The Clinical Study of the Safety and Efficacy of Istaroxime in Treatment of Acute Decompensated Heart Failure
Condition: Acute Decompensated Heart Failure
MeSH terms: Heart Failure
Intervention: Placebo; Istaroxime
Intervention description: IV of matching saline solution; IV infusion of 0.5 µg/kg/min or 1.0 µg/kg/min istaroxime
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Cohort I: Participants enrolled in a 2:1 ratio to istaroxime 0.5 µg/kg/min or placebo.
Cohort II: Participants enrolled in a 2:1 ratio to istaroxime 1.0 µg/kg/min or placebo.
Cohort I was enrolled first, followed by Cohort II.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Double-blind
Enrollment: 120.0
Sex: All
Minimum age: 18 Years
Maximum age: 85 Years
Healthy volunteers: No
Keywords: safety; efficacy; istaroxime

Summary:

      To assess the safety, tolerability and efficacy of two different doses of istaroxime, a new
      agent with lusitropic and inotropic activities that improves the cardiac
      contraction-relaxation cycle. The 2 doses of istaroxime (0.5 and 1.0 µg/kg/min) will be
      infused via i. v. for 24 hours in comparison with placebo, in treatment of Chinese and
      Italian patients with Acute Decompensated Heart Failure.
    

Eligibility criteria:

        Inclusion Criteria:

        Patients who fulfill the following inclusion criteria at screening will be considered for
        the study:

          1. Signed informed consent;

          2. Male or female patients 18-85 years (inclusive);

          3. 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);

          4. 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;

          5. Left ventricular (LV) Ejection fraction (EF) ≤ 40 % measured by 2D-Echocardiography

          6. E/Ea ratio >10

          7. BNP ≥ 350pg/mL or NT-pro-BNP ≥1400 pg/mL

          8. 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:

          1. 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)

          2. 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

          3. Current or need of mechanical support (intra-aortic balloon pump, endotracheal
             intubation, mechanical ventilation, or any ventricular assist device),

          4. 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.

          5. History of hypersensitivity to the study medication or any related medication

          6. Diagnosis of cardiogenic shock within the past month;

          7. Acute coronary syndrome or stroke within the past 3 months;

          8. Coronary artery bypass graft or percutaneous coronary intervention within the past
             month or planned in the next month;

          9. Primary hypertrophic or restrictive cardiomyopathy or systemic illness known to be
             associated with infiltrative heart disease;

         10. Cor pulmonale or other causes of right-sided heart failure (HF) not related to left
             ventricular dysfunction;

         11. Pericardial constriction or active pericarditis;

         12. Atrial fibrillation with marked irregularities of heart rhythm;

         13. Life threatening ventricular arrhythmia or implantable cardioverter-defibrillator
             (ICD) shock within the past month;

         14. Cardiac resynchronization therapy (CRT), ICD, or pacemaker implantation within the
             past month;

         15. Valvular disease as primary cause of HF;

         16. Heart rate >120 bpm or < 50 bpm

         17. Acute respiratory distress syndrome or ongoing sepsis;

         18. Fever >38°

         19. History of bronchial asthma or porphyria;

         20. Donation or loss of blood equal to or exceeding 500 mL, during the 8 weeks before
             administration of study medication;

         21. Positive testing for HIV, Hepatitis B and/or Hepatitis C;

         22. Participation in another interventional study within the past 30 days;

         23. The following laboratory exclusion criteria, verified based on results obtained within
             the last 24 hours of hospitalization:

               1. Serum creatinine > 3.0 mg/dl (> 265 µmol/L);

               2. Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) > 3 x upper
                  limit of normal,

               3. Hemoglobin (Hb) < 10 g/dL,

               4. Platelet count < 100,000/µL,

               5. Serum potassium > 5.3 mmol/L or < 3.8 mmol/L,