ESSENTIAL-"The Studies of Oral Enoximone Therapy in Advanced Heart Failure"

ESSENTIAL Protocol No. My-021 and Protocol No. My-026, Each Titled: A Phase III, Randomized, Double-Blind, Multicenter, Parallel Group, Placebo-Controlled Study of Oral Enoximone vs. Placebo in Advanced Chronic Heart Failure Subjects

To determine if low-dose enoximone therapy is an effective treatment for advanced chronic heart failure.

The study is a randomized, double-blind, multicenter, parallel group, placebo-controlled trial of oral enoximone in approximately 700 subjects with advanced chronic heart failure of either ischemic or nonischemic etiology receiving optimal conventional heart failure therapy.

Eligible subjects will be randomized in a 1:1 ratio to receive either enoximone or placebo at the Randomization Visit. The initial dose of study drug will be 25 mg t.i.d.(3xday) and will be administered immediately after randomization. Subjects who tolerate this initial dose will be continued on 25 mg t.i.d. for at least two weeks. After two weeks, eligible subjects will be titrated to 50 mg t.i.d. for the duration of the study.

In order to be considered eligible subjects, the following entry criteria must be met:

• At least 18 years of age
• ischemic or nonischemic cardiomyopathy
• NYHA Class III or IV
• one hospitalization, or two outpatient visits, for the treatment of worsening heart failure within 12 months requiring the administration of I.V. heart failure therapy
• LVEDD >3.2 cm/m2 or >=6.0 cm
• LVEF of less than or equal to 30%
• concomitant treatment with optimal conventional heart failure therapy

Exclusion Criteria

Subjects who meet any one of the following criteria will be deemed ineligible for participation in the study:

Subjects on the following concomitant medications:

• Calcium antagonists other than amlodipine or felodipine

• Flecainide, encainide, propafenone, dofetilide or disopyramide

• Subjects receiving I.V. positive inotropic agents within seven days of the Screening Visit or Randomization Visit

• Subjects receiving a human B-type natriuretic peptide, including nesiritide, within seven days of the Screening Visit or Randomization Visit

• Subjects receiving oral or I.V. phosphodiesterase III inhibitors (PDEI III), including levosimendan and cilostazol, within seven days of the Screening Visit or Randomization Visit

  • Subjects with active hepatic (screening serum total bilirubin >= 3.0 mg/dl (>=51.3 umol/l), renal (screening serum creatinine >= 2.0 mg/dl (=178.8 umol/l)), hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease
  • Subjects with a serum potassium <4.0 mEq/L or >5.5 mEq/L (<4.0 mmol/l or >5.5 mmol/l) at Randomization Visit
  • Subjects with a magnesium level of <1.0 mEq/L (<0.5 mmol/l) at Randomization Visit (Visit 0)
  • Subjects with a serum digoxin of >1.2 ng/ml (>1.5 nmol/l) or a serum digitoxin of >20 ng/ml (>26.2 nmol/l) at the Randomization Visit are excluded. A target serum digoxin level of <=1.0 ng/ml (<=1.3 nmol/l) is recommended