Tapering of Rituximab Based on Interval Prolongation Compared to Disease Activity-guided Dose Reduction in Patients With Rheumatoid Arthritis

Study Overview
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Brief Summary
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The goal of this open label multicenter randomized controlled pragmatic superiority trial is to investigate the optimal treatment/tapering strategy with rituximab for patients with rheumatoid arthritis. The main questions it aims to answer are: What is the optimal treatment/tapering strategy for rituximab in patients with rheumatoid arthritis in terms of reducing patient reported disease impact? What is the optimal treatment/tapering strategy for rituximab in patients with rheumatoid arthritis in terms of therapeutic efficacy? Participants will be randomized to one of two study arms: Tapering based on disease-activity guided dose reduction (experimental arm) Tapering based on interval prolongation (active comparator arm)

Official Title
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Tapering of Rituximab Based on Interval Prolongation Compared to Disease Activity-guided Dose Reduction in Patients With Rheumatoid Arthritis: The RITUXERA Trial

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to give written informed consent and participate in the study before any study procedure. Age ≥ 18 years. Understanding and able to write in Dutch or French. Diagnosis of rheumatoid arthritis according to the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Classification Criteria for rheumatoid arthritis. Previous response to rituximab, defined as a minimum of one successful rituximab cycle (= a moderate/good EULAR response 16 weeks after the first administration of rituximab). Current treatment with rituximab. Need for a subsequent rituximab cycle according to the Belgian reimbursement criteria for the use of rituximab in rheumatoid arthritis (DAS28 score ≥3.2). Stable dose of methotrexate or other conventional synthetic disease-modifying antirheumatic drugs (DMARDs) 4 weeks prior to baseline. Exclusion Criteria: Current treatment with another biological DMARD than rituximab. Current treatment with a targeted synthetic DMARD. Pregnancy or pregnancy wish. Presence of an absolute contraindication to treatment with rituximab, according to the label of rituximab and according to medical judgement.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open label multicenter pragmatic randomized controlled superiority trial. Patients will be 1:1 randomized to either the experimental arm or the active comparator arm. Study visits are scheduled every 12 weeks (3 months). Recruitment period: 1 year. Trial duration: 2 years.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tapering of rituximab based on disease activity guided dose reduction<br>Treatment with rituximab every 6 months (24 weeks) with dosing based on disease activity, measured by the DAS28-CRP. DAS28-CRP ≤ 3.2: dose reduction according to the following sequence: 1 x 1000 mg IV (maximum), 1 x 500 mg IV, 1 x 200 mg IV (minimum). DAS28-CRP > 3.2: administration of previously effective dose. | Drug: Rituximab<br>* IV rituximab<br>* