E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute decompensated heart failure (ADHF) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064653 |
E.1.2 | Term | Acute decompensated heart failure |
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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 |
To assess the hemodynamic effects of istaroxime in patients with ADHF not requiring inotropic therapy at admission and receiving one of 3 doses (0.5, 1.0, and 1.5 µg/kg/min) of istaroxime i.v. infusion for 24 hours. |
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E.2.2 | Secondary objectives of the trial |
- To assess clinical efficacy and safety including cardiovascular and renal tolerability as well as changes in biological markers such as brain natriuretic peptide (BNP) and cardiac troponin, and the neurohormones renin and aldosterone.
- To assess the PK of istaroxime and its metabolites (plasma concentration at infusion end in all patients and full PK profile in a subset of about 56 patients).
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Screening Inclusion Criteria: 1. Male or female patients ≥18 years. 2. Enrolled into the study during the first 48 hours of hospitalization. 3. Admission for ADHF defined as dyspnea at rest or orthopnea, with or without chest x-ray findings of pulmonary congestion. 4. Systolic blood pressure ≤ 120 mmHg. 5. Ejection fraction (EF) ≤ 35 % by any method (to be performed if not measured within the last 12 months). 6. Signed informed consent.
Randomization Inclusion Criteria: 1.Persistence of ADHF signs (JVD, pulmonary rales, peripheral edema) despite initial treatment with i.v. diuretics and/or vasodilators. 2.Cardiac index ≤ 2.5 L/min/m². 3.Pulmonary capillary wedge pressure ≥ 20 mmHg: 2 consecutive determinations at 30 minute intervals should not exceed a maximum of 10% variability; if the first 2 consecutive determinations fail to show the required stability, further determinations are allowed at the same interval within a maximum of 2 hours of evaluation. If stability is not demonstrated by 2 consecutive determinations within the 2-hour period, the patient will be excluded from the study. 4.Systolic BP comprised between 85 and 120 mmHg (limits included) without signs or symptoms of hypoperfusion including cardiogenic shock, cold extremities and peripheral vasoconstriction, oliguria/anuria, signs of cerebral hypoperfusion such as confusion.
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E.4 | Principal exclusion criteria |
Screening Exclusion Criteria: 1. Positive pregnancy test in females of childbearing potential or breast feeding females. 2. Systolic blood pressure < 85 mmHg or > 120 mmHg. 3. Oral treatment with digoxin within one week before current hospitalization. 4. Any inotrope administered during the current hospitalization (e.g. dobutamine, dopamine, milrinone, levosimendan, digoxin, enoximone). 5. Presence of cardiogenic shock or its occurrence within the past month. 6. Acute coronary syndrome within the past 3 months. 7. Coronary artery bypass graft or percutaneous coronary intervention within the past month. 8. Stroke within the past 6 months. 9. Primary hypertrophic or restrictive cardiomyopathy or systemic illness known to be associated with infiltrative heart disease. 10. Presence of signs or symptoms of uncontrolled hyperthyroidism or hypothyroidism. 11. Cor pulmonale or other causes of right-sided HF not related to left ventricular dysfunction. 12. Pericardial constriction or active pericarditis. 13. Atrial fibrillation with uncontrolled HR (HR > 100 beats per minute (bpm)). 14. Life threatening ventricular arrhythmia or ICD (implantable cardioverter defibrillator) shock within the past month. 15. Presence of a CRT (cardiac resynchronization therapy), ICD or pacemaker devices implanted within the past month. 16. Second or third degree atrio-ventricular block without pacemaker. 17. Valvular disease as the primary cause of HF. 18. Hemodynamic support devices. 19. Need for mechanical ventilation. 20. Acute respiratory distress syndrome or ongoing sepsis. 21. Terminal illness other than HF with expected survival less than 1 year. 22. Participation in another interventional study within the past 30 days. 23. The following laboratory exclusion criteria must be verified based on results obtained within the last 24 hours of the screening period prior to pulmonary arterial catheter (PAC) insertion: a. Serum creatinine > 2.5 mg/dL (> 221 µmol/L), b. Aspartate aminotransferase (ASAT) or alanine aminotransferase (ALAT) > 3 x upper limit of normal, c. Hemoglobin (Hb) < 10 g/dL, d. International normalized ratio (INR) > 1.4 in patients not receiving anticoagulant therapy, e. Platelet count < 100,000/µL, f. Brain natriuretic peptide value < 500 pg/mL or NT-proBNP < 2000 pg/mL. g. Any of the two cTnI assessments during screening > 0.5. ng/mL; or if the second assessment > ULN and > 1.25x the first assessment or h. Any of the two cTnT assessments during screening > 0.1 ng/mL; or if the second assessment > ULN and > 1.25x the first assessment.
