Evaluation of Ocrelizumab Efficacy and Safety in Multiple Sclerosis Patients from a Prior Phase IIIb/IV Trial

The primary objective of this study is to evaluate the **effectiveness** of ocrelizumab therapy in patients with **multiple sclerosis** (MS) who were previously enrolled in a Roche-sponsored phase IIIb/IV trial. This objective is clinically relevant as it aims to assess the therapeutic impact of ocrelizumab, a monoclonal antibody, in a real-world setting, providing insights into its potential benefits in managing MS, a chronic and often disabling disease.

Secondary objectives include:

• Evaluating different effectiveness measures for ocrelizumab in MS patients who participated in the previous trial, which will help in understanding the broader impact of the therapy on various clinical outcomes.
• Assessing the safety and tolerability of ocrelizumab therapy in these patients, which is crucial for determining the risk-benefit profile of the treatment and ensuring patient safety during long-term use.

The clinical trial involves a total of **260 participants** diagnosed with **multiple sclerosis (MS)**. The study population includes both male and female subjects, with an age range of 18 to 65 years. Participants were selected based on their previous enrollment in a Roche-sponsored phase IIIb/IV trial and their eligibility for roll-over into the MN39158/LIBERTO study. The trial population includes individuals who are able to comply with the study protocol and meet re-treatment criteria with ocrelizumab. Lifestyle considerations such as diet and physical activity are not specified. The study also includes a vulnerable population, and women of childbearing potential are required to agree to remain abstinent or use an acceptable birth control method during the treatment period and for a specified duration after the final dose of ocrelizumab. The sponsor has not provided additional information regarding the general health status or specific lifestyle habits of the participants.

The clinical trial is designed to evaluate the effectiveness and safety of **ocrelizumab** in patients with **multiple sclerosis** who were previously enrolled in a Roche-sponsored Phase IIIb/IV trial. This is a single-arm, open-label, multicenter extension study. The trial is expected to run until March 2025, with recruitment having started in July 2018. Participants will be involved in the study for a maximum treatment period of 72 weeks. The study includes several key visits: an inclusion (screening) visit, multiple follow-up visits, and an end-of-study visit. The inclusion visit will assess eligibility based on criteria such as the ability to comply with the study protocol and meeting re-treatment criteria with ocrelizumab. Follow-up visits will monitor clinical measures related to disease progression, including disability progression and other clinical endpoints. The end-of-study visit will evaluate the overall effectiveness and safety of the treatment.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include the inability to comply with the study protocol or adverse events that outweigh the benefits of continued participation. The study will utilize a range of clinical and patient-reported outcomes to assess the primary and secondary endpoints. Primary endpoints focus on evaluating clinical measures related to disease progression, while secondary endpoints include assessments of disability progression, clinical measures, and MRI-related outcomes. The trial will also monitor patient-reported outcomes such as quality of life and employment status. The study is not categorized as low intervention and is part of a confirmatory/registrational trial, with the development program for the molecule ongoing.

The clinical trial involves the administration of several treatments, including **Methylprednisolone**, **Diphenhydramine Hydrochloride**, **Ocrelizumab**, and **Paracetamol**. Each treatment is administered according to specific protocols to ensure the safety and efficacy of the trial.

**Methylprednisolone** is provided as a 500 mg powder and solvent for solution for injection/infusion. It is a synthetic glucocorticoid administered via **intravenous infusion**. The maximum daily dose is 100 mg, with a total maximum dose of 440 mg over a treatment period of up to 72 hours. This medication is not a pediatric formulation and is manufactured by Kent Pharma UK Limited.

**Diphenhydramine Hydrochloride** is available in 50 mg tablet form and is classified as a synthetic antihistamine. It can be administered both orally and intravenously, with a maximum daily dose of 300 mg and a total maximum dose of 1200 mg over a 72-hour period. This product is also not formulated for pediatric use and is produced by Crescent Pharma Limited.

**Ocrelizumab** is provided as a 300 mg concentrate for solution for infusion, intended for **intravenous infusion**. It is a protein-based therapeutic agent with a maximum daily dose of 600 mg and a total maximum dose of 2.4 grams over a 72-hour treatment period. This medication is not a pediatric formulation and is manufactured by Roche Registration GmbH. It is the primary investigational product in the trial, aimed at evaluating its effectiveness in patients with multiple sclerosis.

**Paracetamol** is administered as a 1000 mg effervescent tablet, which dissolves to form an oral solution. It is a synthetic analgesic and antipyretic compound with a maximum daily dose of 4 grams and a total maximum dose of 16 grams over a 72-hour period. This product is not intended for pediatric use and is produced by Accord Healthcare Polska Sp. z o.o.

Throughout the trial, participant compliance with dosing schedules is monitored to ensure adherence to the treatment protocols. The trial is designed to evaluate the effectiveness and safety of these treatments, particularly focusing on the investigational use of Ocrelizumab in patients with multiple sclerosis.

The efficacy of **ocrelizumab** in patients with Multiple Sclerosis (MS) will be assessed through a series of clinical measures and endpoints. The primary endpoint focuses on evaluating clinical measures related to disease progression over the duration of treatment. Secondary endpoints include a variety of parameters related to disability progression, such as the time to onset of confirmed disability progression (CDP) sustained for at least 24 and 48 weeks, and the proportion of patients with confirmed disability improvement (CDI) or CDP over similar timeframes. Additionally, changes in the Expanded Disability Status Scale (EDSS) score from baseline, time to a 20% increase in the timed 25-foot walk test (T25FWT) and the timed nine-hole peg test (9HPT), and the proportion of patients achieving sustained increases will be evaluated.

Other clinical measures include the time to the first protocol-defined event of disease activity, the time to first relapse, annualized relapse rate, and the proportion of patients who remain relapse-free. The study will also assess the proportion of patients with no evidence of protocol-defined disease activity (NEDA) and no evidence of progression, as measured by EDSS, 9HPT, and T25FW. Cognitive performance changes will be measured using the Symbol Digit Modalities Test (SDMT). MRI-related endpoints will include the total number of T1 Gd-enhancing lesions, new and/or enlarging T2 lesions, changes in total T1 hypointense lesion volume, and changes in brain volume over time. Patient-reported outcomes will be evaluated using the Work Productivity and Activity Impairment Questionnaire (WPAI), SymptoMScreen score, and the Multiple Sclerosis Impact Scale (MSIS)-29. Safety assessments will include the rate and nature of adverse events, changes in vital signs, neurological examinations, clinical laboratory results, and locally reviewed MRI for safety.