Efficacy and Safety Evaluation of Ocrelizumab in Adults with Primary Progressive Multiple Sclerosis: A Phase IIIb Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of ocrelizumab compared with placebo in patients with primary progressive multiple sclerosis (PPMS). This is assessed by the time to onset of composite 12-week confirmed disability progression (CDP), defined as the time from randomization to the first occurrence of at least one of the following progression events: a 20% worsening from baseline in the 9-Hole Peg Test (9-HPT) confirmed for at least 12 weeks, or an increase in the Expanded Disability Status Scale (EDSS) score confirmed for at least 12 weeks. This objective is clinically relevant as it aims to determine the potential of ocrelizumab to slow disease progression in PPMS, a condition characterized by a steady worsening of neurological function.

Secondary objectives include: - Evaluating the efficacy of ocrelizumab compared with placebo based on various endpoints such as time to 12-week and 24-week CDP in 9-HPT and EDSS, annual rate of percent change from baseline in total volume of T2 lesions, and annual rate of percent change from Week 24 in total brain volume. - Assessing the safety of ocrelizumab compared with placebo over time by the proportion of patients with adverse events and laboratory abnormalities. - Evaluating the immunogenicity by the presence of anti-drug antibodies to ocrelizumab during the study relative to baseline and the relationship to pharmacokinetics (PK), pharmacodynamics, efficacy, and safety. - Characterizing the PK profile of ocrelizumab and its pharmacodynamics (PD), measured by blood B-cell levels.

The clinical trial involves a total of **637 participants** diagnosed with **primary progressive multiple sclerosis (PPMS)**. The study population includes both male and female subjects, with an age range corresponding to category code 3, which typically includes adults. Participants were selected based on specific criteria, including a diagnosis of PPMS according to the McDonald criteria and an Expanded Disability Status Scale (EDSS) score between 3.0 and 8.0 at screening and baseline. The trial population also includes individuals with a documented history or presence of certain laboratory findings in cerebrospinal fluid specimens. The study considers lifestyle factors such as neurological stability for at least 30 days prior to baseline. The trial includes a vulnerable population, ensuring a comprehensive evaluation of the efficacy of ocrelizumab compared to placebo. The selection process ensures a representative sample of the PPMS population, allowing for a robust analysis of the treatment's impact.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **ocrelizumab** in adults with **primary progressive multiple sclerosis** (PPMS). The trial aims to assess the time to onset of composite 12-week confirmed disability progression (CDP) as the primary endpoint. Secondary endpoints include time to 12-week and 24-week CDP in Expanded Disability Status Scale (EDSS) and 9-Hole Peg Test (9-HPT), annual rate of percent change in total volume of T2 lesions, and incidence of adverse events. The trial is expected to run until September 2030, with participant recruitment having commenced in October 2019.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as a diagnosis of PPMS according to the McDonald criteria, an EDSS score between 3.0 and 8.0, and specific laboratory findings in cerebrospinal fluid. Following randomization, participants will receive either ocrelizumab or placebo via **intravenous infusion**. The maximum treatment period is 244 weeks. Follow-up visits will be conducted to monitor efficacy and safety outcomes, including MRI scans and laboratory tests. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects.

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 study is structured to ensure rigorous monitoring and data collection, contributing to the understanding of ocrelizumab's impact on PPMS progression.

The clinical trial involves the administration of **Ocrevus**, a 300 mg concentrate for solution for infusion, which contains the active substance **ocrelizumab**. This pharmaceutical form is a concentrate that is prepared for intravenous infusion. The administration route is via **intravenous infusion**, and the maximum daily dose is 600 mg, with a total maximum dose of 6 g over the treatment period. The treatment period is set for a maximum of 244 days. The product has been re-labelled specifically for clinical trial use. The active substance, ocrelizumab, is a protein of non-human origin, and the product is manufactured by Roche Registration GmbH. The trial aims to evaluate the efficacy and safety of ocrelizumab in adults with primary progressive multiple sclerosis.

In addition to the experimental medication, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is designed to mimic the appearance and administration method of Ocrevus but does not contain the active substance. The placebo is administered in the same manner as the experimental drug, ensuring that neither the participants nor the investigators are aware of which treatment is being administered, thus maintaining the study's integrity. The placebo is also prepared for intravenous infusion, although it does not have a specific pharmaceutical form or active substance. The use of a placebo allows for a controlled comparison to assess the true efficacy and safety of ocrelizumab in the study population.

The efficacy of ocrelizumab in the treatment of **Primary Progressive Multiple Sclerosis (PPMS)** will be assessed through a Phase IIIb multicenter, randomized, double-blind, placebo-controlled study. The primary endpoint for evaluating efficacy is the time to onset of composite 12-week confirmed disability progression (CDP). This is defined as the time from randomization to the first occurrence of either a 12-week CDP in the 9-Hole Peg Test (9-HPT) or a 12-week CDP in the Expanded Disability Status Scale (EDSS). The 12-week CDP in 9-HPT is characterized by a 20% worsening from baseline, confirmed for at least 12 weeks. The 12-week CDP in EDSS is defined as an increase of ≥ 1.0 point from baseline in patients with a baseline EDSS score ≤ 5.5, or an increase of ≥ 0.5 point in patients with a baseline EDSS score > 5.5, confirmed for at least 12 weeks.

Secondary endpoints include the time to 12-week CDP in EDSS, time to 24-week CDP in 9-HPT, and time to 24-week CDP in EDSS. Additional secondary measures involve the annual rate of percent change from baseline in total volume of T2 lesions, annual rate of percent change from Week 24 in total brain volume, and the incidence and nature of adverse events. Laboratory test results for hematology and chemistry, presence of anti-drug antibodies (ADA), and pharmacokinetic parameters such as total plasma clearance, volumes of distribution, and area under the concentration-time curve of ocrelizumab will also be evaluated. These assessments will be conducted at specified intervals throughout the study duration, ensuring a comprehensive evaluation of the drug's efficacy and safety profile.