Evaluation of Levosimendan Versus Placebo in Preoperative Management of Right Ventricular Dysfunction in Patients Undergoing Tricuspid Valve Surgery

The primary objective of this study is to demonstrate the **superiority** of preoperative **levosimendan** compared to placebo in preventing post-operative low cardiac output syndrome in patients undergoing cardiac surgery for the correction of moderate to severe functional tricuspid regurgitation. This is clinically relevant as low cardiac output syndrome is a significant complication following cardiac surgery, which can lead to increased morbidity and mortality.

Secondary objectives include:

• Demonstrating the ability of levosimendan to reduce perioperative mortality.
• Confirming the safety of levosimendan in the context of tricuspid surgery.

The clinical trial involves **patients** referred for isolated or combined surgical correction of functional moderate to severe tricuspid regurgitation. The study population includes both male and female participants aged 18 years and older. Participants are required to be affiliated with the French health care system and must provide written informed consent. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. The selection criteria focus on individuals with severe tricuspid regurgitation, defined by specific clinical measurements. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the **superiority** of preoperative **levosimendan** compared to a placebo in preventing post-operative low cardiac output syndrome in patients undergoing cardiac surgery for moderate to severe functional tricuspid regurgitation. This is a randomized, double-blind, controlled trial with an estimated duration from September 2022 to December 2025. Participants will be randomly assigned to receive either levosimendan or a placebo, administered intravenously. The trial will include several key phases, starting with an inclusion visit where eligibility criteria such as age (≥18 years), informed consent, and specific medical conditions are assessed. The primary endpoint is a composite measure of low cardiac output syndrome at 90 days, including prolonged catecholamine infusion, the need for circulatory mechanical assist devices, and renal replacement therapy during ICU stay. Secondary endpoints include mortality at day 90 and the safety profile of the study drug, particularly regarding refractory hypotension.

Participants will be involved in the study for a maximum treatment period of one day, with follow-up visits scheduled to monitor outcomes and adverse events. The end-of-study visit will occur at 90 days post-surgery to assess the primary and secondary endpoints. Conditions that may lead to early termination from the study include withdrawal of consent or any adverse event that poses a significant risk to the participant's health. The trial is conducted under strict ethical guidelines, ensuring that all participants are treated with the highest standard of care throughout the study duration.

The clinical trial involves the administration of **ZIMINO 2.5 mg/ml**, a **solution for infusion** containing the active substance **levosimendan**. This pharmaceutical form is specifically designed for **intravenous use**. The dosing regimen for ZIMINO is calculated based on body weight, with a maximum daily dose of 0.29 mg/kg. The total dose administered should not exceed 0.29 mg/kg over the course of the treatment period, which is limited to one day. The solution is provided by Orion Corporation and is classified under the ATC code C01CX08. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

The study also includes a **placebo** group, which will receive a **placebo of ZIMINO** formulated as a glucose 5% solution. The placebo is administered in the same manner as the active treatment, via **intravenous infusion**. This approach is intended to maintain blinding and ensure that any observed effects can be attributed to the active substance rather than the administration process itself. The placebo is used to compare the efficacy of levosimendan in preventing post-operative low cardiac output syndrome in patients undergoing cardiac surgery for moderate to severe functional tricuspid regurgitation.

Efficacy in the clinical trial titled "LEONARD.LEvOsimendaN vs. Placebo Before Tricuspid VAlve Surgery in Patients with Right Ventricular Dysfunction (LEONARD)" will be assessed using both primary and secondary endpoints. The primary endpoint is a composite measure reflecting low cardiac output syndrome at 90 days post-surgery. This includes the persistence of catecholamine infusion beyond 48 hours after cardiac surgery, the need for circulatory mechanical assist devices in the postoperative period, and the requirement for renal replacement therapy at any time during the intensive care unit stay.

Secondary endpoints include mortality at day 90, each component of the primary endpoint, and the safety of the study drug, which will be assessed by recording the incidence of refractory hypotension. Refractory hypotension is defined as a failure to increase mean arterial pressure above 60 mmHg despite optimal management. These efficacy parameters will be collected and analyzed at specified timepoints, ensuring a comprehensive evaluation of the treatment's impact on patients undergoing cardiac surgery for moderate to severe functional tricuspid regurgitation.