Advanced chronic heart failure
Conditions
Interventions
Trade Name: Simdax 2,5mg/ml
Product Name: Simdax
Pharmaceutical Form: Concentrate and solvent for solution for infusion
INN or Proposed INN: LEVOSIMENDAN
CAS Number: 141505-33-1
Current Sponsor code:
Sponsors
Medical University Innsbruck
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Written, signed and dated informed consent. 2. Male and female patients over 18 years of age. 3. Women of childbearing potential must have a monthly negative pregnancy test and must refrain from breastfeeding. Women who are postmenopausal (1 year since last menstrual cycle), surgically sterilised or who have undergone a hysterectomy are considered not to be of childbearing potential. 4. CHF diagnosed at least 6 months before screening and treated with individually optimised long-term oral treatment for the last month, unless not tolerated (e.g., ACE-inhibitor or AT II blocker, beta-blocker, mineralocorticoid receptor antagonist, angiotensin II receptor blocker neprilysin inhibitor [ARNI] and with devices [e.g., CRT/ICD], as needed). 5. Left ventricular ejection fraction less than or equal to 35% as assessed using echocardiography, radionuclide ventriculography or contrast angiography within the index hospitalisation. 6. Currently hospitalised for decompensated HF requiring i.v. diuretics, or i.v. vasodilators, or i.v. inotropic therapy, or their combination. 7. Previous hospitalisation or visit to outpatient clinic requiring i.v. diuretics, i.v. vasodilators, or i.v. inotropic therapy, or their combination for acute decompensated HF within 12 months before the current hospitalisation. 8. NT-proBNP level after recompensation (= haemodynamically stable euvolemic, established on evidence-based oral medication and with stable renal function for at least 24hrs before discharge) in patients in sinus rhythm of =2000ng/L (BNP =600mg/L), in patients in atrial fibrillation of =2500 ng/L (BNP =900 ng/L) and/or NYHA class III or IV at study entry. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 52 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 212
Exclusion criteria
Exclusion criteria: 1. Severe obstruction of ventricular outflow tracts such as haemodynamically significant uncorrected primary valve disease or hypertrophic cardiomyopathy or impaired ventricular filling such as restrictive cardiomyopathy. 2. Predominantly right heart failure and/or severe tricuspid regurgitation 3. Cardiac surgery or coronary angioplasty within 30 days before study drug initiation. 4. Acute coronary syndrome within 30 days before study drug initiation. 5. Patients who are scheduled for cardiac surgery or angioplasty in the next 3 months. 6. History of torsades de pointes. 7. Stroke or transient ischaemic attack (TIA) within 3 months before study drug initiation. 8. Systolic blood pressure less than 90 mmHg at baseline. 9. Heart rate 120 bpm or greater at baseline. 10. Serum potassium less than 3.5 mmol/l before study drug initiation. 11. Severe renal insufficiency (estimated glomerular filtration rate [eGFR] less than 20 ml/min/1.73m2). 12. Anaemia (haemoglobin less than 10 g/dl). 13. Significant hepatic impairment at discretion of the investigator. 14. Hypersensitivity to levosimendan. 15. Other serious diseases limiting life expectancy considerably (e.g. end-stage cancer, end-stage renal disease, end-stage lung disease). 16. Participation in a clinical trial with any experimental treatment within 30 days prior to screening or previous participation in the present study. 17. Administration of levosimendan within 14 days prior the study drug initiation. (The first study drug application has to be postponed for at least 14 days after the end of this premedication) 18. Suspected non-compliance 19. Pregnant women and nursing mothers 20. Failure to use highly effective (a Pearl Index lower than 1%) contraceptive methods. 21. Persons with any kind of dependency on the investigator 22. Persons held in an institution by legal or official order
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary efficacy objective of the study is to compare the effects of pulsed application of levosimendan versus placebo in patients with advanced chronic heart failure during a vulnerable period of 14 weeks following a recent hospitalisation on a global rank endpoint in which all participants are ranked across three hierarchical groups: • time to death or high-urgent heart transplantation or ventricular assist device (VAD), • time to non-fatal HF event requiring i.v. vasoactive therapy (i.v. diuretics, i.v. vasodilators or i.v. inotropes) and • time-averaged proportional change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to 14 weeks. ;Secondary Objective: The secondary efficacy objectives are to determine the effects of pulsed application of Levosimendan on: a. individual components of the primary endpoint at 14 weeks and 26 weeks (time-averaged proportional change in NT-proBNP from baseline to 14 weeks), b. changes in symptoms and functional status at 26 weeks, c. number of combined events at 14 and 26 weeks, d. cumulative number of AHF events at 14 weeks and 26 weeks, e. cumulative number of hospital admissions, and f. cumulative days alive and out of hospital ;Primary end point(s): The hypothesis will be tested based on a global rank endpoint in which all participants are ranked across three hierarchical groups that include deaths, non-fatal HF events and positive neurohormonal response on NT-proBNP (12). Each patient is given a global rank score based on the outcome during the follow-up. The components are analysed in a hierarchical manner so that deaths are the most important events, followed by non-fatal HF events and finally by the effect on NT-pro-BNP. This hierarchical approach increases the clinical validity of the endpoint: 1. time to death or high-urgent heart transplantation or VAD, 2. time to non-fatal HF event requiring i.v. vasoactive therapy (i.v. diuretics, i.v. vasodilators or i.v. inotropes) | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Individual components of the primary endpoint at short-term (14 weeks) and intermediate-term (26 weeks). • time to death / high-urgent heart transplantation / VAD implantation • time to non-fatal HF event defined as an episode requiring i.v. vasoactive therapy (i.v. diuretic, i.v. inotropic) at week 14 and 26 • time-averaged proportional change in NT-proBNP from baseline to 14 weeks 2. Change in functional status • 6-minute walk test at baseline and 14 weeks • New York Heart Association (NYHA) class at baseline and 14 weeks 3. Change in symptoms • Kansas City Cardiomyopathy Questionnaire (KCCQ) – clinical summary score - from baseline to 14 weeks • Difference in the patient global assessment (PGA) between groups at 14 weeks 4. Number of combined events • death / heart transplantation / VAD implantation / non-fatal HF event 5. Cumulative number of non-fatal HF events 6. Cumulative number of hospital admissions (non-fatal HF vs cardiovascular admissions vs. non-cardiovascular admissions) 7. Cumulative days alive and out of hospital 8. Cumulative number of death and total (first and recurrent) non-fatal HF events 9. Safety assessment ;Timepoint(s) of evaluation of this end point: week 1 till week 26 | — |
Countries
Austria, Denmark, Finland, Germany, Hungary, Italy, Slovenia, Switzerland
Contacts
Public ContactDr. Gerhard Pölzl
Medical University Innsbruck
Outcome results
None listed