Evaluation of Efficacy, Safety, and Pharmacokinetics of Increased Ocrelizumab Dose in Adults with Primary Progressive Multiple Sclerosis

The primary objective of this study is to demonstrate the superiority of a higher dose of **ocrelizumab** over the approved dose in reducing the risk of composite confirmed disability progression (cCDP) sustained for at least 12 weeks in patients with Primary Progressive Multiple Sclerosis (PPMS). This is clinically relevant as it aims to improve the management of disability progression in PPMS, a condition characterized by a steady worsening of neurological function.

Secondary objectives include:

• Demonstrating the superiority of a higher dose of ocrelizumab over the approved dose based on various clinical and imaging endpoints, such as time to onset of 24-week cCDP, progression independent of relapse activity, and changes in brain volume and neurofilament light chain (NfL) levels.
• Evaluating the ability of both higher and standard doses of ocrelizumab to significantly reduce NfL from baseline at Week 96.
• Assessing the safety profile of a higher dose of ocrelizumab compared to the approved dose.
• Assessing the exposure to ocrelizumab in serum across all patients in both study arms.
• Characterizing the pharmacodynamic 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 **459 participants** diagnosed with **Primary Progressive Multiple Sclerosis (PPMS)**. The study population includes both male and female subjects, aged between 18 and 55 years, who meet specific diagnostic criteria in accordance with the revised McDonald criteria 2017. Participants were selected based on their Expanded Disability Status Scale (EDSS) score, which ranges from 3 to 6.5, and a score of at least 2.0 on the Functional Systems scale for the pyramidal system due to lower extremity findings. Additionally, participants must have a documented MRI of the brain with abnormalities consistent with multiple sclerosis and must be neurologically stable for at least 30 days prior to randomization and baseline assessments. The trial includes a vulnerable population, and lifestyle factors such as diet and physical activity were not specified by the sponsor.

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 **Primary Progressive Multiple Sclerosis (PPMS)**. The trial aims to demonstrate the superiority of a higher dose of ocrelizumab over the approved dose by assessing risk reduction in composite confirmed disability progression (cCDP) sustained for at least 12 weeks. The study is expected to run from December 2020 to July 2029, with participant involvement lasting up to 322 weeks.

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 trial includes multiple follow-up visits to monitor the primary endpoint, which is the time to onset of cCDP sustained for at least 12 weeks, and secondary endpoints, including time to onset of 24-week cCDP and changes in brain volume and neurofilament light chain levels. The end-of-study visit will conclude the participant's involvement, assessing long-term outcomes and safety.

Participants are expected to adhere to the study protocol, with conditions for early termination including significant adverse events or non-compliance with study procedures. The trial will utilize a placebo control, with participants receiving either the investigational higher dose of ocrelizumab, the approved dose, or a placebo, administered via **intravenous infusion**. The study will ensure blinding by maintaining the indistinguishability of the placebo from the active treatment. The trial's comprehensive design aims to provide robust data on the potential benefits of a higher dose of ocrelizumab in managing PPMS.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Methylprednisolone** is provided as a 500 mg powder and solvent for solution for injection/infusion. It is administered via **intravenous infusion**. The maximum daily dose is 100 mg, with a total maximum dose of 1300 mg over a treatment period of up to 322 days. This medication is manufactured by Kent Pharma UK Limited and is classified under the ATC code H02AB04.

**Paracetamol** is administered in the form of 500 mg tablets for **oral use**. The maximum daily dose is 1 gram, with a total maximum dose of 13 grams over the same treatment period. This medication is produced by Galpharm Healthcare Limited and is classified under the ATC code N02BE01.

A **placebo** is also utilized in the trial, referred to as Placebo Ocrelizumab. It does not contain an active substance and serves as a control to evaluate the efficacy of the experimental treatment.

**Ocrelizumab** is the primary experimental medication, provided as a 300 mg concentrate for solution for infusion. It is administered via **intravenous infusion**. The maximum daily dose is 1800 mg, with a total maximum dose of 23.4 grams over the treatment period. This medication is manufactured by Roche Registration GmbH and is identified by the sponsor product code RO 496-4913.

**Diphenhydramine Hydrochloride** is administered as 50 mg tablets, with the option for **oral and intravenous** routes. The maximum daily dose is 50 mg, with a total maximum dose of 650 mg over the treatment period. This medication is produced by Crescent Pharma Limited and is classified under the ATC code R06AA02.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed treatment regimen. The trial aims to evaluate the efficacy, safety, and pharmacokinetics of a higher dose of ocrelizumab in adults with primary progressive multiple sclerosis.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. 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 various measures such as the time to onset of 24-week cCDP, time to onset of cCDP12 independent of protocol-defined relapses, and time to onset of 12-week CDP. Additional secondary endpoints involve the time to a ≥20% increase in 12-week confirmed T25FWT, annual rate of percent change from baseline in total brain volume and thalamic volume, and time to 12-week confirmed 4-point worsening in the Symbol Digit Modalities Test (SDMT). Biomarker assessments include changes in Neurofilament Light Chain (NfL) levels at Week 96, both in the higher dose and approved dose ocrelizumab groups, and levels of Interleukin-6 (IL-6) in blood.

Other secondary endpoints focus on the incidence and severity of adverse events, changes from baseline in clinical laboratory test results, vital signs, serum concentration of ocrelizumab at specified timepoints, and B-cell levels in blood. The proportion of participants achieving 5 or fewer B-cells per microliter of blood, particularly in those with different Fcgamma Receptor 3A (FcγR3A) genotypes, will also be evaluated. The trial will utilize validated scales and laboratory tests to measure these parameters at various timepoints throughout the study duration, which is estimated to conclude by July 2029.