Clinical trial NCT00323037: A Study to Compare the Effects of Coreg CR and Coreg IR on 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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Congestive Heart Failure
Keywords: heart failure
Lead sponsor: CTI-1, LLC
Sponsor class: INDUSTRY
Collaborators: name: CTI Clinical Trial and Consulting Services
name: GlaxoSmithKline
First posted: 2006-05-09
Enrollment: 318
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility 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.

Primary outcomes:
measure: Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI) Characterized by 2-D Echocardiography
timeFrame: 24 weeks after entry into the maintenance period
Secondary outcomes:
measure: Change From Baseline in Left Ventricular Ejection Fraction (LVEF)
timeFrame: 24 weeks after entry into the maintenance period
measure: Change From Baseline in Left Ventricular End Diastolic Volume (LVEDV)
timeFrame: 24 weeks after entry into the maintenance period
measure: Change From Baseline in Left Ventricular End Systolic Volume (LVESV)
timeFrame: 24 weeks after entry into the maintenance period
measure: Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)
timeFrame: 24 weeks after entry into the maintenance period
measure: Change From Baseline in Intraventricular Septal Thickness (IVST)
timeFrame: 24 weeks after entry into the maintenance period
measure: Change From Baseline in Posterior Wall Thickness (PWT)
timeFrame: 24 weeks after entry into the maintenance period
measure: Change From Baseline in Left Ventricular Mass (LVM)
timeFrame: 24 weeks after entry into the maintenance period
measure: Change From Baseline in End Diastolic Dimension (EDD)
timeFrame: 24 weeks after entry into the maintenance period
measure: Change From Baseline in End Systolic Dimension (ESD)
timeFrame: 24 weeks after entry into the maintenance period
measure: Change From Baseline in Deceleration Time
timeFrame: 24 weeks after entry into the maintenance period
measure: Change From Baseline in Early to Late Atrial Ratio (E:A Ratio)
timeFrame: 24 weeks after entry into the maintenance period
measure: Change From Baseline in BNP Levels
timeFrame: 24 weeks after entry into the maintenance period
measure: Incidence of Hospitalizations
timeFrame: Up to 32 weeks (titration and maintenance phases)
measure: Drug Dose Tolerability
timeFrame: Up to 32 weeks (titration and maintenance phases)
measure: Treatment Compliance
timeFrame: Up to 32 weeks (titration and maintenance phases)
measure: Safety and Tolerability of Coreg CR
timeFrame: 24 weeks after entry into the maintenance phase (after unblinding)
Other outcomes:
Locations:
city: Mobile
country: United States
facility: Cardiology Associates
state: Alabama
city: Mobile
country: United States
facility: Mobile Heart Specialists
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Scottsdale
country: United States
facility: Scottsdale Cardiovascular Research Institute
state: Arizona
city: Tucson
country: United States
facility: South West Heart
state: Arizona
city: Corona
country: United States
facility: Inland Heart Doctors Medical Group
state: California
city: Downey
country: United States
facility: Rancho Los Amigos USC
state: California
city: Healdsburg
country: United States
facility: William Bowden, DO Private Practice
state: California
city: Merced
country: United States
facility: Merced Heart Associates
state: California
city: Sacramento
country: United States
facility: Sutter Memorial Hospital
state: California
city: San Diego
country: United States
facility: Southern California Cardiology Medical Group, Inc.
state: California
city: Van Nuys
country: United States
facility: Medvin Clinical Research
state: California
city: Denver
country: United States
facility: Aurora Denver Cardiology Associates
state: Colorado
city: Loveland
country: United States
facility: Medical Center of the Rockies Foundation
state: Colorado
city: Brandon
country: United States
facility: Bay Area Cardiology
state: Florida
city: Clearwater
country: United States
facility: Clearwater Cardiovascular and Interventional Consultants
state: Florida
city: Fort Walton Beach
country: United States
facility: White-Wilson Medical Center, PA
state: Florida
city: Miami
country: United States
facility: South Florida International Cardiology Consultants, Inc.
