Rituximab Tapering Strategies in Rheumatoid Arthritis: Interval Prolongation Versus Disease Activity-Guided Dose Reduction

The primary objective of this trial is to evaluate the optimal **treatment/tapering strategy** with **rituximab** for patients with **rheumatoid arthritis**. The goal is to reduce the disease impact, which is clinically significant as it aims to improve patient outcomes by minimizing disease activity and potentially reducing medication-related side effects. The main secondary objective is to investigate the optimal treatment/tapering strategy with rituximab to reduce disease activity in these patients. This secondary focus is crucial for understanding how to maintain disease control while potentially decreasing the frequency or dosage of rituximab, thereby optimizing long-term management of rheumatoid arthritis.

The clinical trial focuses on patients diagnosed with **rheumatoid arthritis** and aims to explore the optimal treatment strategy with rituximab. The study population includes both male and female participants aged 18 years and older. Participants are required to have a previous response to rituximab and currently be on rituximab treatment, with a need for a subsequent cycle as per Belgian reimbursement criteria. The trial does not involve a vulnerable population. Participants must have a stable dose of methotrexate or other conventional synthetic disease-modifying antirheumatic drugs (DMARDs) for at least four weeks prior to the baseline. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as an open-label, multicenter, randomized controlled pragmatic superiority trial to evaluate the optimal treatment and tapering strategy of **rituximab** in patients with rheumatoid arthritis. The trial aims to compare interval prolongation with disease activity-guided dose reduction over a period of 104 weeks. Participants will be randomly assigned to one of the two study arms, with the primary endpoint being the comparison of disease impact using the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire. Secondary endpoints include the assessment of disease activity, cumulative doses of rituximab and glucocorticoids, maintenance of disease control, and the occurrence of serious adverse events.

The trial will commence with a screening visit to confirm eligibility based on criteria such as age, language proficiency, diagnosis of rheumatoid arthritis, and previous response to rituximab. Participants must be on a stable dose of methotrexate or other conventional synthetic disease-modifying antirheumatic drugs (DMARDs) for at least four weeks prior to baseline. Following the screening, eligible participants will undergo baseline assessments before randomization. Study visits will occur at regular intervals to monitor disease activity, adjust treatment as necessary, and ensure participant safety. The end-of-study visit will conclude the trial, with a comprehensive evaluation of the participant's health status and treatment outcomes.

Participant involvement is expected to last for the entire 104-week duration of the trial, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The trial is set to begin recruitment on November 1, 2023, with an estimated end date of November 1, 2026. The study will adhere to ethical guidelines, ensuring that all participants provide informed consent prior to any study-related procedures.

The clinical trial involves the administration of several **rituximab**-based medications, each formulated as a concentrate for solution for infusion. The primary experimental medication is **MabThera**, available in two dosages: 500 mg and 100 mg. This medication is manufactured by Roche Registration GmbH and is administered intravenously. The maximum daily dose is 1000 mg, with a total maximum dose of 5000 mg over a treatment period of up to 104 weeks. The pharmaceutical form is a solution for infusion, and the active substance is derived from a protein of other origin.

Another experimental medication used in the trial is **Rixathon**, produced by Sandoz GmbH. It is available in 500 mg and 100 mg dosages, also as a concentrate for solution for infusion. The administration route is intravenous, with the same dosing limits as MabThera. The active substance, **rituximab**, is consistent across all formulations, ensuring uniformity in the treatment protocol.

**Ruxience**, manufactured by Pfizer Europe MA EEIG, is included in the trial in both 500 mg and 100 mg concentrations. Like the other medications, it is administered intravenously as a solution for infusion. The dosing schedule and maximum allowable doses are identical to those of MabThera and Rixathon, maintaining consistency in the treatment regimen.

**Truxima**, provided by Celltrion Healthcare Hungary Kft, is another rituximab-based medication used in the trial. It is available in 500 mg and 100 mg dosages, formulated as a concentrate for solution for infusion. The administration is intravenous, with dosing parameters matching those of the other rituximab formulations in the study.

All medications in the trial are non-paediatric formulations and are not classified as orphan drugs. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. Participant compliance is monitored through adherence to the intravenous administration schedule and dosing limits. The trial aims to determine the optimal treatment strategy for patients with **rheumatoid arthritis**, focusing on reducing disease impact through rituximab tapering strategies.

Efficacy in the clinical trial titled "Tapering of Rituximab Based on Interval Prolongation Compared to Disease Activity-Guided Dose Reduction in Patients with Rheumatoid Arthritis: The RITUXERA Trial" will be assessed using both primary and secondary endpoints. The primary endpoint involves the comparison of disease impact between the study arms, measured by the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire over a period of 104 weeks. Secondary endpoints include several parameters: the area under the curve (AUC) of the Disease Activity Score in 28-joints - C-reactive Protein (DAS28-CRP) and the Simplified Disease Activity Index (SDAI) over 104 weeks, cumulative doses of **rituximab** and glucocorticoids, maintenance of disease control with a DAS28-CRP score of ≤3.2, and the rituximab drug retention rate in both study arms.

Additional secondary endpoints include the proportion of patients achieving a good or moderate European League Against Rheumatism (EULAR) response 12 weeks post-treatment, the proportion of patients tapering the dose of **rituximab** below 1 x 1000 mg intravenously in the experimental arm, the mean or median interval between **rituximab** administrations in the active control arm, and the proportion of patients experiencing serious adverse events or infections in both study arms. These efficacy parameters will be collected and analyzed over the course of the trial, which is estimated to conclude by November 2026.