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”

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 Type: Interventional

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

Study Primary Completion Date: April 2008

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.

Intervention(s) in this Clinical Trial

• 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.
• Drug: carvedilol immediate release
  • Carvedilol immediate release (3.125, 6.25, 12.5 or 25 mg) and placebo, taken PO, twice-daily.

Arms, Groups and Cohorts in this Clinical Trial

• Active Comparator: 1
  • Treatment arms are blinded until final analysis
• Active Comparator: 2
  • Treatment arms are blinded until final analysis

Primary Measures

• 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
    Safety Issue?: No

Secondary Measures

• Change from baseline in left ventricular ejection fraction
  • Time Frame: 24 weeks after entry into the maintenance period
    Safety Issue?: No
• Change from baseline in left ventricular remodeling (IVST, PWT, LVM, ESV, EDV, EDVI, ESD, EDD, deceleration time, and E:A ratio)
  • Time Frame: 24 weeks after entry into the maintenance period
    Safety Issue?: No
• Change from baseline in BNP levels
  • Time Frame: 24 weeks after entry into the maintenance period
    Safety Issue?: No
• Incidence of hospitalizations from exacerbation of heart failure
  • Time Frame: Up to 32 weeks (titration and maintenance phases)
    Safety Issue?: Yes
• Hospitalizations from all causes
  • Time Frame: Up to 32 weeks (titration and maintenance phases)
    Safety Issue?: Yes
• Drug dose tolerability
  • Time Frame: Up to 32 weeks (titration and maintenance phases)
    Safety Issue?: Yes
• Safety and tolerability of Coreg CR
  • Time Frame: 24 weeks after entry into the maintenance phase (after unblinding)
    Safety Issue?: Yes
• Drug compliance
  • Time Frame: Up to 32 weeks (titration and maintenance phases)
    Safety Issue?: No

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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: CTI-1, LLC

Overall Clinical Trial Officials and Contacts

Barry Greenberg, MD Study Chair Unaffiliated  

Information obtained from ClinicalTrials.gov on August 20, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00323037

Study ID Number: 104852

ClinicalTrials.gov Identifier: NCT00323037

Health Authority: United States: Food and Drug Administration