Evaluation of Ocrelizumab Versus Fingolimod in Pediatric and Adolescent Patients with Relapsing-Remitting Multiple Sclerosis: A Phase III Randomized, Double-Blind Study

The primary objective of this study is to demonstrate the **non-inferiority** of ocrelizumab compared with fingolimod, based on the protocol-defined annualized relapse rate (ARR) in children and adolescents with **Relapsing-Remitting Multiple Sclerosis**. This is clinically relevant as it aims to establish ocrelizumab as an effective alternative treatment option, potentially offering different safety or administration benefits compared to fingolimod.

Secondary objectives include:

• Demonstrating the non-inferiority of ocrelizumab compared with fingolimod based on the number of new or enlarging T2-hyperintense lesions as detected by brain MRI.
• Demonstrating the superiority of ocrelizumab versus fingolimod based on the number of new or enlarging T2-hyperintense lesions, number of T1 gadolinium lesions, and protocol-defined ARR.
• Evaluating the safety of ocrelizumab administered by intravenous infusion every 24 weeks compared with fingolimod administered once a day by mouth.
• Assessing the pharmacokinetics of ocrelizumab in all children/adolescents enrolled in this study.
• Assessing the pharmacodynamics in all children/adolescents enrolled in this study, as measured by blood B-cell count.
• Evaluating the immune response to ocrelizumab.

The clinical trial involves a total of **89 participants** diagnosed with **Relapsing-Remitting Multiple Sclerosis**. The study population includes both male and female subjects, aged between 10 to less than 18 years, with a body weight of at least 25 kilograms. Participants were selected based on their diagnosis in accordance with the international pediatric multiple sclerosis study group criteria or McDonald criteria, confirmed by an independent review committee. The trial includes individuals who have experienced at least one relapse in the year prior to screening or have evidence of active disease on MRI. The participants are required to have an Expanded Disability Status Scale (EDSS) score between 0 and 5.5. All participants must have received childhood vaccinations as per local or national recommendations. Female participants of childbearing potential are required to use contraception or remain abstinent during the treatment period and for a specified duration after the final dose. The trial population is considered vulnerable, given the age range and health condition of the participants.

The clinical trial is designed as a **randomized**, **double-blind**, and controlled study to evaluate the safety and efficacy of **ocrelizumab** compared to **fingolimod** in children and adolescents with **relapsing-remitting multiple sclerosis**. The trial aims to demonstrate the non-inferiority of ocrelizumab based on the protocol-defined annualized relapse rate (ARR). The study is expected to run from March 31, 2022, to September 17, 2029, with participants involved for a maximum treatment period of 67 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, body weight, and disease activity. Following randomization, participants will receive either ocrelizumab or fingolimod, with some receiving a placebo as part of the double-dummy design. The trial includes multiple follow-up visits to monitor the number of new or enlarging T2 lesions, T1 gadolinium lesions, and other secondary endpoints such as adverse events and changes in vital signs. The end-of-study visit will conclude the participant's involvement, assessing the overall safety and efficacy outcomes.

The expected length of participant involvement is determined by the treatment period, with conditions for early termination including significant adverse events or withdrawal of consent. The trial's methodology ensures rigorous data collection and analysis, maintaining the integrity of the study's findings. Participants are required to adhere to the study protocol, including the use of contraception for female participants of childbearing potential, to ensure safety and compliance throughout the trial duration.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Methylprednisolone sodium succinate** is provided in two formulations: 250 mg and 1000 mg, both as a powder and solvent for the preparation of a solution for injection or infusion. The pharmaceutical form is a **solution for injection/infusion**, and the route of administration is intravenous infusion. The maximum daily dose is 100 mg, with a total maximum dose of 1200 mg over a treatment period of up to 67 days. This medication is manufactured by ACIS ARZNEIMITTEL GMBH and is classified under the ATC code H02AB04.

**Ocrelizumab** is administered as a 300 mg concentrate for solution for infusion, with the pharmaceutical form being a solution for infusion. The route of administration is intravenous infusion, with a maximum daily dose of 600 mg and a total maximum dose of 7200 mg over a 67-day treatment period. This product is manufactured by ROCHE REGISTRATION GMBH and is used as a test treatment in the trial.

**Fingolimod** is provided in the form of hard capsules, with each capsule containing 0.25 mg or 0.5 mg of the active substance. The pharmaceutical form is a hard capsule, and the route of administration is oral. The maximum daily dose is 0.5 mg, with a total maximum dose of 518 mg over a 34-day treatment period. This medication is manufactured by NOVARTIS EUROPHARM LIMITED and serves as a comparator treatment in the study.

**Dimenhydrinate** is administered in the form of tablets, with each tablet containing 50 mg of the active substance. The pharmaceutical form is a tablet, and the route of administration is oral. The maximum daily dose is one dosage form, with a total maximum dose of one dosage form over a 67-day treatment period. This product is manufactured by ALIUD PHARMA GMBH and is used as an auxiliary treatment in the trial.

The study also includes the use of placebos for both **Fingolimod** and **Ocrelizumab**. These placebos are used to maintain the double-blind nature of the trial and do not contain any active substances. The pharmaceutical form and route of administration for these placebos are not specified.

The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the **annualized relapse rate (ARR)**, which is defined by the protocol to demonstrate the non-inferiority of ocrelizumab compared to fingolimod in children and adolescents with relapsing-remitting multiple sclerosis (RRMS). Secondary endpoints include the number of new or enlarging T2 lesions detected by brain MRI during the double-blind period, the number of T1 gadolinium (Gd) lesions at Week 12, and the protocol-defined ARR during the double-blind period to assess superiority.

Additional secondary endpoints involve the incidence and severity of adverse events, which will be determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0). Changes from baseline in targeted vital signs, clinical significant abnormalities in electrocardiogram (ECG) parameters, and clinical laboratory test results will also be evaluated. Furthermore, the study will measure concentrations of ocrelizumab at indicated time points, levels of CD19 B-cell count in blood, and the prevalence and incidence of anti-drug antibodies (ADAs) against ocrelizumab at baseline and during the study.