Evaluation of Early Continuous Intravenous Infusion of Hypertonic Saline Solution on Neurological Outcomes in Traumatic Brain Injury Patients at High Risk of Intracranial Hypertension

The primary objective of this clinical trial is to demonstrate the efficacy of early continuous intravenous infusion of **hypertonic saline solution** (HSS) in improving survival and independence in daily life activities at 6 months for patients with **traumatic brain injury** who are at high risk of intracranial hypertension. This is clinically relevant as it addresses the critical need for effective interventions that can enhance long-term outcomes and quality of life in this patient population.

Secondary objectives include:

• Demonstrating the efficacy of a continuous infusion of HSS on the prevention and treatment of intracranial hypertension, as well as on neurological recovery and quality of life at 6 months.
• Studying the tolerance of the treatment.
• Performing a cost-effectiveness analysis with a 12-month perspective to evaluate economic efficiency.
• Identifying genetic biomarkers associated with response to treatment and long-term recovery.

The clinical trial focuses on patients with **traumatic brain injury** at high risk of intracranial hypertension. The study population includes both male and female participants, aged between 18 and 75 years, who have been admitted to an intensive care unit. Participants are required to have a Glasgow Coma Scale score of 12 or less and must be included in the study within the first 12 hours after intracranial pressure monitoring placement. The trial involves a vulnerable population, and all participants must provide informed and signed consent, as well as have national health insurance. 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 to evaluate the efficacy of early continuous intravenous infusion of **hypertonic saline solution** in improving survival and independence in daily life activities for patients with **traumatic brain injury** at high risk of intracranial hypertension. This study is a single-blinded, multicenter, randomized, controlled trial with a blinded evaluation of the primary outcome. The trial is expected to commence recruitment on November 1, 2025, and conclude by November 1, 2028. Participants will be involved in the study for a maximum treatment period of 7 days, with the primary endpoints being survival at 3 months and moderate to no dependency in activities of daily living at 6 months, assessed by a blinded evaluator.

The trial will include an initial screening visit to confirm eligibility based on criteria such as age between 18 and 75 years, admission to an intensive care unit, a Glasgow Coma Scale score of 12 or less, and inclusion within 12 hours after intracranial pressure monitoring placement. Informed consent and national health insurance are also required. Follow-up visits will assess secondary endpoints, including the evolution of natremia, chloremia, plasma osmolarity over 7 days, therapeutic intensity level, and survival at 1, 6, and 12 months. Additional assessments will include quality-adjusted life years, residency status, and cognitive evaluations at specified intervals.

The end-of-study visit will occur at the conclusion of the 7-day treatment period, with further follow-up assessments conducted at 1, 3, 6, and 12 months post-treatment to evaluate long-term outcomes. Participants may be terminated early from the study if they experience severe adverse events, such as thrombotic events or central-pontine myelinolysis, or if they no longer meet the inclusion criteria. The trial will also monitor for severe hypernatremia and acute kidney injury, with safety and cost-effectiveness analyses conducted over a one-year time horizon. The study aims to provide robust data on the clinical benefits and safety of hypertonic saline solution in this patient population.

The clinical trial involves the administration of **Sodium Chloride** as a **solution for injection**. This experimental medication is administered via **intravenous use**. The maximum daily dose is 120 grams, with a total maximum dose of 663 grams over a treatment period of up to 7 days. The solution is not formulated for pediatric use and is classified as a chemical substance. The role of Sodium Chloride in this trial is auxiliary, supporting the primary treatment objectives.

Another treatment used in the trial is **Mannitol**, provided as a **solution for infusion**. Mannitol is also administered intravenously, with a maximum daily dose of 1 liter and a total maximum dose of 7 liters over a 7-day period. Similar to Sodium Chloride, Mannitol is not a pediatric formulation and is categorized as a chemical substance. In this study, Mannitol serves as a test treatment, playing a central role in evaluating the trial's primary outcomes.

The trial also includes the use of **Sodium Chloride** in a **solution for infusion** form. This auxiliary treatment is administered intravenously, with a maximum daily dose of 60 grams and a total maximum dose of 420 grams over a 7-day period. As with the other treatments, this formulation is not intended for pediatric use and is classified as a chemical substance. The administration of this solution supports the overall treatment strategy within the trial.

The efficacy of the clinical trial will be assessed through a series of co-primary and secondary endpoints. The co-primary endpoints include survival at 3 months and moderate to no dependency in activities of daily living at 6 months. These will be evaluated centrally by a blinded evaluator to ensure objectivity. Secondary endpoints encompass a range of parameters, including the evolution of natremia, chloremia, and plasma osmolarity over 7 days, therapeutic intensity level during the first 7 days, and survival rates at 1, 6, and 12 months. Additionally, quality of life will be measured using the EQ-5D-5L at 1, 3, 6, and 12 months, and cognitive and functional outcomes will be assessed using the G.O.A.T and MOCA, GOS-E at 6 months.

Further secondary endpoints include the rates of severe **hypernatremia** (Na> 160 mmol/L) and acute kidney injury at Month 1, evaluated using the KDIGO score 2-3. Safety assessments will focus on thrombotic events and central-pontine myelinolysis. The trial will also analyze the incremental cost-effectiveness ratio with a one-year time horizon and investigate single nucleotide polymorphisms correlated with clinical outcomes. These efficacy parameters will be collected and analyzed at specified timepoints, ensuring a comprehensive evaluation of the treatment's impact on patients with traumatic brain injury.