A Multicenter Non-Inferiority Trial Comparing Rituximab and Ocrelizumab in Patients with Active Relapsing-Remitting Multiple Sclerosis Aged 18-60 Years

The primary objective of the study titled "Ocrelizumab VErsus Rituximab off-Label at the Onset of Relapsing MS Disease (OVERLORD-MS)" is to establish the **non-inferiority** of the study treatment **rituximab** compared to the comparator **ocrelizumab** in patients with active **relapsing-remitting multiple sclerosis** (RRMS) aged 18-60 years. This objective is clinically relevant as it aims to determine whether rituximab, an off-label treatment, can provide similar therapeutic benefits as ocrelizumab, which is an approved treatment for RRMS. Establishing non-inferiority could potentially expand treatment options for patients with RRMS, offering flexibility in clinical decision-making and potentially impacting treatment guidelines.

The clinical trial involves a study population of **male and female** participants aged between 18 and 60 years, diagnosed with **relapsing-remitting multiple sclerosis** (RRMS) within the last 12 months. The trial aims to compare the efficacy of rituximab with ocrelizumab in patients with active RRMS. Participants are required to be treatment-naïve and exhibit disease activity, defined as at least one relapse or one new MRI lesion in the past year. The Expanded Disability Status Scale (EDSS) score must be 4.0 or lower, and participants should not have any comorbidities that would preclude study participation. The trial does not include a vulnerable population, and participants must be able to understand Norwegian or Swedish and complete the study's treatment or follow-ups. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is a multicenter, non-inferiority study designed to compare the efficacy of **rituximab** with **ocrelizumab** in patients with active relapsing-remitting **multiple sclerosis** (RRMS). The trial employs a randomized, double-blind, controlled design to ensure unbiased results. The study commenced on October 21, 2020, and is expected to conclude by April 30, 2025, with an estimated recruitment start date of November 2, 2020. Participants will be involved in the study for a maximum treatment period of 60 months.

Study visits are structured to include an initial screening visit, where eligibility is confirmed based on criteria such as a diagnosis of RRMS within the last 12 months, age between 18 and 60 years, and an Expanded Disability Status Scale (EDSS) score of 4.0 or less. Following the screening, participants will undergo regular follow-up visits to monitor disease progression and treatment efficacy. The primary endpoint is the proportion of patients with no new or enlarging T2-weighted brain MRI lesions from month 6 to month 24. Secondary endpoints include measures of disability progression and improvement, annual relapse rate, and changes in brain volume and quality of life.

The end-of-study visit will assess the overall outcomes and safety of the treatments. Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or choose to withdraw consent. The trial aims to provide comprehensive data on the comparative effectiveness of rituximab and ocrelizumab in managing RRMS, contributing valuable insights into treatment strategies for this condition.

The clinical trial involves the administration of **Ocrelizumab**, marketed under the name Ocrevus, which is provided as a 300 mg **concentrate for solution for infusion**. This pharmaceutical form is intended for **intravenous infusion**. The maximum daily dose of Ocrevus is 600 mg, with a total maximum dose of 3000 mg over the course of the treatment period. The treatment period is set to a maximum of 60 days. Ocrelizumab is a protein-based therapeutic agent, specifically classified under the ATC code L04AA36. The administration of Ocrevus is monitored to ensure compliance with the dosing schedule and to assess any potential adverse reactions during the infusion process.

The comparator treatment in this study is **Rituximab**, marketed as MabThera, which is also provided as a **concentrate for solution for infusion** at a concentration of 500 mg. Similar to Ocrevus, MabThera is administered via **intravenous infusion**. The maximum daily dose for Rituximab is 1000 mg, with a total maximum dose of 3000 mg over the treatment period, which is also capped at 60 days. Rituximab, like Ocrelizumab, is a protein-based therapeutic agent and is classified under the ATC code L01FA01. The administration of MabThera is carefully monitored to ensure adherence to the dosing regimen and to manage any infusion-related reactions.

Both Ocrelizumab and Rituximab are provided by Roche Registration GmbH and are not formulated for pediatric use. The trial is designed to compare the efficacy and safety of these two treatments in patients with active relapsing-remitting multiple sclerosis. Participant compliance with the treatment protocol is closely monitored throughout the study to ensure the integrity of the trial data and the safety of the participants.

The efficacy of the clinical trial titled "Ocrelizumab VErsus Rituximab off-Label at the Onset of Relapsing MS Disease (OVERLORD-MS)" will be assessed using a series of primary and secondary endpoints. The primary endpoint is the proportion of patients with no new or enlarging T2-weighted brain MRI lesions from month 6 (re-baseline) to month 24. Secondary endpoints include various measures of disability progression and improvement, such as the proportion of patients with 6-months confirmed disability progression (6M-CDP) and 6-months confirmed disability improvement (6M-CDI) as measured by the Expanded Disability Status Scale (EDSS) from baseline to month 24. Additional secondary endpoints include the annual relapse rate, the proportion of patients without relapses, and changes in brain volumes from baseline to month 24.

Other secondary endpoints involve assessments of functional performance, such as the Timed 25-Foot Walk (T25FW), the 9-Hole Peg Test (9-HPT), and the Symbol Digit Modalities Test (SDMT), with specific criteria for confirmed disability progression. The trial will also evaluate the proportion of patients with no new gadolinium-enhancing T1-weighted brain MRI lesions at specified time points, changes in quality of life as measured by the MS Impact Scale 29 (MSIS-29), and changes in health-related anxiety and depression using the Hospital Anxiety and Depression Scale (HADS). The frequency of serious adverse events (SAE), serious adverse reactions (SAR), and adverse events of special interest (AESI) will be monitored throughout the 24-month treatment period.