Evaluation of Disease-Modifying Therapy Withdrawal Versus Continuation in Inactive Secondary Progressive Multiple Sclerosis Patients Aged Over 50 Years

The primary objective of this study is to demonstrate the non-inferiority of **disease-modifying therapies** (DMTs) withdrawal compared to treatment continuation over a period of two years, specifically focusing on disability progression in "inactive" Secondary Progressive Multiple Sclerosis (SPMS) patients older than 50 years. The clinical relevance of this objective lies in potentially reducing unnecessary medication exposure and associated side effects in patients who may not benefit from continued treatment, thereby optimizing patient care and resource allocation.

Secondary objectives include:

• Comparing the two groups at two years for disability progression using a composite score.
• Evaluating the frequency of relapses between the groups.
• Assessing differences in **MRI** parameters.
• Determining disease-free survival rates.
• Measuring patients' quality of life.
• Analyzing the medico-economic impact through a cost-utility study, focusing on the differential cost per quality-adjusted life year (QALY) gained.

The clinical trial involves participants diagnosed with **Multiple Sclerosis**, specifically those with a secondary progressive phenotype. The study population includes both male and female subjects aged 50 years and older. Participants are required to have a history of disease-modifying therapy for at least three years and must not have shown evidence of focal inflammatory activity for the same duration. The trial does not include a vulnerable population. The sponsor has not provided the total number of participants. The selection criteria emphasize individuals with progressive deterioration of disability, as defined by an increase in the Expanded Disability Status Scale (EDSS) score. Participants must have an EDSS score of 3 or higher. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the non-inferiority of disease-modifying therapies (DMTs) withdrawal compared to treatment continuation in patients with **Secondary Progressive Multiple Sclerosis** (SPMS) who are older than 50 years and classified as "inactive" according to the Lublin classification. This trial is a randomized, double-blind, controlled study with an estimated duration of 10 years, starting from January 24, 2019, and concluding on January 24, 2029. The primary endpoint is the percentage of patients experiencing disability progression, confirmed at 6 months, at the 2-year mark. Secondary endpoints include time to disability progression, changes in disability scores, relapse rates, MRI findings, disease-free survival, quality of life, and medico-economic impact.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease phenotype, and treatment history. Follow-up visits will occur at regular intervals to monitor clinical and radiological outcomes, assess disability progression, and evaluate any relapses or adverse events. The end-of-study visit will finalize data collection and assess long-term outcomes. The expected length of participant involvement is up to 24 months, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with study protocols.

Eligible participants must be at least 50 years old, have a secondary progressive phenotype for at least 3 years, and have been on a DMT for at least 3 years. They must also show no evidence of focal inflammatory activity for at least 3 years and have an Expanded Disability Status Scale (EDSS) score of 3 or higher. The trial will involve various DMTs, including **glatiramer acetate**, **cyclophosphamide**, **interferon beta-1a**, **mycophenolate mofetil**, **ocrelizumab**, **rituximab**, **teriflunomide**, **peginterferon beta-1a**, **dimethyl fumarate**, **azathioprine**, and **methotrexate**, administered through different routes such as subcutaneous, oral, intramuscular, and intravenous. The maximum treatment period for each product is 24 months, with specific dosing regimens tailored to each medication.

The clinical trial involves the administration of several experimental medications, each with specific pharmaceutical forms, dosages, and routes of administration. **Glatiramer Acetate** is provided as a solution for injection in a pre-filled syringe. It is administered subcutaneously with a maximum daily dose of 40 mg, and the treatment period extends up to 24 months. This medication is a polymer-based active substance.

**Cyclophosphamide** is utilized in two forms: as a tablet and as a powder for solution for injection. The tablet form is administered orally with a maximum daily dose of 400 mg, while the powder form is administered intravenously with a maximum dose of 750 mg/m². Both forms are used for a treatment period of up to 24 months. Cyclophosphamide is a chemical-based active substance.

**Interferon Beta-1A** is available as a solution for injection, administered either intramuscularly or subcutaneously. The intramuscular form has a maximum daily dose of 30 µg, while the subcutaneous form has a maximum daily dose of 44 µg. The treatment duration for both forms is up to 24 months. This medication is a protein-based active substance.

**Mycophenolate Mofetil** is provided as a film-coated tablet and a capsule, both administered orally. The maximum daily dose for both forms is 2 g, with a treatment period of up to 24 months. This medication is a chemical-based active substance.

**Ocrelizumab** is administered as a solution for infusion intravenously, with a maximum daily dose of 600 mg. The treatment period is up to 24 months. Ocrelizumab is a protein-based active substance.

**Interferon Beta-1B** is available as a solution for injection, administered subcutaneously with a maximum daily dose of 250 µg. The treatment period extends up to 24 months. This medication is a protein-based active substance.

**Rituximab** is administered as a solution for infusion intravenously, with a maximum daily dose of 500 mg/m². The treatment period is up to 24 months. Rituximab is a protein-based active substance.

**Teriflunomide** is provided as a coated tablet, administered orally with a maximum daily dose of 14 mg. The treatment period is up to 24 months. This medication is a chemical-based active substance.

**Peginterferon Beta-1A** is available as a solution for injection, administered subcutaneously with a maximum daily dose of 125 µg. The treatment period extends up to 24 months. This medication is a protein-based active substance.

**Dimethyl Fumarate** is provided as a gastro-resistant capsule, administered orally with a maximum daily dose of 480 mg. The treatment period is up to 24 months. This medication is a chemical-based active substance.

**Azathioprine** is administered as a film-coated tablet orally, with a maximum daily dose of 150 mg. The treatment period is up to 24 months. This medication is a chemical-based active substance.

**Methotrexate** is available in two forms: as a tablet and as a solution for injection in a pre-filled syringe. The tablet form is administered orally, while the solution is administered subcutaneously, both with a maximum daily dose of 25 mg. The treatment period for both forms is up to 24 months. Methotrexate is a chemical-based active substance.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percentage of patients experiencing **disability progression** at two years, confirmed at six months. Disability progression is defined as an increase in the Expanded Disability Status Scale (EDSS) of at least 1 point if the baseline EDSS was 5.5 or less, or 0.5 point if the baseline EDSS was more than 5.5.

Secondary endpoints include various measures of disability, relapses, MRI findings, disease-free survival, quality of life, and medico-economic impact. Disability will be evaluated by the time from disease-modifying therapy (DMT) withdrawal to disability progression confirmed at six months, changes in a composite disability progression score, and changes in the Symbol Digit Modalities Test (SDMT) score from baseline to two years. Relapse metrics will include the percentage of patients with at least one relapse from baseline to two years, the annualized relapse rate during this period, and the time from DMT withdrawal to the first relapse.

MRI assessments will focus on the percentage of patients with new or enlarging brain lesions from baseline to two years, the presence of gadolinium-enhancing lesions at specified intervals, and changes in brain volume. Disease-free survival will be measured by the percentage of patients with no evidence of disease activity (NEDA 3) at two years and the percentage of patients who resume DMT in the treatment withdrawal group. Quality of life will be assessed through changes in the SEP-59 score and the EuroQOL EQ-5D from baseline to two years. The medico-economic impact will be evaluated using the Incremental Cost Effectiveness Ratio (ICER), defined as the cost per Quality-Adjusted Life Year (QALY) gained in the treatment withdrawal group versus the treatment continued group.