Evaluation of Levosimendan in Enhancing Left Ventricular Ejection Fraction Recovery in Takotsubo Syndrome with Low Ejection Fraction: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate whether the off-label use of **levosimendan** accelerates in-hospital left ventricular ejection fraction (LVEF) recovery and reduces the 12-month incidence of all-cause mortality or major adverse cardiovascular events (MACE) in patients with Takotsubo syndrome (TTS) and an LVEF ≤40% at admission, compared to placebo. This is clinically relevant as it aims to improve cardiac function and reduce mortality and cardiovascular complications in a population with compromised cardiac output.

The secondary objectives include assessing the composite endpoint of 12-month all-cause mortality or the rate of major adverse cardiovascular events, such as rehospitalization due to TTS recurrence or heart failure, stroke, or transient ischemic attack (TIA). Additional components of this objective involve evaluating all-cause mortality, rehospitalization due to TTS recurrence or heart failure, stroke or TIA, length of hospitalization, the need for inotropic support, functional capacity as measured by NYHA class, and a decrease in B-natriuretic peptide levels. These objectives are crucial for understanding the broader impact of levosimendan on patient outcomes and healthcare resource utilization.

The clinical trial focuses on patients diagnosed with **Takotsubo syndrome**. The study population includes both male and female participants, with an age range primarily over 60 years. Participants are selected based on their current hospitalization due to Takotsubo syndrome, with a left ventricular ejection fraction (LVEF) of 40% or less at admission, as assessed by echocardiography within 24 hours, or a decrease in LVEF by 10% or more compared to the last documented value before hospitalization. Additionally, participants must have an NTproBNP concentration of 500 pg/mL or higher. The trial includes a vulnerable population, but specific lifestyle considerations such as diet or physical activity are not detailed. The sponsor has not provided information regarding the total number of participants involved in the study.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy of **levosimendan** in patients with **Takotsubo syndrome** and a left ventricular ejection fraction (LVEF) of 40% or less at admission. The primary objective is to assess whether levosimendan accelerates in-hospital LVEF recovery and reduces the 12-month incidence of all-cause mortality or major adverse cardiovascular events (MACE), including rehospitalization due to Takotsubo syndrome recurrence or heart failure, stroke, or transient ischemic attack. The trial is expected to run from February 28, 2023, to June 28, 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age over 60 years, current hospitalization due to Takotsubo syndrome, and specific echocardiographic and biomarker thresholds. Following randomization, participants will receive either levosimendan or placebo via **intravenous** infusion. The maximum treatment period is one day, with a maximum daily dose of 12.5 mg for levosimendan. Follow-up visits will be scheduled to monitor LVEF recovery and record any adverse events or endpoints, with the final visit marking the end of the study. The expected length of participant involvement is up to 12 months, with conditions for early termination including withdrawal of consent or significant adverse events.

The clinical trial involves the administration of **Simdax**, a pharmaceutical product containing the active substance **levosimendan**. Simdax is provided as a **solution for infusion** with a concentration of 2.5 mg/mL. The product is manufactured by Orion Corporation and is authorized for use in Poland. The maximum daily dose of Simdax is 12.5 mg, with a total maximum dose of 12.5 mg over a treatment period of one day. The administration route is **intravenous**, ensuring direct delivery into the bloodstream. The chemical origin of levosimendan is confirmed, and the product is not formulated for pediatric use. Compliance with dosing schedules will be monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, the trial utilizes **GLUCOSUM 5% FRESENIUS**, a non-experimental treatment serving as a comparator. This product contains **glucose monohydrate** as the active substance and is also provided as a **solution for infusion** with a concentration of 50 mg/mL. Manufactured by Fresenius Kabi Polska Sp. z o.o., it is authorized for use in Poland. The maximum daily and total dose is 100 mL, administered intravenously over a one-day treatment period. The chemical origin of glucose monohydrate is confirmed, and similar to Simdax, it is not intended for pediatric use. The administration of GLUCOSUM 5% FRESENIUS will be closely monitored to ensure participant compliance and accurate dosing throughout the study.

Efficacy in the clinical trial titled "A Randomized, Double-Blind, Placebo-Controlled Multicenter Study of Levosimendan Therapy in low ejection fraction Takotsubo Syndrome (LevoTako Trial)" will be assessed using both primary and secondary endpoints. The primary endpoint is the in-hospital recovery of left ventricular ejection fraction (**LVEF**). This will be measured to determine the effectiveness of levosimendan in accelerating LVEF recovery in patients with Takotsubo Syndrome (TTS) and an LVEF of 40% or less at admission. The secondary endpoint is a composite measure that includes the 12-month incidence of all-cause mortality or major adverse cardiovascular events (MACE), such as rehospitalization due to TTS recurrence or heart failure, stroke, or transient ischemic attack (TIA).

The trial aims to evaluate whether the off-label use of levosimendan can improve these outcomes compared to a placebo. The efficacy parameters will be collected and analyzed at specified timepoints, with LVEF being assessed by echocardiography within 24 hours of admission. The trial will also monitor the NTproBNP concentration, which must be 500 pg/mL or higher for inclusion. The study is designed to provide robust data on the potential benefits of levosimendan in this patient population, with the ultimate goal of improving clinical outcomes in TTS.