Non-Inferiority Trial of 200 mg Rituximab vs. 1 g Rituximab in Maintenance Therapy for Rheumatoid Arthritis Patients

The primary objective of this study is to demonstrate the **non-inferiority** of a 200 mg dose of **rituximab** compared to the standard 1 g dose in terms of disease activity, as measured by the mean DAS28-CRP score, over a 12-month period in patients with **rheumatoid arthritis**. This is clinically relevant as it may offer a lower-dose treatment option that maintains efficacy while potentially reducing side effects and treatment costs.

Secondary objectives include:

• Comparing disease activity measured by DAS28-CRP between the two treatment arms at inclusion, 6, and 12 months.
• Assessing disease activity status, including low disease activity, DAS-remission, and Boolean remission, between the two arms at 6 and 12 months.
• Evaluating treatment failure rates.
• Comparing the occurrence of disease flares.
• Assessing the patient disability index.
• Evaluating patient quality of life.
• Comparing B, T, and NK cell subpopulations.
• Assessing changes in IgG, IgA, and IgM levels.
• Evaluating vaccine response.
• Comparing Human antichimeric antibody (HACAs) levels.
• Monitoring humoral immunosuppression by measuring Torque Teno Virus in the serum.
• Comparing the incidence of infections and serious infections.
• Evaluating adverse events and serious adverse events.

The clinical trial involves participants diagnosed with **Rheumatoid Arthritis**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a diagnosis of rheumatoid arthritis according to the EULAR/ACR 2010 classification criteria and a DAS28 score of 5.1 or lower. All participants must be on a current maintenance treatment with Rituximab, having completed at least the first cycle of Rituximab treatment, with the last infusion occurring between 6 and 18 months prior to inclusion. The trial does not involve a vulnerable population. Participants are expected to maintain corticosteroid use at 10 mg/day or less within four weeks prior to inclusion and must be affiliated with a social insurance system or be a beneficiary. Written informed consent is mandatory, and an effective method of birth control is required during the study. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the **non-inferiority** of a 200 mg dose of **rituximab** compared to the standard 1 g dose in patients with **rheumatoid arthritis**. This is a prospective, randomized, controlled trial with a double-blind design. The trial aims to assess the disease activity as measured by the mean DAS28-CRP score over a 12-month period. The trial is expected to commence recruitment on June 2, 2025, and conclude by July 1, 2030. Participants will be involved in the study for a maximum of 12 months, with the treatment period lasting up to 6 months.

Study visits are structured to include an initial screening visit, followed by regular follow-up visits at 6 and 12 months, and an end-of-study visit. The inclusion visit will confirm eligibility based on criteria such as age (≥18 years), a diagnosis of rheumatoid arthritis according to EULAR/ACR 2010 classification criteria, and current maintenance treatment with rituximab. Follow-up visits will monitor the primary endpoint, which is the mean reduction in rheumatoid arthritis activity score (DAS28-CRP), and secondary endpoints, including DAS28 categories, number of rituximab infusions, and various health assessments such as RAPID-3 and EQ5D-5L scores.

Participants are expected to adhere to the study protocol, including maintaining an effective method of birth control and providing written informed consent. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or any adverse events that compromise participant safety. The trial will ensure rigorous monitoring of safety and efficacy outcomes throughout the study duration.

The clinical trial involves the administration of **Sodium Chloride** in combination with **Potassium Chloride** and **Sodium Hydrogen Carbonate**. This experimental medication is provided in the pharmaceutical form identified as PHF00169MIG. The active substances include **Potassium Chloride Ph. Eur.**, **Sodium Hydrogen Carbonate Ph. Eur.** (also known as Sodium Bicarbonate Ph. Eur.), and **Sodium Chloride Ph. Eur.**. The medication is administered via infusion, with a maximum daily dose of 2.25 grams and a total maximum dose of 4.5 grams over a treatment period of up to 6 months. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

**Rituximab** is utilized as a comparator treatment in this study. It is provided as a concentrate for solution for infusion. The trial evaluates two dosing regimens of Rituximab: a standard dose of 1 gram and a reduced dose of 200 milligrams. Both doses are administered via infusion every 6 months, with a maximum daily dose of 1 gram and 200 milligrams, respectively. The total maximum dose for the standard regimen is 2 grams, while the reduced regimen allows for a total of 400 milligrams over the same 6-month period. The primary objective is to demonstrate the non-inferiority of the 200 mg dose compared to the standard 1 g dose in patients with rheumatoid arthritis, as measured by disease activity scores.

Efficacy in this clinical trial will be assessed primarily through the measurement of disease activity in patients with **rheumatoid arthritis**. The primary endpoint is the mean reduction of the Disease Activity Score 28 - C-reactive protein (DAS28-CRP) between inclusion and 12 months, aiming to demonstrate the non-inferiority of a 200 mg dose of rituximab compared to the standard 1 g dose. Secondary endpoints include DAS28-CRP scores at inclusion, 6, and 12 months, and categorization of disease activity levels, such as remission and low, moderate, or high disease activity. Additional secondary endpoints involve the number of rituximab infusions, patient transitions to other treatments, and corticosteroid usage.

Further assessments will include the number of flares, evaluated using the FLARE questionnaire at 6 and 12 months, and patient-reported outcomes such as the RAPID-3 score and RAID at the same timepoints. Quality of life will be measured using EQ5D-5L and SF-36 scales. Biomarker analysis will include B, T, and NK cell phenotyping, immunoglobulin levels (IgG, IgA, IgM), and vaccinal serologies for various pathogens at inclusion, 6, and 12 months. The evolution of Torque Teno Virus (TTV) viral load will also be monitored. Safety and tolerability will be evaluated by recording the number of infections, serious infections, adverse events, and serious adverse events throughout the study period.