A Safety and Efficacy Trial of Istaroxime for Cardiogenic Shock Stage C

Prior treatment

• Patient is in SCAI B (BP increased above 90 mmHg despite no vasoactive or inotrope therapy) or SCAI D (continuously deteriorating BP and hypoperfusion despite vasoactive or inotrope therapy);
• Current (within 6 hours of screening) or anticipated need for treatment with renal support including ultrafiltration, or mechanical circulatory, ventilatory or renal support (intra-aortic balloon pump, endotracheal intubation, mechanical ventilation, or any ventricular assist device) such as persistent hypoperfusion and hypotension;
• 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);
• Significant ventricular arrhythmia prior to screening (such as sustained ventricular tachycardia or ventricular fibrillation) or implantable cardioverter defibrillator (ICD) shock within the past month or history of sudden death within 6 months;
• Systolic BP \> 120 mmHg during the hour prior to randomization
• Ongoing drug or alcohol abuse;

Other illness

• Cardiogenic shock due to any other condition besides acute decompensation of chronic heart failure;
• Any of the following in the past 30 days: acute coronary syndrome, coronary revascularization, MI, CABG, or percutaneous coronary intervention;
• History of heart transplant or UNOS priority 1a heart transplant listing
• Hypersensitivity to the trial medication and its excipients (including known lactose hypersensitivity) or any related medication;
• Stroke or TIA within 3 months;
• Primary hypertrophic or restrictive cardiomyopathy or systemic illness known to be associated with infiltrative heart disease;
• 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 COPD, planned admission for device implantation, or over-diuresis as a cause of hypotension;
• Cardiac resynchronization therapy (CRT), ICD, or pacemaker implantation within the past month;
• Acute respiratory distress syndrome;
• Suspected sepsis; fever \> 38° or active infection requiring IV antimicrobial treatment;
• Severe pulmonary or thyroid disease;

Lab values

• Lactate \< 2 mmol/L (unless the patient meets the criteria in bullet 2 of Table 5-1) or lactate \> 5 mmol/L prior to randomization;
• Severe renal impairment (eGFR \< 30 ml/min, calculated by the MDRD formula);
• Laboratory exclusions:
  • Hemoglobin \< 9 g/dl,
  • Platelet count \< 100,000/µl,
  • Serum potassium \> 5.3 mmol/l or \< 3.5 mmol/l;

Other

• Severe obstructive valvular lesions including severe aortic or mitral stenosis;
• Pericardial constriction or active pericarditis;
• Uncontrolled arrythmia;
• Sustained hypotension (SBP \< 70 mmHg) for at least 30 minutes from the time of arrival to the hospital;
• Cor pulmonale or other causes of isolated right-sided HF or not related to left ventricular dysfunction;
• Body weight \< 40 kg or ≥ 150 kg;
• A life expectancy \< 3 months based on the judgment of the investigator;
• Pregnant, planning on becoming pregnant, or currently breast-feeding;
• Participation in another interventional trial within the past 30 days.

• Signed informed consent form (ICF);
• Clinical presentation consistent with SCAI Stage C cardiogenic shock caused by ADHF and meeting the criteria in below table;
• Admitted to ICU within 36 hours prior to randomization with congestion on chest x-ray or lung ultrasound and BNP ≥ 400 pg/mL or NT-proBNP ≥ 1400 pg/mL;
• Males and females, 18 to 85 years of age (inclusive);
• History of left ventricular ejection fraction (LVEF) ≤ 40%;
• Persistent hypotension defined as SBP between 70 and 90 mmHg for 2 readings with concomitant signs of hypoperfusion;
• Echocardiogram during initial hospitalization confirming ejection fraction ≤ 40% and no evidence of other pathology to confound interpretation of cardiac physiology (eg, pericardial effusion).
  • Table: Definition of SCAI Stage C Required for Inclusion. These criteria must be present at screening or prior to screening in patients actively treated by vasoactive agents or/and inotropes concomitantly (at the same time)
  • Must have at Least One of:
• Hypoperfusion: Venous Lactate ≥ 2 mmol/L, urine output \< 30 mL/hour, cold and clammy or acute alteration in mental status.
• Hemodynamic Instability: SBP 70-90 mmHg, cardiac index \< 2.2 L/min/meter2 and PCW \> 15 mmHg
  • Without Any Of:
• Venous lactate \> 5 mmol/L
• Worsening clinical status despite initial therapy (e.g., worsening hemodynamics, worsening renal or liver function)
• ALT \>500 U/L (8.333 µkat/L)