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

Congestive Heart Failure Clinical Trial

— COMPARE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00323037
• Other study ID #: 104852
• Status: Completed
• Phase: Phase 3
• Start date: March 2006
• Est. completion date: June 2008

Study information

• Verified date: March 2023
• Source: CTI-1, LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 318
• Est. completion date: June 2008
• Est. primary completion date: April 2008
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Congestive Heart Failure
• Heart Failure

Intervention

Drug:
• carvedilol controlled release
Carvedilol controlled release (10, 20, 40 or 80 mg) and placebo taken in the morning. Two placebos taken in the evening. A total of 4 pills will be taken PO daily.
• carvedilol immediate release
Carvedilol immediate release (3.125, 6.25, 12.5 or 25 mg) and placebo, taken PO, twice-daily.

Locations

Country	Name	City	State
United States	Albany Associates in Cardiology	Albany	New York
United States	University of New Mexico	Albuquerque	New Mexico
United States	Blair Medical Associates	Altoona	Pennsylvania
United States	Cardiac Disease Specialists, PC	Atlanta	Georgia
United States	One Heart, LLC	Baltimore	Maryland
United States	North Shore Cardiovascular Research Consortium	Bannockburn	Illinois
United States	Tri-State Medical Group	Beaver	Pennsylvania
United States	Bay Area Cardiology	Brandon	Florida
United States	Montefiore Medical Center	Bronx	New York
United States	Buffalo Heart Group, LLP	Buffalo	New York
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Charleston Cardiology	Charleston	South Carolina
United States	Sterling Research Group Ltd.	Cincinnati	Ohio
United States	The Lindner Clinical Trial Center	Cincinnati	Ohio
United States	University Hospital	Cincinnati	Ohio
United States	Clearwater Cardiovascular and Interventional Consultants	Clearwater	Florida
United States	South Carolina Heart Center	Columbia	South Carolina
United States	Inland Heart Doctors Medical Group	Corona	California
United States	Samaritan Cardiology	Corvallis	Oregon
United States	Aurora Denver Cardiology Associates	Denver	Colorado
United States	Rancho Los Amigos USC	Downey	California
United States	Central Bucks Specialists	Doylestown	Pennsylvania
United States	Luther Midelfort Mayo Health Systems	Eau Claire	Wisconsin
United States	Minnesota Heart Clinic	Edina	Minnesota
United States	Saint Francis Hospital	Evanston	Illinois
United States	Comprehensive Cardiology Associates	Florence	Kentucky
United States	White-Wilson Medical Center, PA	Fort Walton Beach	Florida
United States	Heart Specialists	Friendswood	Texas
United States	Green Bay HeartCare	Green Bay	Wisconsin
United States	LeBauer Cardiovascular Research Foundation	Greensboro	North Carolina
United States	William Bowden, DO Private Practice	Healdsburg	California
United States	Illinois Heart and Vascular	Hinsdale	Illinois
United States	The Care Group LLC	Indianapolis	Indiana
United States	River Cities Cardiology	Jeffersonville	Indiana
United States	Rocky Mountain Heart & Lung	Kalispell	Montana
United States	Mid-America Cardiology	Kansas City	Kansas
United States	Cardiovascular Associates	Louisville	Kentucky
United States	Louisville Cardiology Medical Group	Louisville	Kentucky
United States	Medical Center of the Rockies Foundation	Loveland	Colorado
United States	Texas Cardiac Center	Lubbock	Texas
United States	Merced Heart Associates	Merced	California
United States	South Florida International Cardiology Consultants, Inc.	Miami	Florida
United States	Long Island Heart Associates	Mineola	New York
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Cardiology Associates	Mobile	Alabama
United States	Mobile Heart Specialists	Mobile	Alabama
United States	Intermountain Medical Center	Murray	Utah
United States	New York Cardiovascular Associates	New York	New York
United States	Oklahoma Cardiovascular Research Group	Oklahoma City	Oklahoma
United States	Palm Beach Cardiology	Palm Beach Gardens	Florida
United States	HeartCare Midwest	Peoria	Illinois
United States	Cardiology Consultants of Philadelphia	Philadelphia	Pennsylvania
United States	Mid State Medical Service	Philipsburg	Pennsylvania
United States	Mayo Clinic Arizona	Phoenix	Arizona
United States	Rhode Island Heart Failure Center	Providence	Rhode Island
United States	Rockford Cardiology Research Foundation	Rockford	Illinois
United States	Harbin Clinic	Rome	Georgia
United States	Sutter Memorial Hospital	Sacramento	California
United States	Regions Hospital Cardiology Research	Saint Paul	Minnesota
United States	St. Paul Cardiology	Saint Paul	Minnesota
United States	Heart Center	Salt Lake City	Utah
United States	Southern California Cardiology Medical Group, Inc.	San Diego	California
United States	Scottsdale Cardiovascular Research Institute	Scottsdale	Arizona
United States	Buxmont Cardiology Associates, PC	Sellersville	Pennsylvania
United States	Prairie Cardiovascular Consultants	Springfield	Illinois
United States	Northwest Ohio Cardiology Consultants	Toledo	Ohio
United States	South West Heart	Tucson	Arizona
United States	Cardiology Associates Research, LLC	Tupelo	Mississippi
United States	Medvin Clinical Research	Van Nuys	California
United States	Iowa Heart Center	West Des Moines	Iowa
United States	South Bay Cardiovascular Associates	West Islip	New York
United States	Diagnostic and Clinical Cardiology	West Orange	New Jersey
United States	Via Christi Research, Inc.	Wichita	Kansas
United States	Winchester Medical Center	Winchester	Virginia
United States	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (3)

