Evaluation of Levetiracetam for Delirium Prevention in Adult ICU Patients with Septic Shock: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to assess the impact of early 7-day administration of **levetiracetam** in patients with septic shock hospitalized in the ICU on the number of days alive without coma or delirium at day 14. This is clinically relevant as it aims to improve patient outcomes by potentially reducing the duration of delirium and coma, which are common complications in septic shock and can significantly affect recovery and long-term prognosis.

Secondary objectives include evaluating the impact of treatment with levetiracetam versus placebo on various clinical outcomes:

• Mortality in intensive care, in hospital, at day 28 and day 90
• Overall survival at day 90
• Duration of mechanical ventilation at day 28
• Length of stay in intensive care and in hospital
• Occurrence of epileptic seizures and abnormalities from day 1 to day 14
• Time between cessation of sedation and awakening
• Severity of cognitive impairment at day 90 using the T-MoCA
• Health-related quality of life at day 90 using the EQ-5D questionnaire
• Autonomy of daily living at day 90 using the Katz ADL scale
• Anxiety-depressive state at day 90 using the HADS
• Post-traumatic stress disorder at day 90 using the IES-R score

The clinical trial involves **adult ICU patients with septic shock**. The study population includes both male and female participants aged 18 years and older. Participants are required to be hospitalized in intensive care for less than 96 hours with septic shock evolving for less than 24 hours. The trial does not focus on a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants were selected based on specific criteria, including a clinically or microbiologically documented infection, a SOFA score of 2 or more, or an increase in SOFA by 2 points if organ dysfunction was present prior to infection, the need for vasopressor administration to maintain a mean arterial pressure of at least 65 mmHg, and lactatemia greater than 2 mmol/L despite adequate vascular filling. Consent from the patient, a family member, or inclusion in an emergency situation without prior consent is required. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the early administration of **levetiracetam** in the prevention and treatment of delirium during septic shock in adult ICU patients. This study is a **randomized, double-blind, placebo-controlled** trial, ensuring that neither the participants nor the researchers know who is receiving the active treatment or the placebo, thus minimizing bias. The trial is set to commence on January 2, 2025, with an estimated completion date of April 2, 2027. The primary objective is to assess the impact of a 7-day administration of levetiracetam on the number of days patients are alive without coma or delirium by day 14 post-randomization.

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), recent hospitalization in intensive care with septic shock, and consent. Following randomization, participants will receive either levetiracetam or a placebo for a maximum treatment period of 7 days. The primary endpoint is the number of days alive without delirium or coma at day 14. Secondary endpoints include mortality rates at various intervals (D28, D90), overall survival at D90, and other health-related outcomes such as cognitive impairment and quality of life at D90.

Participants are expected to be involved in the study for the duration of their ICU stay, with follow-up assessments extending to 90 days post-randomization. Conditions that may lead to early termination from the study include withdrawal of consent or any adverse events that necessitate discontinuation of the study drug. The trial will adhere to rigorous ethical standards, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **LEVETIRACETAM**, marketed as LEVETIRACETAM VIATRIS 100 mg/ml, solution à diluer pour perfusion. This experimental medication is provided in the form of a **solution for infusion**. The active substance, levetiracetam, is of chemical origin. The maximum daily dose is 2000 mg, with a total maximum dose of 14000 mg over a treatment period of 7 days. The administration route is via infusion, and the medication is intended for use in patients with septic shock to evaluate its efficacy in preventing and treating delirium. The pharmaceutical product is authorized under the marketing authorization number NL 40508 in France, with the manufacturer being VIATRIS SANTE.

In addition to the experimental treatment, the study utilizes **SODIUM CHLORIDE** as a placebo. Sodium chloride is provided as a **solution for injection** and serves as a comparator treatment in the trial. The maximum daily dose for sodium chloride is 20 ml, with a total maximum dose of 140 ml over the same 7-day treatment period. The administration route is also via infusion. Sodium chloride is of chemical origin and is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment allocation.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial is designed to assess the impact of early administration of levetiracetam on the number of days patients remain alive without coma or delirium by day 14. The study is conducted under strict regulatory guidelines to ensure the safety and efficacy of the treatments being evaluated.

Efficacy in the clinical trial titled "KISS Evaluation of early administration of Levetiracetam in the prevention and treatment of delirium during septic shock: a randomized, double-blind, placebo-controlled trial" will be assessed using several parameters. The primary endpoint is the number of days alive without **delirium** or coma at day 14 (D14) following randomization. This will be measured to determine the impact of early 7-day administration of levetiracetam in patients with septic shock hospitalized in the ICU.

Secondary endpoints include mortality rates in intensive care, in hospital, at day 28 (D28) and day 90 (D90), overall survival at D90, and the number of days without mechanical ventilation at D28. Additional secondary endpoints are the number of days alive outside the intensive care unit at D28 and outside the hospital at D90, cumulative incidence and type of epileptic seizures between day 1 (D1) and D14, the time between cessation of sedation and awakening, severity of cognitive impairment at D90, severity of anxiety and depression at D90, presence of post-traumatic stress at day 90 (J90), health-related quality of life at D90, and autonomy in daily life at D90.