Evaluation of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Ocrelizumab in Pediatric Patients with Relapsing-Remitting Multiple Sclerosis

The primary objective of this study is to characterize the **ocrelizumab** pharmacokinetic (PK) profile in children and adolescents with **Relapsing-Remitting Multiple Sclerosis (RRMS)**. Additionally, the study aims to evaluate the relationship between drug exposure and pharmacodynamic (PD) effects, specifically focusing on the cluster of differentiation 19 (CD19) + B-cell count in this population. Understanding the PK profile and PD relationship is clinically relevant as it informs dosing strategies and therapeutic efficacy, ensuring optimal management of RRMS in pediatric patients.

Secondary objectives include:

• To evaluate the safety of **ocrelizumab** in children and adolescents, which is crucial for identifying potential adverse effects and ensuring patient safety during treatment.
• To assess the development of anti-drug antibodies (ADA) to **ocrelizumab**, which is important for understanding immunogenicity and its impact on treatment efficacy and safety.

The clinical trial involves a total of **12 participants** diagnosed with **Relapsing-Remitting Multiple Sclerosis (RRMS)**. The study population comprises both male and female children and adolescents, with an age range corresponding to category code 2, which typically includes individuals from 2 to 11 years old. Participants were selected based on specific criteria, including a body weight of at least 25 kg, and they must have received all childhood vaccinations as per local or national recommendations. The trial includes individuals who have been diagnosed with RRMS according to the International Pediatric Multiple Sclerosis Study Group criteria and the McDonald criteria 2017. Participants are required to have an Expanded Disability Status Scale (EDSS) score between 0 and 5.5 at screening. Additionally, those who have undergone at least six months of disease-modifying therapy within the past year must show evidence of disease activity post-treatment. The trial population is considered vulnerable, and lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **safety**, tolerability, pharmacokinetics, and pharmacodynamic effects of **ocrelizumab** in children and adolescents diagnosed with **Relapsing-Remitting Multiple Sclerosis (RRMS)**. This study is structured as an open-label, parallel-group trial, and it is categorized as a Phase 4 trial. The trial is expected to run from January 15, 2020, to December 1, 2029, with a maximum treatment period of 288 weeks for each participant. The study involves multiple visits, starting with an inclusion (screening) visit to assess eligibility based on criteria such as body weight, vaccination status, and prior treatment history. Participants must have a body weight of at least 25 kg and meet specific diagnostic criteria for RRMS.

Following the screening, participants will undergo a series of study visits, including regular follow-up visits to monitor the primary endpoints, which include serum concentration of ocrelizumab and levels of CD19+ B-cell count in blood. Secondary endpoints will assess the occurrence and severity of adverse events, changes in vital signs, clinical laboratory test results, and other immunological parameters. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the long-term effects of the treatment.

Participants are expected to remain in the study for the entire duration unless specific conditions necessitate early termination. These conditions include the occurrence of severe adverse events, non-compliance with study protocols, or withdrawal of consent. The trial aims to provide comprehensive data on the pharmacokinetic profile of ocrelizumab and its relationship with pharmacodynamic markers in the pediatric population affected by RRMS.

The clinical trial involves the administration of **Ocrevus** (ocrelizumab), a **concentrate for solution for infusion**. This experimental medication is provided in a 300 mg dosage form and is administered via the **intravenous** route. The maximum daily dose is 600 mg, with a total maximum dose of 7200 mg over a treatment period of 288 days. The product has been re-labelled specifically for clinical trial use. Ocrevus is a protein-based therapeutic agent, and its administration is monitored to ensure compliance with the dosing schedule.

In addition to the experimental treatment, **Paracetamol** 500 mg tablets are used as a non-experimental treatment in the study. Paracetamol is administered orally, with a maximum daily dose of 4000 mg and a total maximum dose of 8064000 mg over the same treatment period of 288 days. This medication serves as a standard-of-care therapy to manage symptoms and is chemically derived.

**Methylprednisolone** is also included in the study as a non-experimental treatment. It is provided as a 500 mg powder and solvent for solution for injection/infusion. The administration route is via **intravenous infusion**, with a maximum daily dose of 100 mg and a total maximum dose of 1200 mg over 288 days. Methylprednisolone is a chemically derived corticosteroid used to manage inflammation and immune responses.

Additionally, **Diphenhydramine Hydrochloride** is administered in tablet form at a dosage of 50 mg. This medication can be administered both orally and intravenously, with a maximum daily dose of 300 mg and a total maximum dose of 3600 mg over the treatment period. Diphenhydramine Hydrochloride is a chemically derived antihistamine used to manage allergic reactions and is included as an auxiliary treatment in the study.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the **serum concentration of ocrelizumab** at specified timepoints and the levels of **CD19+ B-cell count** in blood. These parameters will be measured to evaluate the pharmacokinetic and pharmacodynamic effects of ocrelizumab in children and adolescents with Relapsing-Remitting Multiple Sclerosis (RRMS).

Secondary endpoints will provide additional insights into the treatment's efficacy and safety profile. These include the occurrence and severity of adverse events, changes from baseline in vital signs and clinical laboratory test results, levels of circulating B cells, T cells, natural killer cells, and other leukocytes, as well as developmental milestones such as growth and bone age. Non-MS central nervous system pathology will be assessed through brain MRI scans, and levels of blood immunoglobulins and antibody titers against standard vaccines will be monitored. The presence of anti-drug antibodies (ADAs) during the study will also be evaluated relative to baseline levels.