Randomization Exclusion Criteria: 1. Any inotrope administered during the current hospitalization period (e.g. dobutamine, dopamine, milrinone, levosimendan, digoxin, enoximon). 2. Heart rate > 120 bpm or < 50 bpm. 3. cTnI > 0.5 ng/mL; or cTnI > ULN and > 1.25x the first screening cTnI assessment 4. cTnT > 0.1 ng/mL; or cTnT > ULN and > 1.25x the first screening cTnT assessment |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary hemodynamic endpoint: PCWP (Pulmonary capillary wedge pressure) change from baseline at 6 hours after infusion start. Secondary hemodynamic endpoints -PCWP change from baseline at 1, 3, 12, and 24 hours after infusion start, and at 1 and 3 hours after infusion end; -MRAP and systolic, diastolic and mean PAP change from baseline at 1, 3, 6, 12, and 24 hours after infusion start, and at 1 and 3 hours after infusion end; -SVR and PVR change from baseline at 6 and 24 hours after infusion start, and at 1 and 3 hours after infusion end (values will be calculated on the basis of vital sign recordings); -Cardiac output and its indexed value (cardiac index) change from baseline at 1, 3, 6, 12, and 24 hours after infusion start, and at 1 and 3 hours after infusion end; -SBP change from baseline at 1, 3, 6, 12 and 24 hours after infusion start, and at 1 and 3 hours after infusion end. Secondary clinical endpoints -Proportion of patients with at least moderate improvement as defined on the investigator global assessment (IGA) scale (7 point-scale) at 3, 6, and 24 hours after infusion start, at 3 hours after infusion end, and on study Day 5 or at discharge; -Proportion of patients with improvement in JVD, pulmonary rales and peripheral edema at 24 hours after infusion start respect to baseline; -Proportion of patients (within those ones still presenting dyspnea at randomization) with at least moderate improvement as defined on the patient self-assessment of dyspnea (PSAD) scale (7 point-scale) at 3, 6, and 24 hours after infusion start, at 3 hours after infusion end, and on study Day 5 or at discharge; -Proportion of patient hospital readmissions or emergency visits for cardiovascular reasons by Day 30. -Proportion of patients requiring rescue therapy (defined as unplanned introduction of new HF medication [e.g. inotropes] or increase of oral or i.v. dosages of HF medication, or intubation, ultrafiltration, dialysis or hemodynamic support) during the treatment period; -All-cause 30-day mortality. Safety endpoints: -Incidence of AEs; -Vital signs (HR, systolic, diastolic and mean BP, respiratory rate) change from baseline at 1, 3, 6, 12, and 24 hours after infusion start, and 1 and 3 hours after infusion end, and then in the morning on study Day 3 and Day 5 or at discharge, and on study Day 30 during the follow up visit; -ECG (HR, RR, PR, interval, QRS duration, QTc, rhythm, ischemic changes) change from baseline at 6 and 24 hours after infusion start and at 6 hours after infusion end. Changes from screening to Day 3 and Day 5 on the same parameters will be assessed on the local ECGs; -Episodes of sustained ventricular tachycardia (duration >30 seconds or requiring i.v intervention or cardioversion) and any clinically significant episode of supraventricular or ventricular arrhythmia detected by continuous ECG monitoring and documented by the Holter report, defined by the investigator as unexpected according to the patient’s history and/or previous screening observation period; -Standard hematology and biochemistry parameter change from baseline at 24 hours after infusion end (on Day 3); -Serum electrolytes change from baseline at 24 hours after infusion end (on Day 3); -Serum creatinine and estimated glomerular filtration rate (eGFR - calculated according to the modification of diet in renal disease [MDRD] formula) change from baseline at 24 hours after infusion start, 24 hours after infusion end (on Day 3) and on Day 5 or at discharge; - BNP change from baseline at 24 hours after infusion start and on Day 5 or at discharge; - troponin change from baseline at 3, 6, 12, and 24 hours after infusion start, at 24 and 48 hours after infusion end, and on Day 5 or at discharge; - Incidence of troponin elevation; -Renin, and aldosterone change from baseline at 24 hours after infusion start and on Day 5 or at discharge. PK endpoints: -Plasma concentration of istaroxime and its metabolites at infusion end in all patients. -Full plasma and urine PK profile in a subset of patients; the subset will comprise about 56 patients from approximately 10 centers to ensure inclusion of approximately 14 patients per dose level. The following PK metrics will be computed for istaroxime plasma concentrations using non-compartmental analysis: Cmax, tmax, AUC0-t, AUC0-∞, λz, t½, Cl, MRT, Vss, Vz. - In the same subset of patients, the following PK metrics will be computed for istaroxime urine concentrations: Ae, Ae%, ClR. In addition, in this patient subset, the following PK metrics will be computed as above for plasma and urine concentrations of the istaroxime metabolites PST2915, PST2922, and PST3093: Cmax, tmax, AUC0-t, AUC0-∞, λz, t½ and, if possible, Ae and Ae%. - A compartmental PK analysis will also be conducted for istaroxime and its metabolites if data permits, according to standard PK analysis methods.
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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 | No |
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 | Yes |
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.8.3 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
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 | Information not present in EudraCT |
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 |
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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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- The study will be considered as completed when the last patient who entered the study completed the follow up visit on study Day 30.
- The active part of the study will last a maximum of 7 days beginning on the screening day and ending with the last assessment on study Day 5 for each patient. A 25-day follow-up period will ensure that patient outcomes are established by the Investigator. Follow-up includes one study visit on study Day 30 |
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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 | |
E.8.9.1 | In the Member State concerned months | 16 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 16 |