Evaluation of Efficacy, Safety, and Pharmacokinetics of Increased Ocrelizumab Dose in Adults with Relapsing Multiple Sclerosis: A Phase IIIb Randomized Controlled Trial

The primary objective of this study is to demonstrate the **superiority** of a higher dose of ocrelizumab over the approved dose in patients with **Relapsing Multiple Sclerosis**. This is assessed by evaluating the risk reduction in composite confirmed disability progression (cCDP) sustained for at least 12 weeks. This objective is clinically relevant as it aims to establish a more effective dosing regimen that could potentially improve patient outcomes by slowing disease progression.

Secondary objectives include: - Demonstrating the superiority of a higher dose of ocrelizumab over the approved dose based on various clinical endpoints such as time to onset of 24-week cCDP, time to onset of cCDP48, and others. - Evaluating the reduction in Neurofilament light chain protein (NfL) levels at Week 48 for both dosing groups. - Assessing the safety profile of a higher dose compared to the approved dose. - Evaluating serum exposure to ocrelizumab in all patients. - Characterizing the pharmacodynamic (PD) profile of ocrelizumab. - Evaluating the immune response to ocrelizumab. - Identifying biomarkers predictive of response to a higher dose of ocrelizumab.

The clinical trial involves a total of **507 participants** diagnosed with **Relapsing Multiple Sclerosis (MS)**, specifically targeting individuals with either relapsing-remitting MS (RRMS) or active secondary progressive MS (aSPMS) who continue to experience relapses. The study population includes both male and female subjects, aged between **18 and 55 years**. Participants were selected based on specific criteria, including having at least two documented clinical relapses within the last two years or one relapse in the year prior to screening, with no relapses occurring 30 days before screening and at baseline. Additionally, participants must be neurologically stable for at least 30 days prior to randomization and baseline assessments, with an Expanded Disability Status Scale (EDSS) score ranging from 0 to 5.5. A documented MRI of the brain showing abnormalities consistent with MS is also required. The trial includes a vulnerable population, ensuring a comprehensive assessment of the treatment's efficacy across diverse patient profiles. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy, safety, and pharmacokinetics of a higher dose of **ocrelizumab** in adults with **relapsing multiple sclerosis**. The trial aims to demonstrate the superiority of a higher dose of ocrelizumab over the approved dose by assessing the risk reduction in composite confirmed disability progression (cCDP) sustained for at least 12 weeks. The study is expected to run from November 26, 2020, to August 31, 2028, with a maximum treatment period of 322 days for each participant.

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 neurological stability. The primary inclusion criteria include ages 18-55, a diagnosis of relapsing multiple sclerosis according to the revised McDonald Criteria 2017, and a documented history of clinical relapses. The primary endpoint is the time to onset of cCDP sustained for at least 12 weeks, with secondary endpoints including various measures of disability progression and changes in clinical laboratory test results.

Following the screening visit, participants will be randomized to receive either the higher dose or the approved dose of ocrelizumab, with follow-up visits scheduled to monitor efficacy and safety outcomes. The study will include regular assessments of disability status, brain volume changes, and adverse events. The end-of-study visit will conclude the participant's involvement, with data collected on the long-term effects of the treatment.

Participant involvement is expected to last for the duration of the treatment period, with conditions for early termination including significant adverse events or withdrawal of consent. The trial will ensure that all procedures adhere to ethical standards and regulatory requirements, maintaining the integrity and scientific validity of the study.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Ocrelizumab**, marketed as Ocrevus, is a **concentrate for solution for infusion**. It is administered via **intravenous infusion**. The maximum daily dose is 1800 mg, with a total dose not exceeding 23.4 g over a treatment period of 322 days. This medication is provided by Roche Registration GmbH and is used as the primary investigational product in the study.

A **placebo** for ocrelizumab is also utilized in the trial to serve as a comparator. The placebo is designed to mimic the appearance and administration route of the active drug, ensuring the study remains double-blind. The pharmaceutical form and specific administration details of the placebo are not applicable, as it contains no active substance.

**Methylprednisolone** is included as an auxiliary treatment. It is provided as a **powder and solvent for solution for injection/infusion** and is administered via **intravenous infusion**. The maximum daily dose is 100 mg, with a total dose not exceeding 1300 mg over the course of the study. This medication is supplied by Kent Pharma UK Limited.

**Diphenhydramine Hydrochloride** is administered in the form of **tablets**, with each tablet containing 50 mg of the active substance. The maximum daily dose is 50 mg, and the total dose should not exceed 650 mg throughout the treatment period. This medication is provided by Crescent Pharma Limited and can be administered orally or intravenously.

**Paracetamol** is also used as an auxiliary treatment in the form of **tablets**, each containing 500 mg of the active substance. The maximum daily dose is 1 g, with a total dose not exceeding 13 g over the study duration. This medication is supplied by Galpharm Healthcare Limited and is administered orally.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimens. The study is designed to evaluate the efficacy, safety, and pharmacokinetics of a higher dose of ocrelizumab in adults with relapsing multiple sclerosis, with the primary objective of demonstrating its superiority over the approved dose in reducing the risk of composite confirmed disability progression.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the impact of a higher dose of ocrelizumab in adults with **Relapsing Multiple Sclerosis**. The primary endpoint is the time to onset of composite confirmed disability progression (cCDP) sustained for at least 12 weeks. This is defined as the first occurrence of a predefined confirmed progression event measured by the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk Test (T25FWT), or 9-Hole Peg Test (9-HPT).

Secondary endpoints include the time to onset of 24-week and 48-week cCDP, progression independent of relapse activity (PIRA), and time to a ≥20% increase in confirmed T25FWT at 12 and 24 weeks. Additional measures include the annual rate of percent change from baseline in total brain volume, time to confirmed worsening in the Symbol Digit Modalities Test (SDMT), and the 12-Item Multiple Sclerosis Walking Scale (MSWS-12). Biomarker assessments will include changes in Neurofilament Light Chain (NfL) levels, interleukin-6 (IL-6) levels, and B-cell levels in blood. The study will also evaluate the serum concentration of ocrelizumab and the incidence and severity of adverse events according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.