Non-Inferiority Study of Ofatumumab and Siponimod Versus Fingolimod in Pediatric Multiple Sclerosis Patients Over Two Years

The primary objective of this study is to demonstrate the **non-inferiority** of ofatumumab and/or siponimod compared to fingolimod, as assessed by the annualized relapse rate (ARR) in pediatric patients with **multiple sclerosis** treated for up to two years. This is clinically relevant as it aims to establish alternative treatment options that are at least as effective as the current standard, potentially offering different safety profiles or modes of administration.

Secondary objectives include:

• To demonstrate the superiority of ofatumumab and/or siponimod compared to historical interferon β-1a data, assessed by ARR.
• To evaluate the effects of ofatumumab and/or siponimod versus fingolimod on the number of new or newly enlarging T2 lesions.
• To evaluate the effects of ofatumumab and/or siponimod versus fingolimod on neurofilament light chain (NfL) concentrations.
• To evaluate the pharmacokinetic (PK) properties of ofatumumab and siponimod (and its metabolite M17) in pediatric MS patients.
• To evaluate the immunogenicity of ofatumumab.
• To evaluate the safety and tolerability of ofatumumab and siponimod.

The clinical trial involves a total of **77 participants** diagnosed with **Multiple Sclerosis** in the pediatric population. The study population includes both male and female subjects, aged between 10 to less than 18 years at the time of randomization. Participants were selected based on specific criteria, including a confirmed diagnosis of Multiple Sclerosis as per the consensus definition for pediatric MS, and an **Expanded Disability Status Scale (EDSS)** score ranging from 0 to 5.5 at screening. The trial targets a vulnerable population, with participants required to have experienced at least one MS relapse in the previous year or two relapses in the past two years, or evidence of new T2 lesions or Gd-enhancing T1 lesions on MRI within 12 months prior to randomization. The study does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants have provided signed informed consent or assent prior to their involvement in the study.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study with a non-inferiority framework, aimed at evaluating the efficacy and safety of **ofatumumab** and **siponimod** compared to **fingolimod** in pediatric patients diagnosed with **multiple sclerosis**. The trial is structured into a 2-year treatment period followed by an open-label extension. The primary objective is to demonstrate the non-inferiority of ofatumumab and/or siponimod as compared to fingolimod, assessed by the annualized relapse rate (ARR) in the target pediatric multiple sclerosis participants. The trial is expected to conclude by June 2029, with recruitment having commenced in October 2021.

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 Expanded Disability Status Scale (EDSS) score. Following randomization, participants will attend regular follow-up visits to monitor treatment efficacy and safety, including assessments of ARR, MRI lesion rates, and neurofilament light chain concentrations. The end-of-study visit will conclude the trial, with comprehensive evaluations to assess the long-term impact of the treatments.

The expected duration of participant involvement is up to 2 years, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with the study protocol. The trial will utilize oral administration of siponimod and fingolimod, and subcutaneous administration of ofatumumab, with placebo controls as necessary. The study will adhere to rigorous safety monitoring, including assessments of adverse events, laboratory tests, and vital signs, to ensure participant well-being throughout the trial.

The clinical trial involves the administration of **siponimod fumaric acid**, marketed under the product name BAF312, which is provided in the form of a **film-coated tablet**. The pharmaceutical form is designed for **oral** administration. The maximum daily dose is 2 mg, with a total maximum dose of 5040 mg over a treatment period of 2520 days. The active substance is of chemical origin, and the product is manufactured by Novartis Pharma AG. Participant compliance with the dosing schedule will be monitored throughout the trial.

Another treatment used in the trial is **fingolimod hydrochloride**, which is provided as a **hard capsule**. This medication is also administered **orally** with a maximum daily dose of 0.5 mg and a total maximum dose of 1260 mg over the same treatment period of 2520 days. Fingolimod hydrochloride serves as a comparator in the study, and its administration will be closely monitored to ensure adherence to the dosing regimen.

The trial also includes a **placebo** to fingolimod, which is a mixture of inactive excipients encapsulated in hard gelatin capsules. These placebos are designed to match the appearance of the test drug product, ensuring blinding in the study. The placebo administration will follow the same schedule as the active comparator to maintain consistency in the trial design.

Additionally, the study involves the administration of **ofatumumab**, provided as a **solution for injection**. This biological product is administered via **subcutaneous use** with a maximum daily dose of 20 mg and a total maximum dose of 1780 mg over the treatment period. The administration of ofatumumab will be conducted with the use of a combination product that includes a device, ensuring precise dosing and participant safety.

Participant compliance with all treatments will be monitored through regular assessments and adherence checks, ensuring the integrity of the trial data and the safety of the participants. The trial aims to evaluate the efficacy and safety of these treatments in pediatric patients with multiple sclerosis, with a focus on comparing the annualized relapse rate among the different treatment arms.

The efficacy of the clinical trial will be assessed primarily through the **Annualized Relapse Rate (ARR)** of confirmed relapses in pediatric patients with multiple sclerosis. This primary endpoint will be used to demonstrate the non-inferiority of **ofatumumab** and/or **siponimod** compared to **fingolimod** over a treatment period of up to two years. Secondary endpoints include the annualized rate of new or newly enlarging T2 lesions on MRI, **neurofilament light chain (NfL)** concentration in serum, plasma concentrations of ofatumumab and siponimod (including its metabolite M17), and the proportion of participants with anti-ofatumumab antibodies. Additional assessments will include adverse events, Columbia Suicide Severity Rating Scale (C-SSRS), ECG, laboratory and ophthalmological data, pulmonary function tests, and vital signs.