The Safety and Efficacy of Istaroxime for Pre-Cardiogenic Shock

Cardiogenic Shock Clinical Trial

— SEISMiC  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04325035
• Other study ID #: 04-CL-1904
• Secondary ID: 2020-000885-40
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: September 28, 2020
• Est. completion date: April 30, 2024

Study information

• Verified date: August 2023
• Source: Windtree Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 90
• Est. completion date: April 30, 2024
• Est. primary completion date: March 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Cardiogenic Shock
• Shock
• Shock, Cardiogenic

Intervention

Drug:
• Istaroxime
Reconstituted istaroxime and lactose lyophilized powder delivered via IV infusion
• Placebo
Reconstituted placebo (lactose lyophilized powder) delivered via IV infusion

Locations

Country	Name	City	State
Argentina	Santorio de la Trinidad Palermo	Buenos Aires
Argentina	Hospital Italiano de Bueno Aires	Capital Federal	Buenos Aires
Argentina	Santorio Guemes	Capital Federal	Buenos Aires
Argentina	Hospital Privado de Rosario	Rosario	Sante Fe
Argentina	Instituto Cardiovascular de Rosario	Rosario	Sante Fe
Italy	Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo	Alessandria
Italy	UOC Cardiologia, ASST degli Spedali Civili di Brescia Pizzale Spedali Civili 1	Brescia
Italy	IRCCS San Raffaele Scientific Institute	Milan
Poland	Uniwersytecki Szpital Kliniczny w Bialymstoku	Bialystok
Poland	Uniwersytecki Szpital Kliniczny w Opolu	Opole
Poland	4 Wojskowy Szpital Kliniczny	Wroclaw
Poland	Uniwersytecki Szpital Kliniczny, Centrum Chorub Serca	Wroclaw	Dolnoslaskie
United States	Tufts Medical Center	Boston	Massachusetts
United States	Oregon Health and Sciences University	Portland	Oregon

Sponsors (2)

Lead Sponsor	Collaborator
Windtree Therapeutics	Momentum Research, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Italy,  Poland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	Change from baseline in SBP	Change from baseline in systolic blood pressure	6 hours after initiation of infusion
Secondary	Change from baseline in SBP	Change from baseline in systolic blood pressure	24 hours after initiation of infusion
Secondary	Change from baseline in SBP	Change from baseline in systolic blood pressure in Part B	48 hours after initiation of infusion
Secondary	Change from baseline in SBP	Change from baseline in systolic blood pressure in Part B	60 hours after initiation of infusion
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Change in quality of life	Changes from baseline measured by the EQ-5D in Part A	Baseline to Day 30 from infusion start
Secondary	Change in eGFR	Change from baseline and observed estimated glomerular filtration rate (eGFR)	24 hours from infusion start
Secondary	Change in eGFR	Change from baseline and observed estimated glomerular filtration rate (eGFR)	48 hours from infusion start
Secondary	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
Secondary	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
Secondary	Time to worsening heart failure (HF)	Time to worsening HF	Up to Day 5
Secondary	Time to HF re-admission or death	Time to HF re-admission or death	Up to Day 30
Secondary	Length of initial hospitalization	Length of initial hospitalization	Up to Day 30
Secondary	Days alive and out of the hospital	Days alive and out of the hospital	Up to Day 30
Secondary	Mortality and reasons for death	Mortality and reasons for death	Up to Day 30
Secondary	Change in coronary index (CI)	Change from baseline in CI as assessed by echocardiogram - Part A	24 hours
Secondary	Change in E to e' ratio	Change from baseline in E to e' ratio as assessed by echocardiogram - Part A	24 hours
Secondary	Change in stroke volume index (SVI)	Change from baseline in SVI as assessed by echocardiogram - Part A	24 hours
Secondary	Change in left atrium area (LAA)	Change from baseline in LAA as assessed by echocardiogram - Part A	24 hours
Secondary	Change in CI	Change from baseline in CI as assessed by echocardiogram - Part B	48 hours
Secondary	Change in E to e' ratio	Change from baseline in E to e' ratio as assessed by echocardiogram - Part B	48 hours
Secondary	Change in SVI	Change from baseline in SVI as assessed by echocardiogram - Part B	48 hours
Secondary	Change in LAA	Change from baseline in LAA as assessed by echocardiogram - Part B	48 hours