The Safety and Efficacy of Istaroxime for Pre-Cardiogenic Shock

A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study on the Safety and Efficacy of Istaroxime for Pre-Cardiogenic Shock (SEISMiC)

This is a pilot, multinational, randomized, double-blind, placebo-controlled, 2-part safety and efficacy study. Subjects will consist of patients hospitalized for acute decompensated heart failure with persistent hypotension.

This is a pilot, multinational, multicenter, randomized, double-blind, placebo-controlled, 2-part safety and efficacy study. Subjects will consist of males or females 18 to 85 years of age, hospitalized for acute decompensated heart failure (ADHF) with persistent hypotension (systolic blood pressure [SBP] 70-100 mmHg for two hours).

Part A will dose all subjects for 24 hours with either 1.0 µg/kg/min or placebo; Part B will dose all subjects for 60 hours with two different regimens of istaroxime or placebo. Enrollment of Part A and Part B will be sequential.

Up to 30 sites in Part A; up to 15 sites in Part B. Sites may be located in Europe, Asia, South America, and North America.

Inclusion Criteria:

1. Clinical presentation consistent with SCAI Stage B pre-cardiogenic shock caused by acute decompensation of chronic systolic heart failure (due to arterial hypertension, ischemic heart disease or dilated cardiomyopathy), without evidence for an acute coronary syndrome.

2. Signed informed consent form (ICF);

3. Males and females, 18 to 85 years of age (inclusive);

4. An admission for acute decompensated heart failure (ADHF) episode within 36 hours prior to randomization, defined as:

   1. Dyspnea, at rest or with minimal exertion;
   2. Congestion on chest x-ray or lung US with B-type natriuretic peptide (BNP) ≥ 400 pg/mL or NT-proBNP ≥ 1400 pg/mL; Elective admissions for medications tune up or procedures do not qualify as an ADHF admission.

5. History of left ventricular ejection fraction (LVEF) ≤ 40%;

6. Persistent hypotension defined as:

   1. SBP of 75 to 90 mmHg (Part A) or 70 to 100 mmHg (Part B) for ≥ 2 hours prior to Screening;
   2. SBP does not decrease by > 7 mmHg on two separate measurements during the last 2 hours prior to randomization;

7. Heart rate 75 to 150 bpm. If the subject is on a beta-blocker, the range is 60 to 150 bpm;

8. Echocardiogram during initial hospitalization confirming ejection fraction ≤ 40% and no evidence of other pathology to confound interpretation of cardiac physiology (e.g., pericardial effusion);

9. Subject is monitored by a Pulmonary Artery Catheter (PAC) at the time of randomization (Part B only).

Exclusion Criteria:

1. Cardiogenic shock of SCAI Stage C or worse

2. Cardiogenic shock due to any other condition besides acute decompensation of chronic heart failure.

3. Any of the following in the past 30 days: acute coronary syndrome, coronary revascularization, myocardial infarction (MI), coronary artery bypass graft (CABG), or percutaneous coronary intervention;

4. Current (within 6 hours of Screening) or anticipated need for treatment with positive inotropic agents or vasopressors, renal support including ultrafiltration, or mechanical circulatory, ventilatory or renal support (intra-aortic balloon pump, endotracheal intubation, mechanical ventilation, or any ventricular assist device);

5. Venous Lactate > 2 mmol/L;

6. History of heart transplant or United Network for Organ Sharing (UNOS) priority 1a heart transplant listing

7. Ongoing treatment with digoxin (if digoxin was stopped before signing the ICF and the digoxin plasma level is < 0.5 ng/ml, the patient may be enrolled);

8. Severe renal impairment (estimated glomerular filtration rate (eGFR) < 30 ml/min, calculated by the Modification of Diet in Renal Disease (MDRD) formula);

9. Hypersensitivity to the study medication or any of its excipients (including known lactose hypersensitivity) or any related medication;

10. Stroke or transient ischemic attack (TIA) within 3 months;

11. Active coronary ischemia;

12. Any significant valvular disease (including any moderate or severe valvular stenosis, moderate or severe aortic or pulmonary regurgitation, stenosis or regurgitation);severe tricuspid or mitral regurgitation);

13. Primary hypertrophic or restrictive cardiomyopathy or systemic illness known to be associated with infiltrative heart disease;

14. Admission for AHF triggered primarily by a correctable etiology such as significant arrhythmia, (inclusive of atrial fibrillation as the main reason for admission), infection, severe anemia, acute coronary syndrome, pulmonary embolism, exacerbation of chronic obstructive pulmonary disease (COPD), planned admission for device implantation, or over-diuresis as a cause of hypotension;

15. Pericardial constriction or active pericarditis;

16. Life-threatening ventricular arrhythmia or implantable cardioverter defibrillator (ICD) shock within the past month or history of sudden death within 6 months;

17. Cardiac resynchronization therapy (CRT), ICD, or pacemaker implantation (or planned implantation) within the past 3 months;

18. Sustained ventricular tachycardia in the last 3 months with no defibrillator;

19. Sustained hypotension (SBP < 70 mmHg) for at least 30 minutes from the time of arrival to the hospital;

20. Severe pulmonary disease or cor pulmonale or other causes of isolated right-sided HF or not related to left ventricular dysfunction;

21. Acute respiratory distress syndrome;

22. Suspected sepsis; fever > 38°C or active infection requiring IV antimicrobial treatment;

23. Body weight < 40 kg or ≥ 150 kg;

24. Laboratory exclusions:

    1. Hemoglobin < 9 g/dl,
    2. Platelet count < 100,000/µl,
    3. Serum potassium > 5.3 mmol/l or < 3.5 mmol/l;

25. A life expectancy < 3 months based on the judgment of the investigator;

26. Uncontrolled thyroid disease;

27. Pregnant or breast-feeding;

28. Ongoing drug or alcohol abuse;

29. Participation in another interventional study within the past 30 days.