TRIO: A prospective randomized Trial of non-inferiority comparing RItuximab versus Ocrelizumab in relapsing-remitting multiple sclerosis.

The primary objective of this study is to demonstrate the **non-inferiority** of **rituximab** compared to **ocrelizumab** in patients with active relapsing-remitting **multiple sclerosis** (MS) by evaluating the percentage of patients without disease activity over a period of two years. This is clinically relevant as it aims to establish rituximab as a viable alternative to ocrelizumab, potentially offering more treatment options for patients with this condition.

Secondary objectives include comparing the two groups (ocrelizumab vs rituximab) at two years based on several clinical criteria: annualized relapse rate, time of onset of the first relapse, percentage of patients without relapses, and percentage of patients without disability progression. Additionally, the study will assess patients' quality of life, patients' experience, and the medico-economic impact, specifically the cost-utility ratio. MRI parameters, such as gadolinium-enhancing lesions and new T2 lesions from month 6 to month 24, will also be evaluated.

The clinical trial involves participants diagnosed with **Multiple Sclerosis**, specifically those with active relapsing forms of the disease. The study population includes both male and female subjects, aged between 18 and 55 years, who are generally in good health with an Expanded Disability Status Scale (EDSS) score of 5 or less. Participants were selected based on their presentation of relapsing-remitting MS according to the Mac Donald 2017 criteria, with evidence of clinical or radiological activity, such as at least one relapse or a new T2 lesion within the last 12 months. The trial does not include a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants. Key inclusion criteria include having a brain MRI within six months before inclusion, effective contraception for women of childbearing potential, and coverage by social insurance. Participants must have signed an informed consent form to be eligible for the study.

The clinical trial is designed to evaluate the **non-inferiority** of **rituximab** compared to **ocrelizumab** in patients with **relapsing-remitting multiple sclerosis**. This is a prospective, randomized, double-blind, controlled trial. The primary objective is to assess the percentage of patients without disease activity at two years. The trial is expected to last until July 31, 2031, with recruitment having started on January 31, 2023. Participants will be involved for a maximum treatment period of 24 months.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, disease activity, and **Expanded Disability Status Scale (EDSS)** score. Follow-up visits will occur at regular intervals, including assessments at six months (M6) and 24 months (M24), to evaluate clinical and **MRI** criteria. The end-of-study visit will finalize data collection and assess the primary and secondary endpoints, including relapse rates, disability progression, and quality of life measures.

Participants are expected to adhere to the study protocol for the entire duration unless specific conditions necessitate early termination. These conditions include significant adverse events, withdrawal of consent, or non-compliance with study procedures. The trial will employ a double-blind methodology to ensure unbiased results, with neither participants nor investigators aware of the treatment allocation. The trial's design and procedures are meticulously planned to ensure the integrity and reliability of the findings, contributing valuable insights into the management of **multiple sclerosis**.

The clinical trial involves the administration of **Rituximab**, a **concentrate for solution for infusion**. Rituximab is an active substance classified under the ATC code L01XC02. The pharmaceutical form is a concentrate that is prepared for infusion, and it is administered via the intravenous route. The maximum daily dose of Rituximab is 1000 mg, with a total maximum dose of 6000 mg over a treatment period of 24 months. The administration schedule is designed to ensure participant compliance, with regular monitoring to assess adherence to the dosing regimen. Rituximab is not a pediatric formulation and is not classified as an orphan drug.

In this trial, **Ocrevus** (ocrelizumab) is used as a comparator treatment. Ocrevus is also a **concentrate for solution for infusion** and is administered intravenously. The active substance, ocrelizumab, is categorized under the ATC code L04AA36. The maximum daily dose for Ocrevus is 300 mg, with a total maximum dose of 1800 mg over a 24-month treatment period. The dosing schedule is structured to maintain participant compliance, with monitoring protocols in place to ensure adherence. Similar to Rituximab, Ocrevus is not a pediatric formulation and is not designated as an orphan drug.

The trial aims to compare the efficacy of Rituximab and Ocrevus in patients with relapsing-remitting multiple sclerosis, focusing on the percentage of patients without disease activity over a two-year period. Both treatments are administered as solutions for infusion, and the trial is designed to evaluate the non-inferiority of Rituximab compared to Ocrevus. Participant compliance is closely monitored throughout the study to ensure the integrity of the trial results.

Efficacy in this clinical trial will be assessed by evaluating the **percentage of patients without disease activity** at two years. Disease activity is defined by the occurrence of at least one relapse between baseline and month 24 (M24) or MRI activity, which includes Gd-enhancing lesions at month 6 (M6) or the appearance of at least one new T2 lesion between M6 and M24. Secondary endpoints include clinical criteria such as the annualized relapse rate, mean time to the first relapse, and the percentage of patients without relapse at M24. Disability progression will also be assessed, defined as an increase in the Expanded Disability Status Scale (EDSS) score, confirmed at six months.

Additional MRI criteria will be evaluated, including the mean number of Gd-enhancing lesions at M6 and the percentage of patients with at least one Gd-enhancing lesion at M6. The mean number of new or enlarging brain T2 lesions from M6 to M24 and the percentage of patients with one or more new or enlarging brain T2 lesions during this period will also be measured. Quality of life will be assessed using changes in the EQ5D-5L and MusiQOL scores from baseline to every six months until M24. Patient experience will be evaluated through changes in the Musicare score from baseline to M12 and M24. The Incremental Cost-Effectiveness Ratio (ICER) will be calculated to compare the cost per Quality-Adjusted Life Year (QALY) gained between the ocrelizumab and rituximab groups at 24 months. Safety will be monitored by comparing the number of adverse events and severe adverse events between the two groups.