Evaluation of Ketamine on Therapy Intensity and Intracranial Pressure in Acute Traumatic Brain Injury: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this clinical trial is to demonstrate that the addition of **ketamine** to the sedative regimen for intracranial pressure (ICP) control in patients with **traumatic brain injury** (TBI) results in a reduction of the therapeutic intensity of ICP-reducing measures, as assessed by the Therapy Intensity Level (TIL) score. This is clinically relevant as it may offer a more effective management strategy for controlling ICP in TBI patients, potentially improving outcomes and reducing the need for more invasive interventions.

Secondary objectives include demonstrating that **ketamine** does not cause an increase in ICP. This is important to ensure the safety and efficacy of **ketamine** as a therapeutic option in this patient population.

The clinical trial focuses on patients with **traumatic brain injury** (TBI) and aims to evaluate the impact of adding ketamine to the sedative regimen for intracranial pressure (ICP) control. The study population includes both male and female subjects, aged 18 years and older, who have been admitted to the Intensive Care Unit. Participants are required to have an ICP monitor in place within 72 hours after admission to the initial hospital and must require sedation. The trial involves a vulnerable population, as it includes individuals with significant medical conditions requiring intensive care. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **randomized**, **controlled**, **double-blind** study to evaluate the effects of **ketamine** on therapy intensity level and intracranial pressure in patients with **traumatic brain injury**. The trial aims to demonstrate that adding ketamine to the sedative regimen for intracranial pressure (ICP) control results in a reduction of the therapeutic intensity of ICP-reducing measures, assessed by the Therapy Intensity Level (TIL) score. The study will involve adult patients aged 18 years or older who have been admitted to the Intensive Care Unit (ICU) within 72 hours of hospital admission, with an ICP monitor in place and requiring sedation.

The trial will commence with a screening visit to confirm eligibility based on the inclusion criteria, which include the presence of a traumatic brain injury and the need for sedation in the ICU. Following randomization, participants will receive either the investigational product, Ketalar 50 mg/ml solution injectable, or a placebo, 0.9% NaCl, administered via **intravenous infusion**. The primary endpoints include a reduction in the cumulative daily TIL score and the number of high ICP episodes, defined as an ICP greater than 22 mmHg for more than 25 minutes. Secondary endpoints will assess various parameters such as average ICP per 24 hours, total duration of sedative treatment, and length of stay in the ICU and hospital.

Participants will be involved in the study for a maximum treatment period of four days, with follow-up visits scheduled to monitor safety and efficacy outcomes. The trial is expected to conclude by December 31, 2025. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or any situation where continued participation is deemed unsafe by the investigator. The study's design ensures rigorous assessment of the investigational product's impact on the specified endpoints, contributing valuable data to the understanding of ketamine's role in managing traumatic brain injury.

The clinical trial involves the administration of **Ketamine**, marketed under the name Ketalar 50 mg/ml solution injectable. This experimental medication is provided in the form of a **solution for injection**. The active substance, ketamine, is of chemical origin and is classified under the ATC code N01AX03. The administration route for Ketalar is via **intravenous infusion**. The dosing regimen specifies a maximum daily dose of 1 mg/kg/h, with a total maximum dose of 120 mg/h. The treatment period is limited to a maximum of 4 days. The pharmaceutical product is manufactured by Pfizer S.A. (Belgium) and holds the marketing authorization number BE005293 in Belgium.

In addition to the experimental treatment, the study utilizes a non-experimental treatment, 0.9% NaCl, which serves as a placebo. This product does not have a specified pharmaceutical form or active substance and is not associated with a marketing authorization number. The role of 0.9% NaCl in the trial is to act as a comparator to the experimental treatment, ensuring the study's double-blind design. The administration details, including dosage and route, are not specified for the placebo, as it is used to maintain the study's blinding integrity.

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoints include the reduction in cumulative daily Therapeutic Intensity Level (TIL) score and the number of high intracranial pressure episodes, defined as an intracranial pressure (ICP) greater than 22 mmHg for more than 25 minutes. These parameters will be measured to evaluate the effect of **ketamine** on therapy intensity level and intracranial pressure in patients with acute brain injury.

Secondary endpoints encompass a range of measures to provide a comprehensive assessment of efficacy. These include the average intracranial pressure per 24 hours, total duration of the first episode of sedative treatment, total duration of the first episode of mechanical ventilation, and total doses of propofol and midazolam per 24 hours. Additional secondary endpoints are the length of stay in the Intensive Care Unit (ICU) and hospital, average daily Richmond Agitation and Sedation Score (RASS) per hour, delirium-free days assessed with the Intensive Care Delirium Screening Checklist (ICDSC) or Confusion Assessment Method-ICU (CAM-ICU) every 8 hours, Extended Glasgow Outcome Score (GOSE) at 6 months post-injury, and the incidence of barbiturate coma, decompressive craniectomy, and Propofol-Related Infusion Syndrome (PRIS).