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

March 1, 2023 updated by: CTI-1, LLC

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

318

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Mobile, Alabama, United States, 36608
        • Cardiology Associates
      • Mobile, Alabama, United States, 36608
        • Mobile Heart Specialists
    • Arizona
      • Phoenix, Arizona, United States, 85054
        • Mayo Clinic Arizona
      • Scottsdale, Arizona, United States, 85251
        • Scottsdale Cardiovascular Research Institute
      • Tucson, Arizona, United States, 85715
        • South West Heart
    • California
      • Corona, California, United States, 92879
        • Inland Heart Doctors Medical Group
      • Downey, California, United States, 90242
        • Rancho Los Amigos USC
      • Healdsburg, California, United States, 95448
        • William Bowden, DO Private Practice
      • Merced, California, United States, 95340
        • Merced Heart Associates
      • Sacramento, California, United States, 95819
        • Sutter Memorial Hospital
      • San Diego, California, United States, 92120
        • Southern California Cardiology Medical Group, Inc.
      • Van Nuys, California, United States, 91405
        • Medvin Clinical Research
    • Colorado
      • Denver, Colorado, United States, 80218
        • Aurora Denver Cardiology Associates
      • Loveland, Colorado, United States, 80538
        • Medical Center of the Rockies Foundation
    • Florida
      • Brandon, Florida, United States, 33511
        • Bay Area Cardiology
      • Clearwater, Florida, United States, 33756
        • Clearwater Cardiovascular and Interventional Consultants
      • Fort Walton Beach, Florida, United States, 32547
        • White-Wilson Medical Center, PA
      • Miami, Florida, United States, 33137-3732
        • South Florida International Cardiology Consultants, Inc.
      • Palm Beach Gardens, Florida, United States, 33410
        • Palm Beach Cardiology
    • Georgia
      • Atlanta, Georgia, United States, 30309
        • Cardiac Disease Specialists, PC
      • Rome, Georgia, United States, 30165
        • Harbin Clinic
    • Illinois
      • Bannockburn, Illinois, United States, 60015
        • North Shore Cardiovascular Research Consortium
      • Evanston, Illinois, United States, 60202
        • Saint Francis Hospital
      • Hinsdale, Illinois, United States, 60521
        • Illinois Heart and Vascular
      • Peoria, Illinois, United States, 61614
        • HeartCare Midwest
      • Rockford, Illinois, United States, 61107
        • Rockford Cardiology Research Foundation
      • Springfield, Illinois, United States, 62701
        • Prairie Cardiovascular Consultants
    • Indiana
      • Indianapolis, Indiana, United States, 46260
        • The Care Group LLC
      • Jeffersonville, Indiana, United States, 47130
        • River Cities Cardiology
    • Iowa
      • West Des Moines, Iowa, United States, 50266
        • Iowa Heart Center
    • Kansas
      • Kansas City, Kansas, United States, 66160
        • Mid-America Cardiology
      • Wichita, Kansas, United States, 67214
        • Via Christi Research, Inc.
    • Kentucky
      • Florence, Kentucky, United States, 41042
        • Comprehensive Cardiology Associates
      • Louisville, Kentucky, United States, 40205
        • Cardiovascular Associates
      • Louisville, Kentucky, United States, 40207
        • Louisville Cardiology Medical Group
    • Maryland
      • Baltimore, Maryland, United States, 21215
        • One Heart, LLC
    • Minnesota
      • Edina, Minnesota, United States, 55435
        • Minnesota Heart Clinic
      • Minneapolis, Minnesota, United States, 55415
        • Hennepin County Medical Center
      • Saint Paul, Minnesota, United States, 55102
        • St. Paul Cardiology
      • Saint Paul, Minnesota, United States, 55101
        • Regions Hospital Cardiology Research
    • Mississippi
      • Tupelo, Mississippi, United States, 38801
        • Cardiology Associates Research, LLC
    • Montana
      • Kalispell, Montana, United States, 59901
        • Rocky Mountain Heart & Lung
    • New Jersey
      • West Orange, New Jersey, United States, 07052
        • Diagnostic and Clinical Cardiology
    • New Mexico
      • Albuquerque, New Mexico, United States, 87131-0001
        • University of New Mexico
    • New York
      • Albany, New York, United States, 12205
        • Albany Associates in Cardiology
      • Bronx, New York, United States, 10467
        • Montefiore Medical Center
      • Buffalo, New York, United States, 14215
        • Buffalo Heart Group, LLP
      • Mineola, New York, United States, 11501
        • Long Island Heart Associates
      • New York, New York, United States, 10035
        • New York Cardiovascular Associates
      • West Islip, New York, United States, 11795
        • South Bay Cardiovascular Associates
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • University of North Carolina
      • Greensboro, North Carolina, United States, 27401
        • LeBauer Cardiovascular Research Foundation
      • Winston-Salem, North Carolina, United States, 27157
        • Wake Forest University Baptist Medical Center
    • Ohio
      • Cincinnati, Ohio, United States, 45219
        • Sterling Research Group Ltd.
      • Cincinnati, Ohio, United States, 45219
        • The Lindner Clinical Trial Center
      • Cincinnati, Ohio, United States, 45267-0542
        • University Hospital
      • Toledo, Ohio, United States, 43615
        • Northwest Ohio Cardiology Consultants
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73120
        • Oklahoma Cardiovascular Research Group
    • Oregon
      • Corvallis, Oregon, United States, 97330
        • Samaritan Cardiology
    • Pennsylvania
      • Altoona, Pennsylvania, United States, 16602
        • Blair Medical Associates
      • Beaver, Pennsylvania, United States, 15009
        • Tri-State Medical Group
      • Doylestown, Pennsylvania, United States, 18901
        • Central Bucks Specialists
      • Philadelphia, Pennsylvania, United States, 19148
        • Cardiology Consultants of Philadelphia
      • Philipsburg, Pennsylvania, United States, 16866
        • Mid State Medical Service
      • Sellersville, Pennsylvania, United States, 18960
        • Buxmont Cardiology Associates, PC
    • Rhode Island
      • Providence, Rhode Island, United States, 02903
        • Rhode Island Heart Failure Center
    • South Carolina
      • Charleston, South Carolina, United States, 29403
        • Charleston Cardiology
      • Columbia, South Carolina, United States, 29204
        • South Carolina Heart Center
    • Texas
      • Friendswood, Texas, United States, 77546
        • Heart Specialists
      • Lubbock, Texas, United States, 79410
        • Texas Cardiac Center
    • Utah
      • Murray, Utah, United States, 84107
        • Intermountain Medical Center
      • Salt Lake City, Utah, United States, 84124
        • Heart Center
    • Virginia
      • Winchester, Virginia, United States, 22601
        • Winchester Medical Center
    • Wisconsin
      • Eau Claire, Wisconsin, United States, 54702
        • Luther Midelfort Mayo Health Systems
      • Green Bay, Wisconsin, United States, 54303
        • Green Bay HeartCare

