E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10007541 |
E.1.2 | Term | Cardiac disorders |
E.1.2 | System Organ Class | 10007541 - Cardiac disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to assess the ability of istaroxime to increase systolic blood pressure (SBP) in patients with cardiogenic shock (CS) or pre-shock (Society for Cardiovascular Angiography & Intervention (SCAI) Stage B), defined as hospitalization for ADHF with persistent hypotension who currently, and since admission to the hospital and throughout Screening, have not received IV vasopressors, inotropes, or digoxin, or not on cardiovascular, respiratory, or renal mechanical support.
Subjects enrolled in Part A will have SBP of 75-90 mmHg and subjects enrolled in Part B will have SBP of 70-100 mmHg.
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E.2.2 | Secondary objectives of the trial |
To assess other measures of efficacy to ensure consistency of results across multiple endpoints. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 within 36 hours prior to randomization for ADHF episode, defined as: a. Dyspnea, at rest or with minimal exertion, b. Congestion on chest x-ray or lung US with 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 a. SBP of 75 to 90 mmHg (Part A) or 70 to 100 mmHg (Part B) for ≥ 2 hours prior to Screening; b. Stable SBP, defined as no decrease in SBP 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 index hospitalization confirming ejection fraction ≤ 40% and no evidence of other pathology to confound interpretation of cardiac physiology (eg, pericardial effusion). 9. Subject is monitored by a PAC at the time of randomization (Part B only). |
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E.4 | Principal 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 60 days: acute coronary syndrome, coronary revascularization, MI, 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 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 (eGFR < 30 ml/min, calculated by the MDRD formula); 9. Hypersensitivity to the study medication and its excipients (including known lactose hypersensitivity) or any related medication; 10. Stroke or 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, or 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 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, uncontrolled arrythmia, or implantable cardioverter defibrillator (ICD) shock or history of sudden death within 6 months; 17.Cardiac resynchronization therapy (CRT), ICD, ablation, 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° or active infection requiring IV antimicrobial treatment; 23. Body weight < 40 kg or ≥ 150 kg; 24. Laboratory exclusions: a. Hemoglobin < 9 g/dl, b. Platelet count < 100,000/μl, c. 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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Change from baseline in systolic blood pressure (SBP) area under the curve (AUC) ) to 6 hours from start of infusion Change from baseline in AUC for systolic blood pressure measured via a sphygmomanometer or arterial line. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
6 hours after start of infusion. |
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E.5.2 | Secondary end point(s) |
Key Secondary Efficacy Variables: - SBP AUC to 12 hours from start of infusion for subjects in Part B - SBP AUC to 24 hours from start of infusion for subjects in Parts A and B. - SBP AUC to 48 hours from start of infusion for subjects in Part B. - SBP AUC to 60 hours from start of infusion for subjects in Part B. Other Secondary Efficacy Variables: • Treatment-failure score, based on death, circulatory, respiratory, or renal mechanical support or intravenous inotrope or vasopressor treatment, and changes in systolic blood pressure • Change from baseline in SBP at 6, 12 and 24 hours of treatment for both parts, and at 48 and 60 hours of treatment for Part B. • Number of subjects with increases from baseline in SBP ≥5% and ≥ 10 mmHg at a timepoint between 4-6 hours after dosing and at least one other measurement separated by ≥ 2 hours during the 24- or 60-hours infusion. • Number of subjects requiring treatment with intravenous vasopressors, inotropes, and/or mechanical cardiac or renal support or have died in the period from randomization to 24 or 48 hours (for subjects in Part A and B, respectively) and Day 5 (“treatment failure”). • Changes in quality of life measured by the EQ-5D from baseline to Day 5 (96 hours) from infusion start and at Day 30 (Part A only). • Change from baseline in Creatinine clearance at 24, 48, 72 and 96 hours from infusion start. • Change from baseline and observed heart rate measurements at 12, 24, 48, 72 and 96 hours from infusion start. • Change from baseline and observed mean arterial pressure (MAP) at 12, 24, 48, 72 and 96 hours from infusion start. • Change from baseline and observed brain natriuretic peptide (BNP), NT-pro-BNP, troponin (cTn; either T or I) and venous lactate at 12, 24, 48, 72 and 96 hours from infusion start. • Time to worsening heart failure through Day 5. • Time to HF re-admission or death through Day 30. • Length in ICU/length of initial hospitalization • Days alive and out of acute care (including all intensive acute care units). • Days alive and out of the hospital through Day 30 • Number of subjects with hospital re-admissions through Day 30 • Mortality and reasons for death through Day 30 • Changes in invasive hemodynamic parameters (e.g. PCWP, RAP, CVP, PAP, CO)from pretreatment to 3, 6, 12, 18, 24, 48, 54, and 60 hours. • Number of subjects with CS SCAI stage progression through Day 30. • Changes in echocardiographic measurements at 24, 36,48, 60, and 72 hours, as applicable. Pharmacokinetics • PK assessments of istaroxime and its primary metabolites (PST 2915, PST 2922, and PST 3903). In addition, diastereoisomers of istaroxime, PST 2890 (E) and PST 2892 (Z), will be measured and assessed. For Part A: blood samples at 6, 12, and 24 hours after infusion start and 0.25, 0.5, 1, 6, 12, and 24 hours after infusion end. For Part B: blood samples at 6, 12, 24, 36, 48, 52, 56, 60 hours after infusion start and 12, 36, 48 hours after infusion end and at discharge.
Safety Variables • Incidence of adverse events (AEs) and serious AEs (SAEs) • Clinically significant arrythmias (arrythmias requiring intervention) for a total of 72 hours from the start of infusion as determined by a Holter monitor (during the infusion and after the infusion has been stopped). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
3,6,12,18,24,30,36,48,54,60,72 and 96 hours and Day 30 from randomization. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
United States |
Italy |
Poland |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |