Long-Term Safety and Efficacy of Repeated Rituximab as Adjunctive Therapy in Patients with Schizophrenia Spectrum Disorders (RITS‑LONG)

Primary objective is to evaluate long‑term outcomes and safety of repeated adjuvant rituximab treatment in adults diagnosed with schizophrenia or schizoaffective disorder, addressing the need for durable disease‑modifying strategies in this population. Secondary objectives include: • assessment of long‑term adherence to the study drug; • investigation of biochemical predictors of response and underlying mechanistic pathways; • evaluation of participant and significant‑other satisfaction and experiences using qualitative interviews.

The trial enrolled adult participants of both sexes who had previously taken part in the RCT‑Rits study and met DSM‑5 diagnostic criteria for schizophrenia or schizoaffective disorder, with a disease duration exceeding two years. All subjects were required to provide informed consent while being clear and oriented, and women of child‑bearing potential had to use effective contraception or abstain for the study duration and one year thereafter. Participants were selected based on prior involvement in the RCT‑Rits trial and verification of the diagnostic criteria; no specific dietary or physical‑activity restrictions were stipulated. The sponsor did not provide the total number of participants, as the reported RowsubjectCount is zero. The investigational agent, the immunomodulatory drug rituximab, was administered as repeated adjuvant therapy to assess long‑term outcomes and safety.

The RITS‑LONG trial is a phase 4, prospective, single‑arm extension study evaluating the long‑term outcomes and safety of repeated adjuvant schizophrenia spectrum disorder treatment with rituximab administered by intravenous infusion (100 mg). Eligible participants must have completed the preceding RCT‑Rits trial, meet DSM‑5 criteria for schizophrenia or schizoaffective disorder, have illness duration > 2 years, and provide informed consent; women of child‑bearing potential must use effective contraception throughout the study and for one year after the final dose. After a screening visit to confirm eligibility, participants receive two rituximab infusions spaced according to the original protocol, followed by scheduled follow‑up visits at approximately 4 months (±1 month) after the second infusion (primary efficacy assessment), and additional visits at predefined time points for secondary assessments including CGI‑I, CGI‑S, PSP, VAS‑Health, SNS, CCSM, I‑CGI‑I, PANSS, biomarker sampling, and satisfaction questionnaires. The end‑of‑study visit occurs roughly 12 months after the last infusion, concluding each participant’s involvement, which may extend up to two years including screening and follow‑up. Early termination may occur for withdrawal of consent, emergence of serious adverse events, or significant protocol non‑compliance. Recruitment commenced in October 2026 and the overall study is planned to close by December 2031.

The investigational product is rituximab, supplied in the pharmaceutical form identified as PHF00230MIG for intravenous administration. Each dose consists of 100 mg (milligram(s)) delivered by infusion. The drug is administered as an adjuvant therapy to participants diagnosed with schizophrenia or schizoaffective disorder, with dosing intervals defined in the study protocol.

Concomitant non‑experimental treatment consists of standard‑of‑care antipsychotic therapy, which may be continued at the discretion of the treating investigator in accordance with local clinical practice. No placebo or alternative comparator is employed in this study. Drug administration is documented in the infusion log, and participant compliance is monitored through scheduled visits, vital‑sign assessments, and laboratory evaluations performed before and after each infusion.

Efficacy will be evaluated primarily by the proportion of participants achieving a rating of more than minimally improved, defined as a CGI‑I score ≤ 2.5, measured at approximately four months (±1 month) after administration of two rituximab infusions. The primary analysis will compare this proportion with a historical placebo response derived from the preceding RCT‑Rits trial, stratified by the initial treatment allocation in that study.

Secondary efficacy will be assessed using clinician‑rated, patient‑reported, and informant‑reported instruments at designated study visits (Time point 1 and Time point 2). Clinical improvement is measured by the proportion of participants with a CGI‑I score ≤ 2.5 at each time point. Illness severity is evaluated with the CGI‑S score. Overall functioning and disability are quantified by the Personal and Social Performance Scale (PSP) score. General well‑being is captured using a Visual Analogue Scale for health (VAS‑Health). Negative symptom severity is assessed with the Self‑Assessment of Negative Symptoms (SNS) total score, and broader psychiatric symptom burden with the Level 1 Cross‑cutting Symptom Measure (CCSM). Informant‑rated improvement is obtained via the Informant‑CGI‑I. Psychotic symptomatology is examined with the PANSS interview at both time points. Changes in peripheral biomarkers are measured through laboratory assays. Patient and significant‑other satisfaction and experience are collected through quantitative questionnaires and qualitative interviews at Time point 1.