state: Florida
city: Palm Beach Gardens
country: United States
facility: Palm Beach Cardiology
state: Florida
city: Atlanta
country: United States
facility: Cardiac Disease Specialists, PC
state: Georgia
city: Rome
country: United States
facility: Harbin Clinic
state: Georgia
city: Bannockburn
country: United States
facility: North Shore Cardiovascular Research Consortium
state: Illinois
city: Evanston
country: United States
facility: Saint Francis Hospital
state: Illinois
city: Hinsdale
country: United States
facility: Illinois Heart and Vascular
state: Illinois
city: Peoria
country: United States
facility: HeartCare Midwest
state: Illinois
city: Rockford
country: United States
facility: Rockford Cardiology Research Foundation
state: Illinois
city: Springfield
country: United States
facility: Prairie Cardiovascular Consultants
state: Illinois
city: Indianapolis
country: United States
facility: The Care Group LLC
state: Indiana
city: Jeffersonville
country: United States
facility: River Cities Cardiology
state: Indiana
city: West Des Moines
country: United States
facility: Iowa Heart Center
state: Iowa
city: Kansas City
country: United States
facility: Mid-America Cardiology
state: Kansas
city: Wichita
country: United States
facility: Via Christi Research, Inc.
state: Kansas
city: Florence
country: United States
facility: Comprehensive Cardiology Associates
state: Kentucky
city: Louisville
country: United States
facility: Cardiovascular Associates
state: Kentucky
city: Louisville
country: United States
facility: Louisville Cardiology Medical Group
state: Kentucky
city: Baltimore
country: United States
facility: One Heart, LLC
state: Maryland
city: Edina
country: United States
facility: Minnesota Heart Clinic
state: Minnesota
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Saint Paul
country: United States
facility: Regions Hospital Cardiology Research
state: Minnesota
city: Saint Paul
country: United States
facility: St. Paul Cardiology
state: Minnesota
city: Tupelo
country: United States
facility: Cardiology Associates Research, LLC
state: Mississippi
city: Kalispell
country: United States
facility: Rocky Mountain Heart & Lung
state: Montana
city: West Orange
country: United States
facility: Diagnostic and Clinical Cardiology
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Albany
country: United States
facility: Albany Associates in Cardiology
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Buffalo
country: United States
facility: Buffalo Heart Group, LLP
state: New York
city: Mineola
country: United States
facility: Long Island Heart Associates
state: New York
city: New York
country: United States
facility: New York Cardiovascular Associates
state: New York
city: West Islip
country: United States
facility: South Bay Cardiovascular Associates
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Greensboro
country: United States
facility: LeBauer Cardiovascular Research Foundation
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Baptist Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Sterling Research Group Ltd.
state: Ohio
city: Cincinnati
country: United States
facility: The Lindner Clinical Trial Center
state: Ohio
city: Cincinnati
country: United States
facility: University Hospital
state: Ohio
city: Toledo
country: United States
facility: Northwest Ohio Cardiology Consultants
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma Cardiovascular Research Group
state: Oklahoma
city: Corvallis
country: United States
facility: Samaritan Cardiology
state: Oregon
city: Altoona
country: United States
facility: Blair Medical Associates
state: Pennsylvania
city: Beaver
country: United States
facility: Tri-State Medical Group
state: Pennsylvania
city: Doylestown
country: United States
facility: Central Bucks Specialists
state: Pennsylvania
city: Philadelphia
country: United States
facility: Cardiology Consultants of Philadelphia
state: Pennsylvania
city: Philipsburg
country: United States
facility: Mid State Medical Service
state: Pennsylvania
city: Sellersville
country: United States
facility: Buxmont Cardiology Associates, PC
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Heart Failure Center
state: Rhode Island
city: Charleston
country: United States
facility: Charleston Cardiology
state: South Carolina
city: Columbia
country: United States
facility: South Carolina Heart Center
state: South Carolina
city: Friendswood
country: United States
facility: Heart Specialists
state: Texas
city: Lubbock
country: United States
facility: Texas Cardiac Center
state: Texas
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Salt Lake City
country: United States
facility: Heart Center
state: Utah
city: Winchester
country: United States
facility: Winchester Medical Center
state: Virginia
city: Eau Claire
country: United States
facility: Luther Midelfort Mayo Health Systems
state: Wisconsin
city: Green Bay
country: United States
facility: Green Bay HeartCare
state: Wisconsin
Study officials:
name: Barry Greenberg, MD
role: STUDY_CHAIR
References:
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.
citation: The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet. 1999 Jan 2;353(9146):9-13.
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.
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.
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.
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.
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.
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.
citation: 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.
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.
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.
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.
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.