Lead Sponsor	Collaborator
CTI-1, LLC	CTI Clinical Trial and Consulting Services, GlaxoSmithKline

Country where clinical trial is conducted

United States, 

References & Publications (13)

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. doi: 10.1161/01.cir.94.11.2807. — View Citation

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. doi: 10.1016/s1071-9164(97)90013-0. — View Citation

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. doi: 10.1161/01.cir.94.11.2800. — View Citation

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. doi: 10.1016/s0140-6736(00)04560-8. — View Citation

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. doi: 10.1016/s0735-1097(97)00012-0. — View Citation

Doughty RN, Whalley GA, Walsh HA, Gamble GD, Lopez-Sendon 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. doi: 10.1161/01.CIR.0000108928.25690.94. Epub 2004 Jan 5. — View Citation

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. — View Citation

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. doi: 10.1016/j.amjcard.2006.08.003. Epub 2006 Aug 28. — View Citation

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. doi: 10.1016/0735-1097(95)00012-S. — View Citation

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. doi: 10.1056/NEJM199605233342101. — View Citation

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. doi: 10.1161/01.cir.94.11.2793. — View Citation

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. — View Citation

The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999 Jan 2;353(9146):9-13. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI) Characterized by 2-D Echocardiography	Maintenance Visit 3 minus Baseline. Maintenance Visit 3 occurred 24 weeks after entry into the maintenance period. The maintenance period started after completion of a titration period of variable duration.	24 weeks after entry into the maintenance period
Secondary	Change From Baseline in Left Ventricular Ejection Fraction (LVEF)		24 weeks after entry into the maintenance period
Secondary	Change From Baseline in Left Ventricular End Diastolic Volume (LVEDV)		24 weeks after entry into the maintenance period
Secondary	Change From Baseline in Left Ventricular End Systolic Volume (LVESV)		24 weeks after entry into the maintenance period
Secondary	Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)		24 weeks after entry into the maintenance period
Secondary	Change From Baseline in Intraventricular Septal Thickness (IVST)		24 weeks after entry into the maintenance period
Secondary	Change From Baseline in Posterior Wall Thickness (PWT)		24 weeks after entry into the maintenance period
Secondary	Change From Baseline in Left Ventricular Mass (LVM)		24 weeks after entry into the maintenance period
Secondary	Change From Baseline in End Diastolic Dimension (EDD)		24 weeks after entry into the maintenance period
Secondary	Change From Baseline in End Systolic Dimension (ESD)		24 weeks after entry into the maintenance period
Secondary	Change From Baseline in Deceleration Time		24 weeks after entry into the maintenance period
Secondary	Change From Baseline in Early to Late Atrial Ratio (E:A Ratio)		24 weeks after entry into the maintenance period
Secondary	Change From Baseline in BNP Levels		24 weeks after entry into the maintenance period
Secondary	Incidence of Hospitalizations		Up to 32 weeks (titration and maintenance phases)
Secondary	Drug Dose Tolerability		Up to 32 weeks (titration and maintenance phases)
Secondary	Treatment Compliance		Up to 32 weeks (titration and maintenance phases)
Secondary	Safety and Tolerability of Coreg CR	SAEs experienced	24 weeks after entry into the maintenance phase (after unblinding)