The clinical study of the safety and efficacy of Istaroxime in Treatment of Acute Decompensated Heart Failure - A multicenter, randomized, double-blind, placebo controlled, parallel group clinical study

INTERVENTION: Product Name: Istaroxime Product Code: PST2744 Pharmaceutical Form: Powder and solvent for solution for infusion INN or Proposed INN: Istaroxime CAS Number: 374559‐48‐5 Current Sponsor code: PST 2744 Other descriptive name: (E,Z)‐3‐(2‐Aminoethoxyimino)androstane‐6,17‐dione hydrochloride Androstane‐3,6,17‐trione (E,Z)‐3‐[O‐(2‐aminoethyl)]oxime hydrochloride Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 2‐ Pharmaceutical form of the placebo: Powder and solvent for solution for infusion Route of administration of the placebo: Intravenous use CONDITION: Acute heart failure decompensated ; MedDRA version: 14.1 Level: LLT Classification code 10066332 Term: Acute cardiac insufficiency System Organ Class: 100000004849 Therapeutic area: Diseases [C] ‐ Cardiovascular Diseases [C14] PRIMARY OUTCOME: Main Objective: To Assess the safety, tolerability and efficacy of two different doses of istaroxime (0.5 and 1.0 µg/kg/min), 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 i. v. for 24 hours in comparison with placebo, in; treatment of Chinese and Italian patients with Acute Decompensated Heart; Failure. Primary end point(s): Change from baseline to 24 hours after infusion start (treatment period Day 1) in the E/Ea ratio assessed by tissue Doppler. Secondary Objective: In all Italian patients and in a subset of Chinese patients pharmacokinetics and metabolism of istaroxime shall also be studied Timepoint(s) of evaluation of this end point: 1 day (24 hours) SECONDARY OUTCOME: Secondary end point(s): Efficacy: ; • Change from baseline to 24 hours in the treatment period Day1 (addressing the differences between the changes at 6 and 24 hours from baseline) of the following Echo‐Doppler parameters: ; ‐ LV Ejection fraction (EF) ; ‐ LV end systolic and end diastolic volumes ; ‐ Stroke volume index (SVI) ; ‐ E, A and E/A ratio ; • Difference between the changes at 6 and 24 hours from baseline of the ; Tissue Doppler parameter E/Ea ; • Others Tissue Doppler parameters such as Sa, Da and Aa ; • Changes in dyspnoea assessed at 3, 6, 12, 24, 48 hours after infusion start by Visual Analog Scale (VAS) (including only patients presenting dyspnoea at baseline); ; • Area under the curve (AUC) on changes in dyspnoea assessed at 3, 6, 12, 24, 48 hours after infusion start by VAS (including only patients presenting dyspnea at baseline); ; • Changes in BNP from baseline at 24 hours; ; • Proportion of patients with hospital readmissions or emergency visits ; for cardiovascular reasons by Day 30; ; • Proportion of patients with episodes of worsening HF defined by the need to increase the dose or reinitiate i.v. therapy with diuretics and/ or other inotropic agents during the hospitalization; ; • Length of the hospitalization. ; Safety: ; • Incidence of adverse events; ; • Change in vital signs (including body temperature and dyspnoea); ; • Change in 12‐lead ECG parameters; ; • Incidence of clinically or hemodynamically significant episodes of supraventricular or ventricular arrhythmias detected by continuous ECG dynamic monitoring; ; • Change in laboratory parameters (hematology, blood chemistry and ; urinalysis); ; • Change in renal function; ; • Change in in cTnT; ; • Mortality at Day 30. ; PK: ; • the following PK metrics will be computed for E and Z isomers (when applicable) of istaroxime urine concentrations: Ae, Ae%, ClR; ; • In addition, the following PK metrics will be computed as above for plasma and urine concentrations of the E and Z isomers (when applicable) of istaroxime metabolites PST2915, PST2922, and ; • Incidence of cTnT elevation (>50% or > 20% relative increase over the basal cTnT levels at baseline, for patients with cTnT levels at baseline < or = of the 99% URL (upper reference levels, as defined for the Roche hs test), respectively); ; The following PK metrics will be computed for E and Z isomers (when applicable) of istaroxime plasma concentrations using non‐compartmental analysis: Cmax, tmax, AUC0‐t, AUC0‐8, ?z, t½, Cl, MRT, Vss, Vz; ; PST3093: Cmax, tmax, AUC0‐t, AUC0‐8, ?z, t½ and, if possible, Ae and Ae%. ; ; ; Timepoint(s) of evaluation of this end point: 30 days INCLUSION CRITERIA: 1. Signed informed consent; 2. Male or female patients = 18 years; 3. Admission for a recurrent 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); Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 18 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of