A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study on the Safety and Efficacy of Istaroxime for Pre-Cardiogenic Shock (SEISMiC)
Overview
- Phase
- Phase 2
- Intervention
- Placebo
- Conditions
- Cardiogenic Shock
- Sponsor
- Windtree Therapeutics
- Enrollment
- 90
- Locations
- 13
- Primary Endpoint
- Change from baseline in systolic blood pressure (SBP) area under the curve (AUC) 0-6
- Status
- Completed
- Last Updated
- last year
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
- •Signed informed consent form (ICF);
- •Males and females, 18 to 85 years of age (inclusive);
- •An admission for acute decompensated heart failure (ADHF) episode within 36 hours prior to randomization, defined as:
- •Dyspnea, at rest or with minimal exertion;
- •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.
- •History of left ventricular ejection fraction (LVEF) ≤ 40%;
- •Persistent hypotension defined as:
- •SBP of 75 to 90 mmHg (Part A) or 70 to 100 mmHg (Part B) for ≥ 2 hours prior to Screening;
- •SBP does not decrease by \> 7 mmHg on two separate measurements during the last 2 hours prior to randomization;
Exclusion Criteria
- •Cardiogenic shock of SCAI Stage C or worse
- •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, myocardial infarction (MI), coronary artery bypass graft (CABG), or percutaneous coronary intervention;
- •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);
- •Venous Lactate \> 2 mmol/L;
- •History of heart transplant or United Network for Organ Sharing (UNOS) priority 1a heart transplant listing
- •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);
- •Severe renal impairment (estimated glomerular filtration rate (eGFR) \< 30 ml/min, calculated by the Modification of Diet in Renal Disease (MDRD) formula);
- •Hypersensitivity to the study medication or any of its excipients (including known lactose hypersensitivity) or any related medication;
- •Stroke or transient ischemic attack (TIA) within 3 months;
Arms & Interventions
Istaroxime and Placebo - Part B
Istaroxime IV infusion at 0.5 µg/kg/min for 48 hours, followed by placebo IV infusion for 12 hours.
Intervention: Placebo
Istaroxime - Part A
Istaroxime IV infusion for 24 hours. Istaroxime administration can begin at 1.0 or 1.5 µg/kg/min; the target infusion rate is 1.5 µg/kg/min
Intervention: Istaroxime
Placebo - Part A
Placebo (lactose lyophilized powder) IV infusion for 24 hours
Intervention: Placebo
Istaroxime - Part B
Istaroxime IV infusion at 1.0 µg/kg/min for 6 hours, 0.5 µg/kg/min for 42 hours, 0.25 µg/kg/min for 12 hours.
Intervention: Istaroxime
Istaroxime and Placebo - Part B
Istaroxime IV infusion at 0.5 µg/kg/min for 48 hours, followed by placebo IV infusion for 12 hours.
Intervention: Istaroxime
Placebo - Part B
Placebo (lactose lyophilized powder) IV infusion for 60 hours.
Intervention: Placebo
Outcomes
Primary Outcomes
Change from baseline in systolic blood pressure (SBP) area under the curve (AUC) 0-6
Time Frame: 0 to 6 hours after initiation of infusion
Change from baseline AUC for systolic blood pressure
Secondary Outcomes
- Change in brain natriuretic peptide (BNP), N-terminal pro hormone B-type natriuretic peptide (NT-pro-BNP), troponin (cTn; either T or I) and venous lactate(48 hours from infusion start)
- Change from baseline in SBP(60 hours after initiation of infusion)
- Time to HF re-admission or death(Up to Day 30)
- Change in coronary index (CI)(24 hours)
- Change in E to e' ratio(48 hours)
- Treatment failure score(60 hours from initiation of infusion)
- Change in left atrium area (LAA)(24 hours)
- Change from baseline in SBP AUC 0-48(0 to 60 hours after initiation of infusion)
- Change from baseline in SBP AUC 0-60(0 to 48 hours after initiation of infusion)
- Change in eGFR(48 hours from infusion start)
- Time to worsening heart failure (HF)(Up to Day 5)
- Days alive and out of the hospital(Up to Day 30)
- Mortality and reasons for death(Up to Day 30)
- Number of treatment failures(Randomization to Day 5)
- Change in quality of life(Baseline to Day 30 from infusion start)
- Change in CI(48 hours)
- Change in LAA(48 hours)
- Length of initial hospitalization(Up to Day 30)
- Change in stroke volume index (SVI)(24 hours)
- Change in SVI(48 hours)