Randomized Controlled Trial of Rituximab Versus Placebo in Adults with Schizophrenia Spectrum Disorder

The primary objective of this study is to evaluate the efficacy of **rituximab**, an immunomodulatory drug, in improving clinical outcomes for patients diagnosed with **schizophrenia spectrum disorder (SSD)**. The treatment response is defined as a ≥ 30% improvement in the Positive and Negative Syndrome Scale (PANSS) combined with a clinician-rated Clinical Global Impressions-Improvement (CGI-I) score of 1 or 2, indicating very much improved or much improved, at week 12. This objective is clinically relevant as it aims to determine the potential of rituximab to significantly enhance the management of SSD, a condition characterized by chronic and severe mental health symptoms.

Secondary objectives include: - Assessing changes in the Personal and Social Performance Scale (PSP) to measure overall disability from baseline up to weeks 12 and 24. - Evaluating the proportion of responders to treatment, defined as those rated as much or very much improved since baseline according to CGI-I up to weeks 12 and 24. - Measuring improvement since baseline using CGI-I up to weeks 12 and 24. - Comparing severity according to the Clinical Global Impressions-Severity (CGI-S) scale at weeks 12 and 24. - Monitoring improvement in PANSS up to week 24 compared to baseline. - Analyzing differences in patient self-rated health using the Visual Analogue Scale (VAS-health) and Patient Global Evaluation (PGE) since baseline at weeks 12 and 24. - Investigating baseline levels of inflammatory markers in relation to treatment response. - Evaluating the safety and tolerability of rituximab during treatment for SSD. - Observing changes in brain morphology and/or activity using functional MRI (fMRI). - Examining mental health symptom domains using the Level 1 Cross-cutting symptom measure of global symptom severity in relation to response.

The clinical trial involves participants diagnosed with **schizophrenia spectrum disorder (SSD)**, as defined by the Diagnostic and Statistical Manual for Mental Disorders, 5th edition (DSM-5). The study population includes both male and female subjects, aged between 18 to 55 years, who have experienced a psychiatric illness for more than one year. Participants are required to have a minimum score of 4 in the Clinical Global Impression-Severity (CGI-Severity) at baseline and must be insufficiently recovered from previous antipsychotic treatments. Female participants with any risk for pregnancy are expected to use contraceptives or practice abstinence if it aligns with their normal and preferred lifestyle. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. Participants were selected based on their ability to be lucid and oriented to person, place, time, and situation when providing informed consent.

The clinical trial is designed as a **randomized**, **controlled** study to evaluate the efficacy of **rituximab** in adults diagnosed with **schizophrenia spectrum disorder (SSD)**. The trial will compare the effects of rituximab, administered via **infusion**, against a placebo (NaCl) to determine improvements in psychiatric symptoms. The primary objective is to assess whether patients show a ≥30% improvement in the Positive and Negative Syndrome Scale (PANSS) and a Clinical Global Impression-Improvement (CGI-I) score of 1 or 2, indicating very much improved or much improved, at week 12. The trial is expected to run until December 31, 2026, with recruitment having commenced on March 20, 2023.

Participants will be involved in the study for a maximum treatment period of one month, with the total trial duration extending over several years to accommodate recruitment and follow-up. The study includes several key visits: an initial **screening** visit to confirm eligibility based on criteria such as age (18-55 years), duration of illness, and diagnosis according to DSM-5, followed by baseline assessments. Subsequent visits will occur at regular intervals to monitor treatment response and safety, with the final visit marking the end of the study. During these visits, assessments will include PANSS, Personal and Social Performance Scale (PSP), and CGI scales, among others.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial is conducted under a double-blind design, ensuring that neither the participants nor the investigators know which treatment the participants receive, thus minimizing bias. The study aims to provide valuable insights into the potential benefits of rituximab for individuals with SSD, contributing to the broader understanding of treatment options for this condition.

The clinical trial involves the administration of **Rituximab**, an immunomodulatory drug, to evaluate its efficacy in treating adults diagnosed with schizophrenia spectrum disorder. **Rituximab** is a monoclonal antibody targeting the CD20 antigen on B-cells, classified under the ATC code L01XC02. The pharmaceutical form of **Rituximab** used in this study is denoted as PHF00230MIG. The drug is administered via **infusion**, with a maximum daily and total dose of 1000 mg. The treatment period is limited to a maximum of one day. The study aims to assess the improvement in psychiatric symptoms, with treatment response defined as a ≥ 30% improvement in the Positive and Negative Syndrome Scale (PANSS) combined with a clinician-rated Clinical Global Impression-Improvement (CGI-I) score of 1 or 2 at week 12.

In addition to the experimental treatment, a placebo comparator is utilized in the study. The placebo consists of NaCl, administered in the same manner as **Rituximab** to maintain blinding and ensure the integrity of the trial. The placebo is also delivered via infusion, with the same administration schedule as the active treatment. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol and to accurately assess the efficacy of the treatment.

Efficacy in the clinical trial involving **Rituximab** for the treatment of schizophrenia spectrum disorder (SSD) will be assessed using several parameters. The primary endpoint is the Positive and Negative Syndrome Scale (PANSS), which measures the severity of symptoms in patients with schizophrenia. This scale involves a clinical interview where patients are rated on 30 different symptoms, with scores ranging from 1 to 7 for each symptom, resulting in a total score between 30 and 210. A treatment response is defined as a ≥ 30% improvement in PANSS scores combined with a clinician-rated Clinical Global Impression-Improvement (CGI-I) score of 1 or 2, indicating very much improved or much improved, at week 12.

Secondary endpoints include the Personal and Social Performance Scale (PSP), which assesses patient functioning in four main areas and expects a 25% reduction in scores for responders. The CGI-I and Clinical Global Impression-Severity (CGI-S) scales will also be used, with CGI-I measuring symptom change on a 7-point Likert scale and CGI-S assessing overall clinical severity. Additional measures include the Visual Analogue Scale for health (VAS-health), Patient’s Global Evaluation (PGE), and baseline levels of inflammatory markers. Changes in brain activity and morphology, as well as the Level 1 Cross-cutting symptom measure of global symptom severity, will also be evaluated. These assessments will be conducted at baseline and at specified endpoints to determine the efficacy of the treatment.