Comparison of Efficacy and Safety in Patients Switching From MabThera® to Rixathon® in Relapsing-Remitting Multiple Sclerosis

This is a retrospective observational study conducted at Uppsala University Hospital. The study aims to evaluate the efficacy and safety of switching from MabThera® (rituximab originator) to Rixathon® (rituximab biosimilar) in people with multiple sclerosis (MS), specifically those diagnosed with relapsing-remitting MS (RRMS) and progressive MS.

Starting in January 2023, the Department of Neurology at Uppsala University Hospital made an administrative decision to move from using rituximab (MabThera®) to rituximab (Rixathon®) in the treatment of MS, primarily for cost-saving reasons. This study will retrospectively analyze clinical and radiological outcomes collected before and after the switch. Data will be extracted from the Swedish MS Registry (SMSreg), a national database containing clinical information on people with MS across Sweden. Only patients treated at Uppsala University Hospital are included.

The primary objective of the study is to determine whether switching to Rixathon® affects disease activity, as measured by changes in plasma neurofilament light (pNfL) concentrations. pNfL is a biomarker of neuroaxonal damage, and elevated levels are associated with ongoing inflammation and neurodegeneration in MS.

Secondary objectives include comparing:

• The number of new T2 lesions on brain MRI scans before and after the switch
• The annualized relapse rate before and after the switch
• Changes in disability progression, measured by the Expanded Disability Status Scale (EDSS)
• Proportion of participants maintaining "No Evidence of Disease Activity" (NEDA) status
• Occurrence of serious adverse events (Grade 3-5 according to CTCAE v5.0)

Exploratory analyses will incorporate quantitative MRI (qMRI) metrics, including brain parenchymal fraction (BPF), myelin correlated fraction (MyCPF), myelin correlated volume (MyC), cerebrospinal fluid (CSF) volume, brain parenchymal volume (BPV), and intracranial volume. These parameters are obtained from SyMRI sequences that have been part of standard clinical practice at Uppsala University Hospital since 2017.

Participants eligible for inclusion were already being treated with MabThera® at the end of 2022 and completed the switch to Rixathon®. These individuals have been followed through routine clinical care with yearly MRI scans, regular EDSS assessments, and quarterly pNfL blood testing.

Data Quality Assurance:

Data will be obtained directly from SMSreg, which ensures quality through national standard operating procedures, regular audits, and predefined data validation rules. The registry will be vetted against clinical source documentation in the electronic medical records. Variables such as MRI findings, pNfL levels, relapse events, and EDSS scores are standardized across Sweden. No additional site-specific audits are planned beyond the SMSreg's internal quality controls.

Handling Missing Data:

In case of missing or inconsistent data points, standard imputation methods will be used as outlined in the analysis plan. For missing values that cannot be resolved, sensitivity analyses will be performed to assess the impact on results.

Sample Size and Power Considerations:

At the time of the medication switch, 184 MS patients were being treated with rituximab at the Department of Neurology. Given this sample size and historical relapse rates in RRMS, the study is adequately powered to detect meaningful differences in clinical and biomarker outcomes pre- and post-switch.

Statistical Analysis Plan:

The primary analysis will use a mixed-model repeated measures ANOVA to compare pNfL levels before and after the switch. Secondary outcomes (MRI activity, relapse rates, EDSS scores, NEDA status, and adverse events) will be analyzed using appropriate methods, including paired t-tests, Wilcoxon signed-rank tests, or McNemar's test, depending on the data distribution. Subgroup analyses will be performed separately for participants with RRMS and progressive MS. All analyses will adjust for potential confounders such as age, sex, disease duration, and prior treatment history.

This study will provide critical real-world evidence on whether switching to a rituximab biosimilar affects clinical outcomes and disease progression in MS.

Inclusion criteria

• Diagnosed with multiple sclerosis (MS) according to the 2017 McDonald criteria (or previous applicable versions at the time of diagnosis).
• Treated with MabThera® (rituximab originator) at the Department of Neurology, Uppsala University Hospital before January 1, 2023.
• Switched to Rixathon® (rituximab biosimilar) for MS treatment starting January 1, 2023.
• Registered in the Swedish MS Registry (SMSreg) with available clinical data.
• At least one clinical follow-up visit recorded before the switch and one after the switch.
• Available plasma neurofilament light chain (pNfL) measurement and/or brain MRI scan during the study period.

Exclusion criteria

• No recorded clinical follow-up visit after switching to Rixathon®.
• Switched to Rixathon® but later discontinued treatment within 3 months for reasons unrelated to disease activity (e.g., administrative, insurance, or non-medical reasons).
• Participation in another interventional clinical trial affecting MS outcomes during the study period.
• Diagnosis of other major neurological diseases that could confound MS outcomes (e.g., stroke, CNS infection, or primary CNS tumors).
• Lack of consent for research use of data in the Swedish MS Registry.