The Safety and Efficacy of Istaroxime for Pre-Cardiogenic Shock

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Cardiogenic Shock

Intervention / Treatment
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* Drug: Istaroxime
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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; Heart rate 75 to 150 bpm. If the subject is on a beta-blocker, the range is 60 to 150 bpm; Echocardiogram during initial hospitalization confirming ejection fraction ≤ 40% and no evidence of other pathology to confound interpretation of cardiac physiology (e.g., pericardial effusion); Subject is monitored by a Pulmonary Artery Catheter (PAC) at the time of randomization (Part B only). 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; Active coronary ischemia; 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); 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 chronic obstructive pulmonary disease (COPD), planned admission for device implantation, or over-diuresis as a cause of hypotension; Pericardial constriction or active pericarditis; Life-threatening ventricular arrhythmia or implantable cardioverter defibrillator (ICD) shock within the past month or history of sudden death within 6 months; Cardiac resynchronization therapy (CRT), ICD, or pacemaker implantation (or planned implantation) within the past 3 months; Sustained ventricular tachycardia in the last 3 months with no defibrillator; Sustained hypotension (SBP < 70 mmHg) for at least 30 minutes from the time of arrival to the hospital; Severe pulmonary disease or cor pulmonale or other causes of isolated right-sided HF or not related to left ventricular dysfunction; Acute respiratory distress syndrome; Suspected sepsis; fever > 38°C or active infection requiring IV antimicrobial treatment; Body weight < 40 kg or ≥ 150 kg; Laboratory exclusions: Hemoglobin < 9 g/dl, Platelet count < 100,000/µl, Serum potassium > 5.3 mmol/l or < 3.5 mmol/l; A life expectancy < 3 months based on the judgment of the investigator; Uncontrolled thyroid disease; Pregnant or breast-feeding; Ongoing drug or alcohol abuse; Participation in another interventional study within the past 30 days.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Istaroxime - Part A<br>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 | Drug: Istaroxime<br>* Reconstituted istaroxime and lactose lyophilized powder delivered via IV infusion<br>* Other names: PST2744;|
| Placebo Comparator: Placebo - Part A<br>Placebo (lactose lyophilized powder) IV infusion for 24 hours | Drug: Placebo<br>* Reconstituted placebo (lactose lyophilized powder) delivered via IV infusion<br>* Other names: Lactose lyophilized powder;|
| Experimental: Istaroxime - Part B<br>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. | Drug: Istaroxime<br>* Reconstituted istaroxime and lactose lyophilized powder delivered via IV infusion<br>* Other names: PST2744;|
| Experimental: Istaroxime and Placebo - Part B<br>Istaroxime IV infusion at 0.5 µg/kg/min for 48 hours, followed by placebo IV infusion for 12 hours. | Drug: Istaroxime<br>* Reconstituted istaroxime and lactose lyophilized powder delivered via IV infusion<br>* Other names: PST2744;Drug: Placebo<br>* Reconstituted placebo (lactose lyophilized powder) delivered via IV infusion<br>* Other names: Lactose lyophilized powder;|
| Placebo Comparator: Placebo - Part B<br>Placebo (lactose lyophilized powder) IV infusion for 60 hours. | Drug: Placebo<br>* Reconstituted placebo (lactose lyophilized powder) delivered via IV infusion<br>* Other names: Lactose lyophilized powder;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in systolic blood pressure (SBP) area under the curve (AUC) 0-6 | Change from baseline AUC for systolic blood pressure | 0 to 6 hours after initiation of infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in SBP AUC 0-48 | Change from baseline in AUC for systolic blood pressure in Part B | 0 to 60 hours after initiation of infusion | 
| Change from baseline in SBP AUC 0-60 | Change from baseline in AUC for systolic blood pressure in Part B | 0 to 48 hours after initiation of infusion | 
| Treatment failure score | Treatment-failure score, based on death, circulatory, respiratory, or renal mechanical support or intravenous inotrope or vasopressor treatment, and changes in systolic blood pressure | 60 hours from initiation of infusion | 
| Change from baseline in SBP | Change from baseline in systolic blood pressure | 6 hours after initiation of infusion | 
| Change from baseline in SBP | Change from baseline in systolic blood pressure | 24 hours after initiation of infusion | 
| Change from baseline in SBP | Change from baseline in systolic blood pressure in Part B | 48 hours after initiation of infusion | 
| Change from baseline in SBP | Change from baseline in systolic blood pressure in Part B | 60 hours after initiation of infusion | 
| Number of treatment failures | Number of subjects requiring treatment with intravenous vasopressors, inotropes, and/or mechanical cardiac or renal support or have died | Randomization to 24 hours for Part A | 
| Number of treatment failures | Number of subjects requiring treatment with intravenous vasopressors, inotropes, and/or mechanical cardiac or renal support or have died | Randomization to 48 hours for Part B | 
| Number of treatment failures | Number of subjects requiring treatment with intravenous vasopressors, inotropes, and/or mechanical cardiac or renal support or have died | Randomization to Day 5 | 
| Change in quality of life | Changes from baseline measured by the EQ-5D in Part A | Baseline to Day 5 (96 hours) from infusion start | 
| Change in quality of life | Changes from baseline measured by the EQ-5D in Part A | Baseline to Day 30 from infusion start | 
| Change in eGFR | Change from baseline and observed estimated glomerular filtration rate (eGFR) | 24 hours from infusion start | 
| Change in eGFR | Change from baseline and observed estimated glomerular filtration rate (eGFR) | 48 hours from infusion start | 
| 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 | Change from baseline and observed BNP, NT-pro-BNP, troponin (cTn; either T or I) and venous lactate | 24 hours from infusion start | 
| 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 | Change from baseline and observed BNP, NT-pro-BNP, troponin (cTn; either T or I) and venous lactate | 48 hours from infusion start | 
| Time to worsening heart failure (HF) | Time to worsening HF | Up to Day 5 | 
| Time to HF re-admission or death | Time to HF re-admission or death | Up to Day 30 | 
| Length of initial hospitalization | Length of initial hospitalization | Up to Day 30 | 
| Days alive and out of the hospital | Days alive and out of the hospital | Up to Day 30 | 
| Mortality and reasons for death | Mortality and reasons for death | Up to Day 30 | 
| Change in coronary index (CI) | Change from baseline in CI as assessed by echocardiogram - Part A | 24 hours | 
| Change in E to e' ratio | Change from baseline in E to e' ratio as assessed by echocardiogram - Part A | 24 hours | 
| Change in stroke volume index (SVI) | Change from baseline in SVI as assessed by echocardiogram - Part A | 24 hours | 
| Change in left atrium area (LAA) | Change from baseline in LAA as assessed by echocardiogram - Part A | 24 hours | 
| Change in CI | Change from baseline in CI as assessed by echocardiogram - Part B | 48 hours | 
| Change in E to e' ratio | Change from baseline in E to e' ratio as assessed by echocardiogram - Part B | 48 hours | 
| Change in SVI | Change from baseline in SVI as assessed by echocardiogram - Part B | 48 hours | 
| Change in LAA | Change from baseline in LAA as assessed by echocardiogram - Part B | 48 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pre-cardiogenic shock, Heart failure