Efficacy and Tolerability of Ofatumumab Versus First-Line Disease-Modifying Therapies in Newly Diagnosed Relapsing Multiple Sclerosis Patients

The primary objective of this study is to evaluate the **efficacy** of ofatumumab compared to first-line disease-modifying therapies (DMTs) chosen by physicians for self-administration in patients with newly diagnosed or treatment-naïve relapsing multiple sclerosis (RMS) at Month 15. This objective is clinically relevant as it aims to determine the potential of ofatumumab to provide superior therapeutic outcomes in managing RMS, a chronic and often debilitating neurological condition characterized by episodes of neurological dysfunction.

Secondary objectives include:

• Evaluating the efficacy of ofatumumab versus first-line self-administered DMTs (physician’s choice) in the newly diagnosed/naïve-treated RMS patient population.
• Assessing the safety and tolerability of ofatumumab compared to first-line self-administered DMTs (physician’s choice) in the same patient population.

The clinical trial focuses on individuals diagnosed with **relapsing multiple sclerosis (RMS)**, specifically targeting a population of newly diagnosed or treatment-naïve patients. The study includes both male and female participants, aged 18 to 55 years, who are neurologically stable and have an Expanded Disability Status Scale (EDSS) score ranging from 0 to 4.0. Participants must have experienced at least one relapse or have one gadolinium-enhanced lesion on T1 within the year prior to screening. The trial population is selected based on their suitability for treatment with first-line self-administered disease-modifying therapies (DMTs) or ofatumumab, as determined by randomization and physician's choice. The sponsor has not provided the total number of participants involved in the study. Participants are required to be able to undergo MRI assessments. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The inclusion of a vulnerable population is noted, although specific details are not provided.

The clinical trial is designed to evaluate the efficacy and tolerability of **ofatumumab** compared to first-line disease-modifying treatments (DMTs) in patients newly diagnosed with **relapsing multiple sclerosis (RMS)**. This is a randomized, open-label, rater-blind, multi-center, parallel-arm, active-comparator study. The trial will span approximately 15 months, with the estimated end date set for January 30, 2026. Participants will be randomly assigned to receive either ofatumumab or a physician's choice of first-line DMTs, which may include **glatiramer acetate**, **interferon beta-1a**, **teriflunomide**, or **dimethyl fumarate**. The primary objective is to assess the NEDA-3 status, which includes the absence of confirmed clinical relapse, absence of new MRI activity, and absence of 3-month confirmed disability worsening.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, will confirm eligibility based on criteria such as age, neurological stability, and diagnosis according to the 2017 revised McDonald criteria. Follow-up visits will occur at regular intervals, including assessments at months 3, 9, and 15, to evaluate secondary endpoints such as the number of relapses, annual relapse rate, and changes in the expanded disability status scale (EDSS). The end-of-study visit will finalize data collection and assess the overall outcomes of the trial.

Participant involvement is expected to last for the entire 15-month duration of the study. However, conditions that may lead to early termination include the occurrence of serious adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial aims to provide valuable insights into the comparative effectiveness of ofatumumab and other first-line DMTs in managing RMS, contributing to informed treatment decisions in clinical practice.

The clinical trial involves the administration of several experimental and comparator medications. **Ofatumumab** is the primary experimental medication, administered as a **solution for injection**. It is delivered via **subcutaneous use** at a dosage of 20 mg, with a maximum total dose of 340 mg over a 15-month period. The administration is facilitated by an autoinjector device, specifically the Delta-04, which is a pre-filled pen intended for single use. This medication is a clinical variant of an approved product, with the aim to evaluate its efficacy in treating newly diagnosed relapsing multiple sclerosis (RMS).

**Peginterferon beta-1a** is used as a comparator treatment in the trial. It is provided as a **solution for injection** and administered through **subcutaneous injection**. The maximum daily dose is 125 µg, with a total dose not exceeding 4000 µg over the course of the study. This protein-based medication is utilized to compare its effects against the primary experimental drug.

Another comparator, **Interferon beta-1a**, is also administered as a **solution for injection**. It is delivered via both **subcutaneous and intramuscular injection** routes, with daily doses of 44 µg and 30 µg, respectively. The total dose for subcutaneous administration is capped at 8448 µg, while the intramuscular route has a maximum of 1950 µg over the study period. This protein-based treatment serves as a standard comparator in the trial.

**Dimethyl fumarate** is included as a comparator, provided in **gastro-resistant capsules** for **oral administration**. The maximum daily dose is 480 mg, with a total dose of 216,000 mg over the trial duration. This chemical-based medication is used to assess its efficacy relative to the experimental treatment.

**Diroximel fumarate**, another chemical-based comparator, is administered in **gastro-resistant capsules** for **oral use**. The daily dosage is set at 924 mg, with a total dose of 415,800 mg throughout the study. This medication is evaluated alongside other treatments to determine its effectiveness in managing RMS.

**Glatiramer acetate** is administered as a **solution for injection** via **subcutaneous injection**. It is provided in two dosage forms: 40 mg and 20 mg, with total doses of 7720 mg and 9000 mg, respectively, over the study period. This polymer-based medication is used as a comparator to evaluate its therapeutic impact.

**Teriflunomide** is another comparator, administered as a **film-coated tablet** for **oral use**. The maximum daily dose is 14 mg, with a total dose of 6300 mg over the course of the trial. This chemical-based treatment is included to compare its efficacy against the primary experimental drug.

Lastly, **Recombinant interferon beta-1b** is provided as a **powder and solvent for solution for injection**, administered via **subcutaneous injection**. The maximum daily dose is 250 µg, with a total dose of 56,250 µg over the study period. This protein-based medication is used as a standard comparator in the trial.

The efficacy of the clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the **NEDA-3 status**, which includes the absence of confirmed clinical relapse, absence of new MRI activity (Gd+ T1 lesion or new/enlarged T2 lesion) with MRI re-baselined at Month 3, and absence of 3-month confirmed disability worsening. Secondary endpoints include the number of relapses up to Month 15 or end of study (EOS), annual relapse rate (ARR), mean time to first relapse, and the proportion of relapse-free patients at Months 3, 9, and 15. Additionally, the trial will evaluate the proportion of relapse-free patients with MRI activity-free status at the same time points, time to 3-month and 6-month confirmed disability worsening, and change in the expanded disability status scale (EDSS) from baseline to the end of the study.

Further secondary endpoints include the proportion of disability progression-free patients at EOS, the number and volume of Gadolinium enhancing (Gd+) T1 lesions of the brain, and the number and volume of new/enlarging T2 lesions of the brain. Safety and tolerability will be assessed by the proportion of serious adverse events (SAEs), SAEs with hospitalizations, adverse events including injection-related reactions, and treatment discontinuation or interruptions for safety/tolerability reasons. Compliance to treatment will be monitored using a patient diary. These efficacy parameters will be measured and collected at specified time points throughout the trial, with analysis conducted to determine the comparative efficacy of ofatumumab versus first-line disease-modifying therapies (DMTs) in the treatment of newly diagnosed relapsing multiple sclerosis (RMS).