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

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.

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.