Noisy Rebels; Non-inferiority study of rituximab compared to ocrelizumab in relapsing MS

The primary objective of this study is to evaluate the **non-inferiority** of **rituximab** compared to **ocrelizumab** for the treatment of patients with relapsing **multiple sclerosis** who have an indication to start anti-CD20 therapy. This is clinically relevant as it may provide an alternative therapeutic option for managing relapsing multiple sclerosis, potentially offering similar efficacy with different safety or cost profiles. The study does not list any secondary objectives.

The clinical trial focuses on individuals diagnosed with **multiple sclerosis**, specifically those with relapsing forms of the disease. The study population includes both male and female participants aged between 18 and 65 years. Participants are required to have an indication to start anti-CD20 therapy, as determined by their treating neurologist, and must be able to understand written and spoken Dutch or English. The trial does not include vulnerable populations. The sponsor has not provided information regarding the total number of participants. Participants' general health status is assessed with a screening EDSS score of 6.5 or lower. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the **non-inferiority** of **rituximab** compared to **ocrelizumab** in patients with relapsing **multiple sclerosis** (MS) who have an indication to start anti-CD20 therapy. This study is structured as a randomized, double-blind, controlled trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments, thereby minimizing bias. The trial is expected to span a duration from December 2022 to March 2026, with participant involvement lasting up to 24 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and ability to provide informed consent. Following successful screening, participants will be randomized to receive either rituximab or ocrelizumab, both administered as a **solution for infusion** via the **intravenous** route. The primary endpoint is the proportion of patients with no new or enlarged T2 lesions on brain MRI between month 6 and month 24. Secondary endpoints include the annual relapse rate and the proportion of patients with no relapses or contrast-enhancing lesions over the same period.

Study visits will occur at regular intervals to monitor safety, efficacy, and adherence to the treatment protocol. These visits will include assessments such as MRI scans, clinical evaluations, and laboratory tests. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the long-term effects of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with the study protocol, or choose to withdraw consent.

The clinical trial involves the administration of several **experimental medications** and comparator treatments, primarily focusing on the use of **rituximab** and **ocrelizumab** for the treatment of relapsing multiple sclerosis (MS). The experimental medications include MabThera, Rixathon, Truxima, and Ruxience, all of which contain the active substance rituximab. These medications are provided in the form of a concentrate for solution for infusion, with available dosages of 100 mg and 500 mg. The administration route for these medications is intravenous, with a maximum daily dose of 1000 mg and a total maximum dose of 60000 mg over a treatment period of up to 1560 days. The rituximab products are manufactured by various organizations, including Roche Registration GmbH, Sandoz GmbH, Celltrion Healthcare Hungary Kft, and Pfizer Europe MA EEIG.

In addition to the rituximab-based treatments, the trial also includes the use of Ocrevus, which contains the active substance **ocrelizumab**. Ocrevus is also provided as a concentrate for solution for infusion, with a dosage of 300 mg. The administration route is intravenous infusion, with a maximum daily dose of 600 mg or 1200 mg, depending on the specific formulation, and a total maximum dose of 36000 mg over the same treatment period of 1560 days. Ocrevus is manufactured by Roche Registration GmbH. The trial aims to assess the non-inferiority of rituximab compared to ocrelizumab in patients with relapsing MS who have an indication to start anti-CD20 therapy.

Throughout the trial, participant compliance with the dosing schedules will be monitored to ensure adherence to the prescribed treatment regimens. The trial does not include any additional non-experimental treatments such as standard-of-care therapy or placebo. The focus remains on evaluating the efficacy and safety of the rituximab and ocrelizumab treatments in the specified patient population.

The efficacy of the clinical trial comparing **rituximab** to ocrelizumab in patients with relapsing multiple sclerosis (MS) will be assessed using both primary and secondary endpoints. The primary endpoint is the proportion of patients with no new or enlarged T2 lesions on brain MRI between month 6 and month 24 of treatment in each arm. This endpoint will provide insight into the effectiveness of the treatment in preventing disease progression as visualized through MRI imaging.

Secondary endpoints include several measures of disease activity and progression. These are: the annual relapse rate from baseline to month 24 and from month 6 to month 24, the proportion of patients with no relapses from baseline to month 24 and from month 6 to month 24, the time to first relapse, the proportion of patients with no contrast-enhancing lesions between baseline and month 24 and between month 6 and month 24, and the average number of new/enlarged T2 lesions. These endpoints will be measured at specified intervals to evaluate the sustained efficacy of the treatment over the course of the trial.