Levosimendan In Ambulatory Heart Failure Patients

Study Overview
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Brief Summary
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The objective of the study is to determine the efficacy of repeated infusions of levosimendan in the group of outpatients with advanced systolic heart failure (HF).

Detailed Description
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It is a multicentre, randomized, double-blind, placebo-controlled study. 350 subjects will be included (in 12 or more medical centers) with severe HF, ejection fraction ≤35%, in New York Heart Association class III or IV. The other inclusion criteria concern: hospitalization for the HF decompensation in the last 3 months and a reduced six-minute walk test <350m or elevated NTproBNP ≥1000 pg / mL. To the European Society of Cardiology-guided, individually optimized medical therapy (OMT) the investigational product (IP) will be added. The subjects will be randomly assigned to one of the study group: 175 to the levosimendan arm and 175 to the placebo arm. The intervention studied in LEIA-HF trial is the administration of levosimendan as a continuous iv. infusion, every 4 weeks for 48 weeks (12 infusions in total). All study participants will also continue OMT. In the second phase of the study, after completing the levosimendan / placebo infusions, another 6 visits are planned, still double-blind, every 4 weeks, to assess the safety of treatment discontinuation (with optional return to the infusions by the Investigator when additional criteria for HF decompensation are met). The efficacy of the treatment will be assessed after 52 weeks, 4 weeks after the last levosimendan / placebo administration.

Official Title
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Levosimendan In Ambulatory Heart Failure Patients

Conditions
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Heart Failure New York Heart Association Class III, Heart Failure New York Heart Association Class IV, Heart Failure, Systolic, Heart Failure With Reduced Ejection Fraction

Intervention / Treatment
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* Drug: Levosimendan
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent obtained before any trial activities Male or female, age ≥ 18 years at the time of signing informed consent Left ventricle ejection fraction ≤ 35% Hospitalization due to worsening of HF within the last 3 months New York Heart Association functional class III or outpatient IV Individually optimized pharmacotherapy, based on the current European Society of Cardiology recommendations, stable for at least 1 month prior to randomization, according to the knowledge and experience of the qualifying clinician Distance covered in six-minute walk test <350m OR NTproBNP concentration ≥ 1000 pg/mL In the opinion of the Investigator, the patient does not currently require hospitalization Patient protected with an implantable device capable of terminating life-threatening arrhythmias and conduction disturbances (ICD or cardiac resynchronisation therapy-D/P), if indicated and the patient consents to implantation. Exclusion Criteria: Known or suspected hypersensitivity to trial products or related products, Restrictive or hypertrophic cardiomyopathy, uncorrected severe valvular disease, potentially reversible cause of HF Hypotension with symptoms of tissue hypoperfusion Uncontrolled hypertension Planned revascularization or other surgical treatment of HF within the next year Advanced chronic kidney disease Features of liver damage Severe chronic lung disease with features of respiratory distress or severe abnormal spirometry or home oxygen treatment Accompanying chronic diseases with poor prognosis Paroxysmal supraventricular tachycardia, paroxysmal ventricular tachycardia, torsade de pointes, advanced atrioventricular blocks within one month prior to screening Receipt of any investigational product within 30 days before screening visit Any disorder, which in the investigator's opinion may jeopardise subject's safety or compliance with the study protocol and procedures

Ages Eligible for Study
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Minimum Age: 18 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: Levosimendan<br>administration of levosimendan | Drug: Levosimendan<br>* administration of levosimendan as a continuous iv. infusion, every 4 weeks for 48 weeks (12 infusions in total)<br>|
| Placebo Comparator: Placebo<br>administration of placebo | Other: Placebo<br>* administration of glucose as a continuous iv. infusion, every 4 weeks for 48 weeks (12 infusions in total)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the number of unplanned hospitalization | unplanned hospitalization due to heart failure decompensation | 12 months of follow-up period | 
| the number of deaths | death for any cause | 12 months of follow-up period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| total mortality calculations | total mortality for any cause | 0-12, 12-18 and 0-18 months | 
| cardiovascular mortality calculations | mortality due to cardiovascular reasons | 0-12, 12-18 and 0-18 months | 
| the number of planned hospitalization | planned hospitalization due to heart failure decompensation | 0-12, 12-18 and 0-18 months | 
| the number of implantations of mechanical circulatory support | implantation of mechanical circulatory support | 0-12, 12-18 and 0-18 months | 
| the number of heart transplantations | heart transplantation | 0-12, 12-18 and 0-18 months | 
| quality of life measurements | The Kansas City Cardiomyopathy Questionnaire quality of life questionnaire- an overall summary score can be derived from the physical function, symptom (frequency and severity), social function and quality of life domains. For each domain, the validity, reproducibility, responsiveness and interpretability have been independently established. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. | 0-12, 12-18 and 0-18 months | 
| the six-minute walk test | measures the distance an individual is able to walk over a total of six minutes | 0-12, 12-18 and 0-18 months | 
| NTproBNP measurements | measurements of NTproBNP concentrations | 0-12, 12-18 and 0-18 months | 
| estimated glomerular filtration rate measurements | measurements of estimated glomerular filtration rate | 0-12, 12-18 and 0-18 months | 
| echocardiographic parameters | the change in echocardiographic parameters assessed in transthoracic echocardiographic examination (TTE) | 0-12, 12-18 and 0-18 months | 
| patients who returned to levosimendan / placebo infusions | calculations of the percentage of patients who returned to levosimendan / placebo infusions | from the 12th to the 18th months of the study |