A Phase 3, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Oral Levosimendan in Patients with Pulmonary Hypertension and HFpEF

The primary objective is to evaluate the efficacy (5) of 26 weeks of treatment with levosimendan compared to placebo in patients with pulmonary hypertension associated with heart failure with preserved left ventricular ejection fraction, as measured by the change in 6-minute walk distance. The study also aims to assess the safety (4) and tolerability of oral levosimendan. Secondary objectives include evaluating the effectiveness of the treatment in improving:

• the frequency and burden of heart failure symptoms;
• clinical events;
• physical activity limitations resulting from symptom severity.

This clinical trial involves a total of 250 participants diagnosed with pulmonary hypertension associated with heart failure with preserved left ventricular ejection fraction. The study population consists of male and female patients between the ages of 18 and 85 years. Eligible individuals must present with NYHA Class II, NYHA Class III, or ambulatory NYHA Class IV symptoms. Diagnosis requires verification of WHO Group 2 hemodynamics via right heart catheterization and an echocardiogram demonstrating a left ventricular ejection fraction of at least 40%. Participants must have a documented absence of pulmonary thromboembolism through ventilation-perfusion scan, computed tomography pulmonary angiogram, or pulmonary angiography. Additionally, a qualifying 6-minute walk distance between 100 and 450 meters is required at screening and baseline. The study objectives are:

• Evaluate the efficacy of 26 weeks of treatment with levosimendan compared with placebo as measured by the change in 6-minute walk distance.
• Evaluate the safety and tolerability of oral levosimendan versus placebo.

This Phase 3, double-blind, randomized, placebo-controlled study evaluates the efficacy and safety of levosimendan in patients diagnosed with pulmonary hypertension with heart failure with preserved left ventricular ejection fraction. The primary efficacy endpoint is the change from baseline in the 6-minute walk distance from Day 1 to Week 26. Safety is assessed through the incidence of adverse events, physical examinations, vital signs, clinical laboratory values, and electrocardiograms. Secondary objectives include evaluating changes in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score, frequency and time to clinical worsening events, and changes in the New York Heart Association functional class. The study protocol involves a screening period to verify diagnosis via right heart catheterization and echocardiogram, followed by a 26-week treatment period. Participants receive either oral levosimendan in a hard gelatin capsule or an oral placebo. The duration of treatment is 26 weeks.

The investigational medicinal product consists of levosimendan administered in a hard gelatin capsule form. The treatment is provided via the oral route at a dosage of 9999 mg.

The control group receives a placebo, which is an immediate-release dosage form intended for oral administration.

The efficacy of levosimendan in patients with pulmonary hypertension and heart failure with preserved left ventricular ejection fraction is evaluated by comparing treatment effects against a placebo. The primary endpoint is the change from baseline in the 6-Minute Walk Distance (6 MWD) from Day 1 to Week 26.

Secondary efficacy parameters assessed from Day 1 to Week 26 include:

• Change in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS).
• The number of clinical worsening events, defined as unplanned hospitalization due to cardiopulmonary indications, urgent outpatient visits for intravenous diuretic administration, or deaths caused by cardiovascular-related clinical conditions.
• Time to the first occurrence of a clinical worsening event.
• Change in the New York Heart Association (NYHA) functional class.