Efficacy of Rituximab Versus Placebo in Anti-MAG Neuropathy Patients with Predicted Good Response: A Randomized Controlled Trial

The primary objective of the study is to **demonstrate the efficacy** of rituximab compared to placebo in a subgroup of patients with **anti-MAG neuropathy** who are presumed to be good clinical responders. The improvement in neurological disability will be assessed using the I-RODS score from baseline to 12 months. This objective is clinically relevant as it aims to establish rituximab as a potential therapeutic option for improving neurological outcomes in this specific patient population.

Secondary objectives include:

• Evaluating the efficacy of rituximab versus placebo in improving neurological disability in anti-MAG patients, assessed by the I-RODS score between baseline and 6 months.
• Assessing the efficacy of rituximab versus placebo over baseline, 6 months, and 12 months using various measures: INCAT disability score, six-minute walk test, timed 25-foot walk test, 9-hole peg test, ENMG motor and sensory sum scores, and MUNIX sum score.
• Evaluating the tolerability and short-term safety of rituximab from baseline to 12 months.
• Exploring the correlation between clinical response and changes in anti-MAG antibody titre.

The clinical trial focuses on evaluating the efficacy of rituximab in patients with **anti-MAG neuropathy**. The study population includes both male and female participants, aged 18 years and older, who are presumed to be good clinical responders. Participants are required to have a disease duration of 5 years or less, with documented clinical worsening over the past 24 months. The trial excludes individuals who have received immunoglobulin treatment within 3 months or immunosuppressive therapy, including steroid therapy, within 6 months prior to inclusion. Participants must have an **IgM gammopathy**, either MGUS or WM, and a demyelinating polyneuropathy as per the European Federation of Neurological Societies/Peripheral Nerve Society guidelines. The trial does not involve a vulnerable population. 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 available data.

The clinical trial is designed to evaluate the efficacy of **rituximab** compared to placebo in patients with **anti-MAG neuropathy** who are identified as good clinical responders. This is a randomized, double-blind, controlled trial with an estimated duration from June 2023 to December 2025. Participants will be randomly assigned to receive either rituximab or a placebo, with the primary objective being the improvement in neurological disability as measured by the I-RODS score over a 12-month period. The trial will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress and safety, and a final end-of-study visit to assess outcomes and collect final data.

Participants are expected to be involved in the study for a maximum of 15 months, including the treatment and follow-up periods. The inclusion criteria require participants to be over 18 years of age, with a disease duration of 5 years or less, and specific clinical and laboratory findings such as an anti-MAG titre of 10,000 BTU or more. Exclusion criteria include recent immunoglobulin or immunosuppressive therapy. The primary endpoint is a clinical response defined by a 4-point increase in the I-RODS score between baseline and 12 months. Secondary endpoints include various functional and neurological assessments, as well as monitoring for adverse events.

Participants may be withdrawn from the study early 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 in accordance with ethical guidelines and regulatory requirements, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of **MabThera** 500 mg concentrate for solution for infusion, which contains the active substance **rituximab**. Rituximab is a protein-based therapeutic agent classified under the ATC code L01FA01. The pharmaceutical form of MabThera is a concentrate for solution for infusion, and it is administered via the **intravenous** route. The maximum daily dose is 1 gram, with a total maximum dose of 2 grams over a treatment period of 15 days. The product is manufactured by Roche Registration GmbH and is not indicated for IGA neuropathy as per its marketing authorization. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, the trial utilizes **CHLORURE DE SODIUM COOPER 0,9 %**, a solution injectable containing **sodium chloride** as the active substance. This product serves as a placebo in the study. It is presented as a solution for injection and is administered through **intravenous infusion**. The maximum daily dose is 600 milliliters, with a total maximum dose of 1200 milliliters over a 15-day treatment period. The product is manufactured by Cooperation Pharmaceutique Francaise. Participant compliance with the administration of this placebo is also monitored to maintain the integrity of the trial results.

The efficacy of rituximab in the clinical trial will be assessed by evaluating its impact on neurological disability in patients with anti-MAG neuropathy. The primary endpoint for efficacy is defined as a clinical response, which is measured by a 4-point or greater increase in the I-RODS score from baseline to 12 months. This score is a validated tool used to assess disability in patients with neuropathies.

Secondary endpoints include a variety of assessments to further evaluate the efficacy of the treatment. These include the INCAT disability score, the 6-minute walk test, the Timed 25-foot walk test, the 9-hole peg test, ENMG motor and sensory sum scores, MUNIX sum score, and changes in the **anti-MAG** titre. Additionally, adverse events will be monitored as part of the secondary endpoints to assess the safety profile of the treatment.

The efficacy parameters will be collected and analyzed at specified time points, with the primary endpoint being assessed at the 12-month mark. The use of these comprehensive measures will provide a robust evaluation of rituximab's efficacy in improving neurological outcomes in the targeted patient population.