Phase III Multicenter Open-Label Trial Evaluating Rituximab Efficacy in Psychiatric Disorders with Autoimmunity

The primary objective of this Phase III randomized, multicenter open-label clinical trial is to evaluate the **efficacy** of immunotherapy at 3 months for patients with psychotic symptoms and proven auto-immunity, when added to ongoing psychiatric care, with or without standard psychotropic treatment. This is clinically relevant as it aims to determine the potential benefits of immunomodulatory therapy in enhancing treatment outcomes for psychiatric disorders associated with dysimmunity.

Secondary objectives include:

• Assessing the efficacy of immunotherapy at 1, 6, and 12 months when added to ongoing psychiatric care.
• Evaluating the prevalence of auto-immune psychosis in France.
• Assessing the safety of immunotherapy in cases of psychotic symptoms.
• Evaluating the kinetic of auto-antibodies at 3 months.

The clinical trial focuses on evaluating the efficacy of immunotherapy for patients with **psychotic symptoms** and proven auto-immunity, in addition to ongoing psychiatric care. The study population includes both male and female participants, encompassing a wide age range from children aged 6 years to adults. The trial does not specifically target a vulnerable population. Participants were selected based on the presence of a first acute or relapse of psychotic disorders, as defined by the PANSS scale for adults and adolescents, and the Kiddie SADS-PL scale for children. The trial also requires a biological diagnosis of pathogenic CNS autoantibodies in the blood for further inclusion. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet and physical activity are not specified in the trial data. Key inclusion criteria include informed consent and, for women of childbearing potential, effective contraception during the trial and for at least 12 months after the last rituximab administration. The trial does not include individuals with significant heart disease unless a normal ECG is present.

The clinical trial is a **Phase III** randomized, multicenter, open-label study designed to evaluate the efficacy of immunomodulatory therapy in patients with psychiatric disorders associated with proven dysimmunity. The primary objective is to assess the efficacy of immunotherapy, specifically **rituximab**, in conjunction with ongoing psychiatric care over a period of three months. The trial is expected to commence recruitment on October 15, 2024, and conclude by December 15, 2027. Participants will be randomly assigned to receive either the investigational treatment or standard care, ensuring a controlled comparison of outcomes.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, presence of psychotic disorders, and biological markers of autoimmunity. The trial includes two steps: Step 1 involves initial inclusion based on psychotic disorder diagnosis, while Step 2 requires additional criteria such as the presence of pathogenic CNS autoantibodies and a specific MDC scale score. Follow-up visits will occur at regular intervals to monitor the remission of psychiatric symptoms, with primary endpoints measured at three months. Secondary endpoints include assessments of general functioning, cognitive abilities, and the persistence of autoimmunity.

The expected duration of participant involvement is up to 12 months, with conditions for early termination including adverse events, withdrawal of consent, or non-compliance with study protocols. The study will utilize scales such as the BPRS-E, ABC, GAF, MOCA, and PANSS to evaluate psychiatric symptoms and overall health. Safety assessments will include monitoring for adverse events and infections. The trial aims to provide valuable insights into the role of immunotherapy in managing psychiatric disorders with an autoimmune component.

The clinical trial involves the administration of **MabThera**, a **500 mg concentrate for solution for infusion**. The active substance in this experimental medication is **rituximab**, a protein-based therapeutic agent. Rituximab is classified under the ATC code L01FA01 and is utilized in the treatment of various conditions due to its immunomodulatory properties. The pharmaceutical form of MabThera is a solution for infusion, and it is administered intravenously. The dosing regimen for this trial specifies a maximum daily dose of 1000 mg, with a total maximum dose of 2000 mg over the treatment period. The treatment duration is set for a maximum of 2 cycles, with each cycle corresponding to a specific time unit as defined in the study protocol. The administration of rituximab is conducted under controlled conditions to ensure participant safety and adherence to the dosing schedule.

In addition to the experimental treatment, participants may continue to receive ongoing psychiatric care, which may include standard psychotropic treatment. This non-experimental treatment is considered standard-of-care therapy and is not part of the investigational product assessment. The trial aims to evaluate the efficacy of adding immunotherapy to the existing psychiatric treatment regimen for patients with psychotic symptoms and proven auto-immunity. Compliance with the treatment protocol is monitored throughout the study to ensure accurate assessment of the therapeutic outcomes. The trial is designed to provide insights into the potential benefits of immunomodulatory therapy in psychiatric disorders with an autoimmune component.

The efficacy of the immunomodulatory therapy in the clinical trial will be assessed primarily through the remission of psychiatric symptoms at 3 months. For adult and adolescent patients, this is defined as a 20% decrease from baseline on the Brief Psychiatric Rating Scale-Expanded (BPRS-E). For children aged between 6 and 16 years, a 25% decrease from baseline on the Aberrant Behavior Checklist (ABC) scale is required. Secondary endpoints include various assessments for both adults and children. These include general functioning measured by the Global Assessment of Functioning (GAF) scale, cognitive assessment using the Montreal Cognitive Assessment (MOCA) scale, and neurologic evaluation with the KREBS and BUSH scales. Psychotic disorders will be measured using the Positive and Negative Syndrome Scale (PANSS), and the evolution of depressive and manic disorders will be assessed with the Montgomery-Åsberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) for adults and adolescents, and the Children's Depression Rating Scale (CDRS) and YMRS for children. Additional assessments for all participants include the persistence rate of autoimmunity in psychiatric disorders at baseline, remission of psychiatric symptoms at months 1, 6, and 12, evaluation of severity and improvement with the Clinical Global Impressions-Severity (CGI-S) and Clinical Global Impressions-Improvement (CGI-I) scales, and the level of autoimmune antibodies at 3 months. The frequency and nature of serious and non-serious adverse events, as well as infections, will also be monitored in each arm of the trial.