Evaluation of Early Levosimendan Administration Versus Placebo in Cardiogenic Shock Patients on Conventional Inotrope Therapy: A Morbidity-Mortality Endpoint Study

The primary objective of this study is to evaluate the effect of the early use of **levosimendan** versus placebo, in addition to a conventional inotrope strategy, on a composite endpoint of 30-day mortality and/or ExtraCorporeal Life Support (ECLS) requirement and/or dialysis in patients with **cardiogenic shock**. This is clinically relevant as it aims to determine whether levosimendan can improve survival and reduce the need for advanced life support interventions in this critical condition.

Secondary objectives include determining the impact of levosimendan versus placebo on: - A prioritized composite endpoint at day 90, including time to death, escalation to permanent left ventricular assist device or cardiac transplantation, dialysis, ECLS requirement, and number of cardiovascular events. - Major adverse cardiovascular events at day 90, 180, and 12 months. - Composite endpoints of all-cause mortality and/or ECLS requirement and/or dialysis at various time points. - The number of dobutamine, vasopressors, ventilatory, and renal replacement free days. - Lactate clearance from randomization to day 7. - Duration of ICU stay and hospitalization. - Occurrence of arrhythmias requiring therapy. - Changes in biomarkers and their predictive ability for levosimendan's effect and subsequent outcomes.

The clinical trial focuses on evaluating the effect of early use of levosimendan versus placebo in patients with **cardiogenic shock**. The study population includes adult patients aged 18 years and older, encompassing both male and female participants. The trial involves a vulnerable population, as indicated by the inclusion of individuals with cardiogenic shock, a critical condition. Participants are required to have adequate intravascular volume and must be on norepinephrine or dobutamine for a specified duration and dosage to maintain mean arterial pressure. Additionally, signs of tissue hypoperfusion are necessary for inclusion. The sponsor has not provided the total number of participants involved in the study. Participants are selected based on specific clinical criteria, ensuring they meet the necessary health status and treatment conditions. Lifestyle considerations such as diet and physical activity are not specified in the available data. The trial does not provide further details on the selection process or additional lifestyle factors.

The clinical trial is designed to evaluate the effect of early use of **levosimendan** versus placebo in patients with **cardiogenic shock**. This study is a randomized, double-blind, controlled trial, aiming to assess the impact on a composite endpoint of 30-day mortality and/or the requirement for ExtraCorporeal Life Support (ECLS) and/or dialysis. The trial is expected to run from July 2023 to July 2027, with participant involvement lasting up to 30 days post-randomization. The trial will include several study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, medical condition, and current treatment regimen. Participants will be randomly assigned to receive either levosimendan or a placebo via intravenous infusion.

Following the inclusion visit, participants will undergo regular follow-up visits to monitor their health status and response to treatment. These visits will assess primary endpoints, including all-cause mortality and the need for ECLS or dialysis at day 30. Secondary endpoints will be evaluated at days 90, 180, and 12 months, including time to death, escalation to permanent left ventricular assist device, cardiac transplantation, and major adverse cardiovascular events. The end-of-study visit will occur at the conclusion of the participant's involvement, ensuring comprehensive data collection and safety monitoring.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The trial's methodology ensures rigorous data collection and analysis, contributing valuable insights into the management of cardiogenic shock. The study's design, including its randomized and double-blind nature, aims to minimize bias and enhance the reliability of the findings.

The clinical trial involves the administration of **ZIMINO 2.5 mg/ml**, a solution for infusion containing the active substance **levosimendan**. This experimental medication is provided by Orion Corporation and is classified under the ATC code C01CX08, indicating its role as a cardiac stimulant. The pharmaceutical form is a solution to be diluted for infusion, and it is administered via **intravenous infusion**. The maximum daily dose is 288 µg/kg, with a total treatment period of one day. The administration of ZIMINO is monitored to ensure compliance with the dosing schedule.

In addition to the experimental treatment, the trial includes the use of **SOLUVIT**, a lyophilisate for parenteral use, provided by Fresenius Kabi France S.A.S. This product is a solution for infusion containing a combination of vitamins, including **pantothenate sodium**, **riboflavin sodium phosphate**, **biotin**, **cyanocobalamin**, **folic acid**, **nicotinamide**, **sodium ascorbate**, **thiamine nitrate**, and **pyridoxine hydrochloride**. It is classified under the ATC code B05XC, indicating its role as a vitamin supplement. The administration route is also via intravenous infusion, with a maximum daily dose of 288 µg/kg and a treatment period of one day.

The trial also utilizes **CERNEVIT**, a powder for solution injectable or for infusion, provided by Baxter SAS. This product is a solution for injection/infusion containing a comprehensive blend of vitamins, including **retinol palmitate**, **ascorbic acid**, **biotin**, **colecalciferol**, **cyanocobalamin**, **dexpanthenol**, **folic acid**, **nicotinamide**, **pyridoxine hydrochloride**, **dl-alpha-tocopherol**, and **cocarboxylase tetrahydrate**. Like SOLUVIT, CERNEVIT is classified under the ATC code B05XC and is administered via intravenous infusion. The dosing schedule is consistent with a maximum daily dose of 288 µg/kg and a treatment period of one day.

Throughout the trial, participant compliance with the dosing schedules is closely monitored to ensure the integrity of the study results. The trial aims to evaluate the effect of early use of levosimendan versus placebo on a composite endpoint of 30-day mortality and/or extracorporeal life support requirement and/or dialysis in patients with cardiogenic shock.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is a composite measure of all-cause mortality and/or the requirement for ExtraCorporeal Life Support (ECLS) and/or dialysis at day 30 following randomization. This endpoint will provide a direct measure of the treatment's impact on survival and critical interventions in patients with **cardiogenic shock**.

Secondary endpoints will include a prioritized composite endpoint at day 90, which will consider the time to death, escalation to permanent left ventricular assist device or cardiac transplantation, dialysis, ECLS requirement, and the number of cardiovascular events such as stroke, recurrent myocardial infarction, urgent coronary revascularization, and re-hospitalization for heart failure. Additional secondary measures will assess the number of dobutamine-free days, vasopressor-free days, ventilatory-free days, and renal replacement-free days at various time points, including day 30, day 90, and up to 12 months post-randomization. Lactate clearance from randomization to day 7, duration of ICU stay, and hospitalization will also be evaluated.

These endpoints will be measured and collected at specified time points, including days 7, 30, 60, 90, 180, and 12 months following randomization. The analysis will involve comparing the outcomes between the treatment group receiving levosimendan and the placebo group, with the aim of determining the efficacy of levosimendan in improving survival and reducing the need for critical interventions in patients with cardiogenic shock.