Long-term Safety, Tolerability, and Efficacy Evaluation of Ofatumumab in Patients with Relapsing Multiple Sclerosis: An Open-label Extension Study

The primary objective of this study is to evaluate the long-term **safety** and tolerability of **ofatumumab** 20 mg subcutaneously administered once every 4 weeks in subjects with relapsing multiple sclerosis (RMS) from the first dose of ofatumumab. This is clinically relevant as it aims to ensure that the treatment is safe for long-term use, which is crucial for chronic conditions like RMS where ongoing management is necessary.

The secondary objectives include:

• Describing the long-term efficacy of ofatumumab 20 mg subcutaneously once every 4 weeks in subjects with RMS from the first dose of ofatumumab.
• Comparing long-term outcomes in subjects originally in the COMB157G2301 and COMB157G2302 studies who were immediately treated with ofatumumab versus those with delayed use of ofatumumab, by analyzing subjects according to their randomized treatment in these studies.
• For subjects randomized to teriflunomide in the COMB157G2301 and COMB157G2302 studies and switched to ofatumumab in the COMB157G2399, comparing both periods before and after the switch to ofatumumab.
• Exploring the long-term health outcomes in subjects with RMS treated with ofatumumab 20 mg subcutaneously once every 4 weeks from the first dose of ofatumumab.

The clinical trial involves a total of **931 participants** diagnosed with **relapsing multiple sclerosis (RMS)**. The study population includes both male and female subjects, with an age range starting from 18 years and above. Participants were selected based on their prior involvement in a Novartis MS study where they received ofatumumab 20 mg subcutaneously every four weeks. The trial focuses on evaluating the long-term safety and tolerability of this treatment regimen. The population includes individuals who have completed the previous study on the study treatment and provided written informed consent. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The study population is noted to include vulnerable groups, although specific details on these groups are not provided.

The clinical trial is designed to evaluate the long-term safety, tolerability, and effectiveness of **ofatumumab** in subjects with **relapsing multiple sclerosis** (RMS). This study is an open-label, single-arm, multi-center extension trial. Participants will receive **ofatumumab** 20 mg subcutaneously every four weeks. The trial is expected to last until September 2028, with an estimated recruitment start date of January 2019. The trial will include several key phases, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as prior participation in a Novartis MS study and completion of the study treatment. Participants must provide written informed consent to be included in the trial.

Throughout the study, participants will attend regular follow-up visits to monitor safety and efficacy outcomes. These visits will assess the proportion of subjects experiencing adverse events, laboratory or vital sign abnormalities, and changes in electrocardiogram (ECG) results. The study will also evaluate the Columbia Suicide Severity Rating Scale (C SSRS) criteria through Week 240 or the end of the study (EOS). Secondary endpoints include the annualized relapse rate, time to first relapse, and various measures of disability worsening and improvement over time. Changes in the Expanded Disability Status Scale (EDSS), Symbol Digit Modalities Test (SDMT), and neurofilament light chain (NfL) concentration in serum will also be assessed.

The expected length of participant involvement is up to 240 weeks, with conditions for early termination including the occurrence of significant adverse events or failure to adhere to study protocols. The trial aims to provide comprehensive data on the long-term use of **ofatumumab** in managing RMS, contributing valuable insights into its safety and efficacy profile over an extended period.

The clinical trial involves the administration of **Kesimpta** (ofatumumab), a **solution for injection** in a pre-filled pen. The active substance, ofatumumab, is a protein classified as "Protein - Other." The pharmaceutical form is a solution for injection, and the route of administration is **subcutaneous use**. The dosage is 20 mg per administration, with a maximum total dose of 1960 mg over the treatment period. The treatment is administered once every four weeks for a maximum treatment period of 96 weeks. Participant compliance is monitored through the use of an autoinjector device, specifically the Delta-04, which is intended for single use.

In addition to the experimental treatment, the study includes the use of **Pneumovax 23**, a pneumococcal polysaccharide vaccine. This vaccine is available in various forms, including a solution for injection in pre-filled syringes and vials. The active substances are pneumococcal polysaccharide serotypes, and the pharmaceutical form is a solution for injection. The route of administration is **intramuscular injection**. The dosage is 0.5 ml per administration, with a maximum total dose of 0.5 ml. The treatment period is limited to a single administration.

Another non-experimental treatment used in the study is **Boostrix**, a vaccine for diphtheria, tetanus, and pertussis. The active substances include diphtheria toxoid, tetanus toxoid, and pertussis antigens, all adsorbed on aluminium hydroxide and aluminium phosphate. The pharmaceutical form is a suspension for injection, and the route of administration is **intramuscular injection**. The dosage is 0.5 ml per administration, with a maximum total dose of 0.5 ml. The treatment period is limited to a single administration.

Additionally, the study includes the use of **Flucelvax Tetra**, an influenza vaccine. The active substances are influenza virus strains, and the pharmaceutical form is a suspension for injection in pre-filled syringes. The route of administration is **intramuscular injection**. The dosage is 0.5 ml per administration, with a maximum total dose of 0.5 ml. The treatment period is limited to a single administration.

Participant compliance is monitored through regular follow-ups and documentation of administration schedules. The study aims to evaluate the long-term safety, tolerability, and effectiveness of ofatumumab in subjects with relapsing multiple sclerosis, with additional vaccines provided as standard-of-care therapy.

The efficacy of ofatumumab in subjects with **relapsing multiple sclerosis (RMS)** will be assessed through a series of predefined primary and secondary endpoints. The primary endpoints include the proportion of subjects experiencing adverse events, laboratory or vital signs results meeting abnormal criteria, electrocardiogram (ECG) results meeting abnormal criteria, and criteria met in the Columbia Suicide Severity Rating Scale (C SSRS) through Week 240 or the end of the study (EOS).

Secondary endpoints will be evaluated through Week 240 or EOS and include the Annualized Relapse Rate (ARR), time to first relapse, time to 3-month and 6-month Confirmed Disability Worsening (3mCDW and 6mCDW), time to 6-month, 12-month, and 24-month Confirmed Disability Improvement (6mCDI, 12mCDI, and 24mCDI), and time to 6-month Confirmed Disability Improvement sustained until EOS. Additional secondary endpoints include changes in the Expanded Disability Status Scale (EDSS), time to 6-month confirmed 4-point worsening on the Symbol Digit Modalities Test (SDMT), changes in SDMT, annualized T2 lesion rate, number of T1 Gd-enhancing lesions per MRI scan, annual rate of change in brain volume, changes in neurofilament light chain (NfL) concentration in serum, and the relationship between NfL and disease activity, disease course, and treatment response. Patient Reported Outcomes (PRO) will also be assessed.