Non-Inferiority Trial of Anti-CD20 Maintenance Versus De-Escalation Strategy in Relapsing-Remitting Multiple Sclerosis with Ofatumumab and Drug Combination

The primary objective of this study is to demonstrate the non-inferiority of a **de-escalation strategy** from anti-CD20 therapy to platform therapies compared to anti-CD20 maintenance in patients with **relapsing-remitting multiple sclerosis**. This is evaluated by assessing the percentage of patients without clinical and/or MRI disease activity over a period from day 0 to month 36. This objective is clinically relevant as it aims to establish whether a less intensive treatment approach can maintain disease control, potentially reducing treatment burden and associated risks.

Secondary objectives include:

• Comparing the percentage of patients without relapse between the de-escalation and maintenance groups from day 0 to month 36.
• Assessing the percentage of patients without confirmed disability progression, as indicated by an increase in the Expanded Disability Status Scale (EDSS), in both groups over the same period.
• Evaluating the percentage of patients without new or enlarged T2 lesions on MRI in both groups.
• Comparing the number of adverse events and severe adverse events between the groups.
• Assessing the incidence of infections and serious infections in both groups.
• Evaluating changes in B-cell count and serum immunoglobulin levels (IgG, A, M) in both groups.
• Comparing the annualized relapse rate and time to first relapse between the groups.
• Assessing the time to disability progression in both groups.
• Evaluating changes in brain volume and serum neurofilament light chains in both groups.
• Comparing changes in immunoglobulin levels and B-cell repopulation (CD19+/CD20+ and CD27+ memory B-cells) in both groups.
• Assessing patients' quality of life and their experience of the quality of care in both groups.
• Evaluating the medico-economic impact of the treatment strategies.

The clinical trial involves participants diagnosed with **relapsing remitting multiple sclerosis**. The study population includes both male and female subjects, with an age range starting from 40 years and above. Participants are required to have been treated with anti-CD20 therapy for at least the last three years, with no evidence of disease activity during this period. This includes no relapses and no new or enlarged MRI lesions. Additionally, a brain MRI must have been performed according to the OFSEP protocol within six months prior to randomization. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the non-inferiority of a de-escalation strategy from anti-CD20 therapy to platform therapies compared to anti-CD20 maintenance in patients with **relapsing-remitting multiple sclerosis**. The trial aims to assess the percentage of patients without clinical and/or MRI disease activity over a period of 36 months. The study will involve multiple investigational products, including **ofatumumab**, **dimethyl fumarate**, **ocrelizumab**, **peginterferon beta-1a**, **glatiramer acetate**, **teriflunomide**, **diroximel fumarate**, **interferon beta-1a**, and **rituximab**, administered through various routes such as subcutaneous injection, oral, intravenous infusion, and intramuscular injection.

Participants will be involved in the study for a maximum duration of 36 months, with the trial expected to conclude by March 2030. The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age (≥40 years), diagnosis of relapsing-remitting multiple sclerosis according to the 2017 McDonald criteria, and a history of anti-CD20 treatment for at least three years without disease activity. Follow-up visits will be conducted periodically to monitor disease activity, adverse events, and other secondary endpoints such as relapses, disability, and brain volume changes. The end-of-study visit will occur at the conclusion of the 36-month period to assess the primary endpoint of disease activity absence.

Participants may be withdrawn from the study early if they exhibit disease activity, defined as a clinical relapse or new/enlarged T2/FLAIR lesions on MRI, or if they experience severe adverse events. The trial is categorized as a low-intervention study, as the investigational medicinal products are authorized and used in accordance with their marketing authorizations, posing minimal additional risk to participants. The study's primary endpoint is the percentage of patients without disease activity between the start of the trial and month 36, while secondary endpoints include assessments of relapses, adverse events, infections, B-cell counts, serum immunoglobulin levels, and quality of life scores.

**Ofatumumab** is administered as a **solution for injection** via **subcutaneous injection**. The maximum daily dose is 20 mg, with a total maximum dose of 720 mg over a treatment period of 36 months. This medication is not formulated for pediatric use and is not classified as an orphan drug.

**Dimethyl fumarate** is provided in a **gastro-resistant capsule, hard** form and is administered **orally**. The maximum daily dose is 480 mg, with a total maximum dose of 525,600 mg over 36 months. It is a chemical substance and is not intended for pediatric use or classified as an orphan drug.

**Ocrelizumab** is available as a **concentrate for solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose is 600 mg, with a total maximum dose of 3,600 mg over a 36-month period. It is a structurally diverse substance, specifically an immunoglobulin, and is not formulated for pediatric use or classified as an orphan drug.

**Peginterferon beta-1a** is administered as a **solution for injection** via **subcutaneous injection**. The maximum daily dose is 125 µg, with a total maximum dose of 9,750 µg over 36 months. It is a protein-based substance and is not intended for pediatric use or classified as an orphan drug.

**Glatiramer acetate** is provided as a **solution for injection in a pre-filled syringe** and is administered via **subcutaneous injection**. The maximum daily dose is 20 mg, with a total maximum dose of 21,900 mg over 36 months. It is not formulated for pediatric use and is not classified as an orphan drug.

**Teriflunomide** is available as a **film-coated tablet** and is administered **orally**. The maximum daily dose is 14 mg, with a total maximum dose of 15,330 mg over a 36-month period. It is a chemical substance and is not intended for pediatric use or classified as an orphan drug.

**Diroximel fumarate** is provided in a **gastro-resistant capsule, hard** form and is administered **orally**. The maximum daily dose is 924 mg, with a total maximum dose of 1,011,780 mg over 36 months. It is a chemical substance and is not formulated for pediatric use or classified as an orphan drug.

**Interferon beta-1a** is administered as a **solution for injection** via **subcutaneous injection**. The maximum daily dose is 132 µg, with a total maximum dose of 144,540 µg over 36 months. It is a protein-based substance and is not intended for pediatric use or classified as an orphan drug.

**Rituximab** is available as a **concentrate for solution for infusion** and is administered via **intravenous infusion**. The maximum daily dose is 1,000 mg, with a total maximum dose of 6,000 mg over a 36-month period. It is not formulated for pediatric use and is not classified as an orphan drug.

Efficacy in this clinical trial will be assessed by evaluating the percentage of patients without disease activity between Day 0 (D0) and Month 36 (M36). Disease activity is defined as the presence of at least one clinical relapse and/or brain MRI activity, which includes at least one new or enlarged T2/FLAIR lesion on MRI scans between baseline MRI and M36. The primary endpoint focuses on the absence of these indicators of disease activity.

Secondary endpoints will include a range of parameters such as the number of relapses, disability progression, the occurrence of new or enlarged T2/FLAIR lesions, and the incidence of adverse events and severe adverse events. Additional assessments will involve monitoring infections, serious infections, **B-cells** counts, and serum immunoglobulin levels (IgG, A, M). Brain volume changes, neurofilament light chain values, EQ5D-5L score, and MUSICARE score will also be evaluated. Economic assessments will include the incremental cost-utility ratio at year 3 and the annual budget impact from the Système National des Données de Santé (SNDS) hosted by French Health Insurance.