Evaluation of Landiolol Hydrochloride Versus Standard Care in Reducing Mortality in Septic Shock Patients with Hypercontractility: A Randomized Controlled Trial

The primary objective of this study is to demonstrate that the reduction of heart rate using **landiolol** may improve the mortality of patients with septic shock and hypercontractility, compared to a control group, by day 28. This is clinically relevant as septic shock is a critical condition with high mortality rates, and effective management of heart rate could potentially improve patient outcomes.

Secondary objectives include demonstrating that the reduction of heart rate using landiolol, in comparison to standard care, may: - Reduce tachycardia - Reduce hypercontractility - Reduce shock duration - Reduce the length of hospital stay - Reduce multi-organ failure - Reduce the incidence of atrial fibrillation. These objectives aim to assess the broader impact of heart rate management on various clinical parameters associated with septic shock.

The clinical trial involves **patients hospitalized for septic shock with hypercontractility**. The study population includes both male and female participants aged 18 years and older. Participants are selected based on specific health criteria, including a diagnosis of septic shock as per the SEPSIS3 definition, with persistent hypotension requiring vasopressors and elevated lactate levels. The trial includes individuals with a left ventricular ejection fraction greater than 60% and tachycardia exceeding 95 bpm. Participants may be either spontaneously ventilating or intubated and ventilated. The sponsor has not provided information regarding the total number of participants. The trial population is considered vulnerable, and the selection process ensures that participants meet the necessary health and physiological criteria to assess the impact of heart rate reduction using landiolol on mortality rates at day 28.

The clinical trial is designed as an open-label, prospective, randomized study to evaluate the efficacy of **landiolol hydrochloride** in reducing mortality among patients hospitalized for septic shock with hypercontractility. The primary objective is to demonstrate that heart rate reduction using landiolol may improve mortality outcomes compared to the standard of care at day 28. The trial will involve the administration of **Rapibloc 300 mg powder for solution for infusion** and **CHLORURE DE SODIUM 0.9% AGUETTANT, solution for infusion**, both delivered intravenously. The study is expected to run from June 16, 2021, to July 15, 2025, with a maximum treatment period of 2 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), presence of septic shock as per SEPSIS3 definition, and specific cardiovascular parameters. Following inclusion, participants will be randomized to receive either the investigational product or standard care. Follow-up visits will be conducted to monitor primary and secondary endpoints, including mortality at day 28, heart rate reduction, duration of catecholamine and mechanical ventilation use, ICU and hospital stay length, and SOFA scores at specified intervals (inclusion and days 1, 2, 3, 7, 14, and 28). The end-of-study visit will assess overall outcomes and any adverse events.

Participant involvement is expected to last up to 28 days, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that necessitate discontinuation. The trial's design ensures rigorous assessment of the investigational product's impact on mortality and other clinical outcomes in the target patient population.

The clinical trial involves the administration of **Rapibloc**, a 300 mg **powder for solution for infusion** containing the active substance **landiolol hydrochloride**. This experimental medication is designed for intravenous administration. The maximum daily dose is 8064 mg, with a total maximum dose of 16128 mg over a treatment period of up to 2 days. The primary objective of using Rapibloc is to assess its efficacy in reducing heart rate and improving mortality in patients with septic shock exhibiting tachycardia and hypercontractility. The administration of Rapibloc is monitored to ensure participant compliance and accurate dosing.

In addition to the experimental treatment, the study utilizes **CHLORURE DE SODIUM 0.9% AGUETTANT**, a **solution for infusion** containing **sodium chloride** as a non-experimental treatment. This solution is also administered intravenously, with a maximum daily dose of 1344 ml and a total maximum dose of 2688 ml over a 2-day period. The sodium chloride solution serves as a standard-of-care therapy, providing a comparator for evaluating the effects of the experimental medication. The administration of this solution is similarly monitored to ensure adherence to the dosing schedule and participant compliance.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the **mortality at day 28**. Secondary endpoints include several parameters: the number of patients achieving a reduction in heart rate equal to or greater than 20% of the initial heart rate with landiolol, the number of days patients receive catecholamines, the number of days on mechanical ventilation, and the length of stay in the ICU and hospital. Additionally, the Sequential Organ Failure Assessment (SOFA) score will be measured at inclusion and on days 1, 2, 3, 7, 14, and 28 following inclusion. Other secondary endpoints include the number of patients developing atrial fibrillation or flutter during the first three days, hospital mortality, the number of episodes of bradycardia (heart rate <50 bpm), left ventricular ejection fraction (LVEF) <45%, or mean arterial pressure (MAP) <65 mmHg requiring an increase of norepinephrine >40% during the treatment period with landiolol, and unexpected cardiac arrest.