Evaluation of Siponimod on Imaging and Immunological Markers in Secondary Progressive Multiple Sclerosis Patients

The primary objective of this study is to evaluate the effect of **siponimod** on paramagnetic rim lesions as visualized by MRI in patients with secondary progressive multiple sclerosis. This is clinically relevant as paramagnetic rim lesions are indicative of chronic active inflammation and are associated with disease progression in multiple sclerosis. Understanding the impact of siponimod on these lesions could provide insights into its potential to alter disease progression.

Secondary objectives include:

• Evaluating the effect of siponimod in modifying the cerebrospinal fluid (CSF) and serum levels of biomarkers of microglial/macrophage activity and axonal/neuronal damage. This is important for understanding the drug's impact on underlying pathological processes in multiple sclerosis.
• Assessing the effect of siponimod on clinical and cognitive worsening in progressive multiple sclerosis patients and its long-term safety. This will help determine the broader therapeutic benefits and safety profile of siponimod in this patient population.

The clinical trial involves participants diagnosed with **secondary progressive multiple sclerosis** following an initial relapse clinical course. The study population includes both male and female subjects aged between 18 and 65 years. Participants are required to have an Expanded Disability Status Scale (EDSS) score ranging from 3.0 to 6.0 and must have entered the progressive phase of the disease less than five years prior to enrollment. The trial population was selected based on specific criteria, including a history of relapse or radiological activity within the past two years, as evidenced by MRI findings. Participants must have undergone a 3T MRI within the last two years, including specific imaging sequences, and have detailed clinical data on their medical history with neurological evaluations conducted at least twice in the past two years. Female participants must not be pregnant or breastfeeding during the study. The sponsor has not provided information regarding the total number of participants. The trial includes a vulnerable population, emphasizing the need for careful consideration of ethical standards and participant safety.

The clinical trial is designed to evaluate the effect of **siponimod** on paramagnetic rim lesions in patients with secondary progressive multiple sclerosis. This study is a randomized, double-blind, controlled trial with an estimated duration from February 2022 to July 2026. Participants will be randomly assigned to receive either siponimod or a placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the double-blind nature of the trial. The trial will involve multiple study visits, beginning with an inclusion visit to screen participants based on specific eligibility criteria, including age, disease progression, and MRI availability.

Following the inclusion visit, participants will undergo regular follow-up visits at specified intervals to monitor the effects of the treatment. These visits will include assessments of the primary endpoint, which is the change in susceptibility of rim lesions after treatment with siponimod compared to the natural change observed in a recent period before treatment. Secondary endpoints will evaluate the reduction in the number of slowly expanding lesions, changes in cerebrospinal fluid and serum markers, and cognitive functioning over the study period. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the overall impact of the treatment.

Participant involvement is expected to last up to 24 months, with conditions for early termination including significant adverse events or withdrawal of consent. The trial aims to provide comprehensive data on the efficacy and safety of siponimod in managing progressive multiple sclerosis, contributing valuable insights into its potential therapeutic benefits.

The clinical trial involves the administration of **siponimod**, a chemical substance, in the form of film-coated tablets. The experimental medication is marketed under the name Mayzent and is available in three different dosages: 0.25 mg, 1 mg, and 2 mg. The tablets are intended for **oral use**. The 0.25 mg dosage has a maximum daily dose of 1250 micrograms, with a treatment period of up to 5 days. The 1 mg dosage also allows for a maximum daily dose of 1250 micrograms, but the treatment period extends to 24 weeks. The 2 mg dosage has a maximum daily dose of 2 milligrams, with a treatment period of 24 weeks. The active substance in these tablets is siponimod, also known by the synonym BAF312, and is produced by Novartis Europharm Limited.

Additionally, the trial includes the use of BAF312, which contains the active substance **siponimod fumaric acid**. This formulation is also presented as a film-coated tablet for oral administration. The maximum daily dose for BAF312 is 1250 micrograms, with a treatment period of 5 days, or 2 milligrams with a treatment period of 24 weeks, depending on the specific formulation used. The manufacturer of BAF312 is Novartis Pharma AG. Both Mayzent and BAF312 are classified as chemical products and are not designated as orphan drugs. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

The efficacy of siponimod in the treatment of secondary progressive multiple sclerosis (MS) will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the change in susceptibility of **paramagnetic rim lesions** after treatment with siponimod, compared to the natural change observed in a period preceding the treatment. This internal comparison for each patient will provide insights into the drug's impact on lesion susceptibility.

Secondary endpoints include evaluating the effect of siponimod on reducing the number of slowly expanding lesions (SEL) by comparing the retrospective phase with the study phase at specific timepoints (T3 vs T12 and T3 vs T24). Additionally, changes in cerebrospinal fluid (CSF) levels of specific markers of activated microglia/macrophages and neuronal/axonal damage will be described from baseline to T24. Serum levels of these markers will also be evaluated at baseline and at T6, T12, T18, and T24. The Expanded Disability Status Scale (EDSS) change will be assessed between the retrospective phase and the study phase (T0 vs T12 and T12 vs T24), alongside evaluations of cognitive functioning over the two-year study phase (T0-T24). Treatment-emergent adverse effects (TEAE) and serious adverse events (SAE) will be monitored at each follow-up visit.