The Clinical Study of the Safety and Efficacy of Istaroxime in Treatment of Acute Decompensated Heart Failure

To assess the safety, tolerability and efficacy of two different doses of istaroxime (0.5 and 1.0 µg/kg/min) in comparison with placebo, including cardiovascular and renal tolerability, as well as changes in biological markers such as N-terminal prohormone brain natriuretic peptide (NT-proBNP) and troponin T (cTnT). The study will be conducted in 96 Chinese and Italian patients with Acute Decompensated Heart Failure. This is a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel group study. Patients were randomly assigned to one of two doses of istaroxime or placebo in a 2:1 ratio within two sequential cohorts of 60 patients each. This 31-day study includes a screening period (Days -1), a treatment period (Day 1), a post-treatment period (Days 2-4), and a follow-up period (which includes one patient visit on Day 30).

In all the Italian patients and in a subset of Chinese patients pharmacokinetics and metabolism of istaroxime shall also be studied.

Inclusion criteria

Patients who fulfill the following inclusion criteria at screening will be considered for the study:

• Signed informed consent;
• Male or female patients 18-85 years (inclusive);
• Admission for a recurrent acute decompensated heart failure (ADHF) episode with dyspnea at rest or minimal exertion and need of intravenous diuretic therapy (≥40 mg iv. furosemide);
• Systolic blood pressure between 90 and 125 mmHg (limits included) without signs or symptoms of hypoperfusion including cardiogenic shock, cold extremities and peripheral vasoconstriction, oliguria/anuria, signs of cerebral hypo perfusion such as confusion;
• Left ventricular (LV) Ejection fraction (EF) ≤ 40 % measured by 2D-Echocardiography
• E/Ea ratio >10
• BNP ≥ 350pg/mL or NT-pro-BNP ≥1400 pg/mL
• Adequate echocardiography window (defined as visualization of at least 13/16 segment of the left ventricle);

Exclusion criteria

Any of the following criteria established at screening would render a patient ineligible for the study:

• Pregnant or breast-feeding women (women of child bearing potential must have the results of a negative pregnancy test recorded prior to study drug administration)
• Current (within 12 hours prior to screening) or planned (through the completion of study drug infusion) treatment with any iv. therapies, including vasodilators (including nitrates or nesiritide), positive inotropic agents and vasopressors
• Current or need of mechanical support (intra-aortic balloon pump, endotracheal intubation, mechanical ventilation, or any ventricular assist device),
• Ongoing treatment with oral digoxin. Patient treated with digoxin within the last week, can be randomised if the plasma concentration of digoxin is tested before randomization and its value will be less than 0.5 ng/ml.
• History of hypersensitivity to the study medication or any related medication
• Diagnosis of cardiogenic shock within the past month;
• Acute coronary syndrome or stroke within the past 3 months;
• Coronary artery bypass graft or percutaneous coronary intervention within the past month or planned in the next month;
• Primary hypertrophic or restrictive cardiomyopathy or systemic illness known to be associated with infiltrative heart disease;
• Cor pulmonale or other causes of right-sided heart failure (HF) not related to left ventricular dysfunction;
• Pericardial constriction or active pericarditis;
• Atrial fibrillation with marked irregularities of heart rhythm;
• Life threatening ventricular arrhythmia or implantable cardioverter-defibrillator (ICD) shock within the past month;
• Cardiac resynchronization therapy (CRT), ICD, or pacemaker implantation within the past month;
• Valvular disease as primary cause of HF;
• Heart rate >120 bpm or < 50 bpm
• Acute respiratory distress syndrome or ongoing sepsis;
• Fever >38°
• History of bronchial asthma or porphyria;
• Donation or loss of blood equal to or exceeding 500 mL, during the 8 weeks before administration of study medication;
• Positive testing for HIV, Hepatitis B and/or Hepatitis C;
• Participation in another interventional study within the past 30 days;
• The following laboratory exclusion criteria, verified based on results obtained within the last 24 hours of hospitalization:

• Serum creatinine > 3.0 mg/dl (> 265 µmol/L);
• Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) > 3 x upper limit of normal,
• Hemoglobin (Hb) < 10 g/dL,
• Platelet count < 100,000/µL,
• Serum potassium > 5.3 mmol/L or < 3.8 mmol/L,