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 2
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.
Other Names:
  • Coreg CR
Active Comparator: 1
Drug: carvedilol immediate release
Carvedilol immediate release (3.125, 6.25, 12.5 or 25 mg) and placebo, taken PO, twice-daily.
Other Names:
  • Coreg
  • Coreg IR

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change From Baseline in Left Ventricular End Systolic Volume Index (LVESVI) Characterized by 2-D Echocardiography
Time Frame: 24 weeks after entry into the maintenance period
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change From Baseline in BNP Levels
Time Frame: 24 weeks after entry into the maintenance period
24 weeks after entry into the maintenance period
Drug Dose Tolerability
Time Frame: Up to 32 weeks (titration and maintenance phases)
Up to 32 weeks (titration and maintenance phases)
Change From Baseline in Left Ventricular Ejection Fraction (LVEF)
Time Frame: 24 weeks after entry into the maintenance period
24 weeks after entry into the maintenance period
Change From Baseline in Left Ventricular End Diastolic Volume (LVEDV)
Time Frame: 24 weeks after entry into the maintenance period
24 weeks after entry into the maintenance period
Change From Baseline in Left Ventricular End Systolic Volume (LVESV)
Time Frame: 24 weeks after entry into the maintenance period
24 weeks after entry into the maintenance period
Change From Baseline in Left Ventricular End Diastolic Volume Index (LVEDVI)
Time Frame: 24 weeks after entry into the maintenance period
24 weeks after entry into the maintenance period
Change From Baseline in Intraventricular Septal Thickness (IVST)
Time Frame: 24 weeks after entry into the maintenance period
24 weeks after entry into the maintenance period
Change From Baseline in Posterior Wall Thickness (PWT)
Time Frame: 24 weeks after entry into the maintenance period
24 weeks after entry into the maintenance period
Change From Baseline in Left Ventricular Mass (LVM)
Time Frame: 24 weeks after entry into the maintenance period
24 weeks after entry into the maintenance period
Change From Baseline in End Diastolic Dimension (EDD)
Time Frame: 24 weeks after entry into the maintenance period
24 weeks after entry into the maintenance period
Change From Baseline in End Systolic Dimension (ESD)
Time Frame: 24 weeks after entry into the maintenance period
24 weeks after entry into the maintenance period
Change From Baseline in Deceleration Time
Time Frame: 24 weeks after entry into the maintenance period
24 weeks after entry into the maintenance period
Change From Baseline in Early to Late Atrial Ratio (E:A Ratio)
Time Frame: 24 weeks after entry into the maintenance period
24 weeks after entry into the maintenance period
Incidence of Hospitalizations
Time Frame: Up to 32 weeks (titration and maintenance phases)
Up to 32 weeks (titration and maintenance phases)
Treatment Compliance
Time Frame: Up to 32 weeks (titration and maintenance phases)
Up to 32 weeks (titration and maintenance phases)
Safety and Tolerability of Coreg CR
Time Frame: 24 weeks after entry into the maintenance phase (after unblinding)
SAEs experienced
24 weeks after entry into the maintenance phase (after unblinding)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

CTI-1, LLC

Collaborators

GlaxoSmithKline
CTI Clinical Trial and Consulting Services

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2006

Primary Completion (Actual)

April 1, 2008

Study Completion (Actual)

June 1, 2008

Study Registration Dates

First Submitted

May 5, 2006

First Submitted That Met QC Criteria

May 8, 2006

First Posted (Estimate)

May 9, 2006

Study Record Updates

Last Update Posted (Actual)

March 28, 2023

Last Update Submitted That Met QC Criteria

March 1, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 104852

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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