Evaluation of Bortezomib Efficacy and Safety in Severe Autoimmune Encephalitis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this multicenter, randomized, controlled, double-blinded trial is to evaluate the **efficacy** and **safety** of **bortezomib** in patients diagnosed with severe autoantibody-positive **autoimmune encephalitis**. This study aims to determine the therapeutic potential of bortezomib, a proteasome inhibitor, in managing this condition, which is characterized by inflammation of the brain due to an autoimmune response. The clinical relevance of this objective lies in the potential to improve treatment outcomes for patients with this severe neurological disorder, which currently has limited effective treatment options.

The clinical trial focuses on evaluating the efficacy and safety of **bortezomib** in patients with severe autoantibody-positive **autoimmune encephalitis**. The study population includes both male and female participants aged 18 years and older. Participants are required to have a clinical diagnosis of severe autoimmune encephalitis, characterized by a modified Rankin Scale (mRS) score of 3 or higher, and must have detectable autoantibodies against neuronal surface proteins in cerebrospinal fluid or serum, with detection not older than four weeks prior to randomization. Pre-treatment with rituximab is also a prerequisite. The trial includes potentially fertile patients, who must have a negative pregnancy test if they are up to two years post-menopause. The trial population is selected based on these criteria, and the sponsor has not provided information on the total number of participants. The study involves a vulnerable population, and written informed consent is required from the patient or their legal representative. 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** and safety of **bortezomib** in patients diagnosed with severe autoimmune encephalitis. This is a multicenter, randomized, controlled, double-blind trial. The trial will involve the administration of bortezomib, a chemical compound reconstituted for percutaneous use with saline, over a maximum treatment period of nine weeks. The trial is expected to commence recruitment on August 1, 2024, and conclude by April 30, 2026. Participants will be randomly assigned to receive either the investigational product or a placebo, ensuring the study's double-blind nature.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a clinical diagnosis of severe autoimmune encephalitis, presence of autoantibodies, pre-treatment with rituximab, and age of 18 years or older. The primary endpoint will be assessed 17 weeks after the first administration of the investigational product, with secondary endpoints evaluated at various intervals, including 3, 6, 9, and 13 weeks post-administration. These endpoints include measures such as the modified Rankin Scale (mRS), Glasgow Coma Scale (GCS), length of hospital stay, antibody titers, and neurocognitive function.

The expected length of participant involvement is approximately 17 weeks from the first administration of the investigational product. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or the participant's decision to withdraw consent. The trial will monitor safety concerns related to bortezomib, including potential polyneuropathy, liver enzyme increases, hematotoxicity, gastrointestinal toxicity, and secondary infections. The study aims to provide comprehensive data on the therapeutic potential of bortezomib in treating severe autoimmune encephalitis, contributing valuable insights into its clinical application.

The clinical trial involves the administration of **bortezomib**, a chemical compound used as the experimental medication. Bortezomib is provided in a lyophilized form and requires reconstitution with **saline** for percutaneous use. The pharmaceutical form is identified as PHF00231MIG. The dosage is calculated based on body surface area, with a maximum daily dose of 1.3 mg/m² and a total maximum dose of 15.6 mg/m² over the treatment period. The administration is conducted percutaneously, and the treatment duration is set for a maximum of 9 weeks. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Saline** is utilized as a non-experimental treatment in this study, serving as a reconstitution agent for bortezomib. It is a sodium chloride solution, classified as a chemical substance, and is administered percutaneously. Saline does not have an active therapeutic role in the trial but is essential for the preparation of the experimental medication. The use of saline ensures the proper administration of bortezomib and maintains the integrity of the trial's double-blind design.

The efficacy of **bortezomib** in patients with severe autoimmune encephalitis will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the modified Rankin Scale (mRS) score, evaluated 17 weeks after the first administration of the investigational product. Secondary endpoints include mRS and Glasgow Coma Scale (GCS) scores at 3, 6, 9, and 13 weeks, with GCS also assessed at 17 weeks post-administration. Additional secondary endpoints involve the length of hospital or intensive care unit stay, antibody titers, destruction markers in serum and cerebrospinal fluid, and cellular immune response measured by flow cytometry (FACS) at baseline and 17 weeks. Neurocognitive function will be evaluated using the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMST), Verbal Learning and Memory Test (VLMT), and Neuropsychiatric Inventory (NPI) at baseline and 17 weeks. The number of all adverse events, including serious ones, will be recorded within 17 weeks of the first administration. Safety assessments will focus on potential side effects of bortezomib, such as polyneuropathy, increased liver enzymes, hematotoxicity, gastrointestinal toxicity, and secondary infections.