, Brandon, Florida 33511, United States

Clearwater Cardiovascular and Interventional Consultants, Clearwater, Florida 33756, United States

Harbin Clinic, Rome, Georgia 30165, United States

Cardiac Disease Specialists, PC, Atlanta, Georgia 30309, United States

HeartCare Midwest, Peoria, Illinois 61614, United States

Rockford Cardiology Research Foundation, Rockford, Illinois 61107, United States

North Shore Cardiovascular Research Consortium, Bannockburn, Illinois 60015, United States

Illinois Heart and Vascular, Hinsdale, Illinois 60521, United States

Prairie Cardiovascular Consultants, Springfield, Illinois 62701, United States

River Cities Cardiology, Jeffersonville, Indiana 47130, United States

The Care Group LLC, Indianapolis, Indiana 46260, United States

Via Christi Research, Inc., Wichita, Kansas 67214, United States

Mid-America Cardiology, Kansas City, Kansas 66160, United States

Comprehensive Cardiology Associates, Florence, Kentucky 41042, United States

Cardiovascular Associates, Louisville, Kentucky 40205, United States

St. Paul Cardiology, St. Paul, Minnesota 55102, United States

Hennepin County Medical Center, Minneapolis, Minnesota 55415, United States

Minnesota Heart Clinic, Edina, Minnesota 55435, United States

Regions Hospital Cardiology Research, St. Paul, Minnesota 55101, United States

Cardiology Associates Research, LLC, Tupelo, Mississippi 38801, United States

Glacier View Cardiology, Kalispell, Montana 59901, United States

Diagnostic and Clinical Cardiology, West Orange, New Jersey 07052, United States

University of New Mexico, Albuquerque, New Mexico 87131-0001, United States

Albany Associates in Cardiology, Albany, New York 12205, United States

South Bay Cardiovascular Associates, West Islip, New York 11795, United States

New York Cardiovascular Associates, New York, New York 10035, United States

Long Island Heart Associates, Mineola, New York 11501, United States

Montefiore Medical Center, Bronx, New York 10467, United States

University of North Carolina, Chapel Hill, North Carolina 27599, United States

LeBauer Cardiovascular Research Foundation, Greensboro, North Carolina 27401, United States

Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157, United States

The Lindner Clinical Trial Center, Cincinnati, Ohio 45219, United States

Sterling Research Group Ltd., Cincinnati, Ohio 45219, United States

University Hospital, Cincinnati, Ohio 45267-0542, United States

Oklahoma Cardiovascular Research Group, Oklahoma City, Oklahoma 73120, United States

Samaritan Cardiology, Corvallis, Oregon 97330, United States

Central Bucks Specialists, Doylestown, Pennsylvania 18901, United States

Tri-State Medical Group, Beaver, Pennsylvania 15009, United States

Blair Medical Associates, Altoona, Pennsylvania 16602, United States

Rhode Island Heart Failure Center, Providence, Rhode Island 02903, United States

Charleston Cardiology, Charleston, South Carolina 29403, United States

Texas Cardiac Center, Lubbock, Texas 79410, United States

Intermountain Medical Center, Murray, Utah 84107, United States

Heart Center, Salt Lake City, Utah 84124, United States

Winchester Medical Center, Winchester, Virginia 22601, United States

Green Bay HeartCare, Green Bay, Wisconsin 54303, United States

Related publications:

[No authors listed] Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF) Lancet. 1999 Jun 12;353(9169):2001-7.

[No authors listed] The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999 Jan 2;353(9146):9-13.

Packer M, Colucci WS, Sackner-Bernstein JD, Liang CS, Goldscher DA, Freeman I, Kukin ML, Kinhal V, Udelson JE, Klapholz M, Gottlieb SS, Pearle D, Cody RJ, Gregory JJ, Kantrowitz NE, LeJemtel TH, Young ST, Lukas MA, Shusterman NH. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Circulation. 1996 Dec 1;94(11):2793-9.

Packer M, Bristow MR, Cohn JN, Colucci WS, Fowler MB, Gilbert EM, Shusterman NH. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N Engl J Med. 1996 May 23;334(21):1349-55.

Colucci WS, Packer M, Bristow MR, Gilbert EM, Cohn JN, Fowler MB, Krueger SK, Hershberger R, Uretsky BF, Bowers JA, Sackner-Bernstein JD, Young ST, Holcslaw TL, Lukas MA. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carvedilol Heart Failure Study Group. Circulation. 1996 Dec 1;94(11):2800-6.

Cohn JN, Fowler MB, Bristow MR, Colucci WS, Gilbert EM, Kinhal V, Krueger SK, Lejemtel T, Narahara KA, Packer M, Young ST, Holcslaw TL, Lukas MA. Safety and efficacy of carvedilol in severe heart failure. The U.S. Carvedilol Heart Failure Study Group. J Card Fail. 1997 Sep;3(3):173-9.

Olsen SL, Gilbert EM, Renlund DG, Taylor DO, Yanowitz FD, Bristow MR. Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study. J Am Coll Cardiol. 1995 May;25(6):1225-31.

[No authors listed] Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Australia/New Zealand Heart Failure Research Collaborative Group. Lancet. 1997 Feb 8;349(9049):375-80.

Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger RE, Kubo SH, Narahara KA, Ingersoll H, Krueger S, Young S, Shusterman N. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. MOCHA Investigators. Circulation. 1996 Dec 1;94(11):2807-16.

Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001 May 5;357(9266):1385-90.

Doughty RN, Whalley GA, Walsh HA, Gamble GD, López-Sendón J, Sharpe N; CAPRICORN Echo Substudy Investigators. Effects of carvedilol on left ventricular remodeling after acute myocardial infarction: the CAPRICORN Echo Substudy. Circulation. 2004 Jan 20;109(2):201-6. Epub 2004 Jan 5.

Doughty RN, Whalley GA, Gamble G, MacMahon S, Sharpe N. Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. Australia-New Zealand Heart Failure Research Collaborative Group. J Am Coll Cardiol. 1997 Apr;29(5):1060-6.

Greenberg BH, Mehra M, Teerlink JR, Ordronneau P, McCollum D, Gilbert EM. COMPARE: comparison of the effects of carvedilol CR and carvedilol IR on left ventricular ejection fraction in patients with heart failure. Am J Cardiol. 2006 Oct 2;98(7A):53L-59L. Epub 2006 Aug 28.

Starting date: March 2006
Ending date: April 2008
Last updated: January 24, 2008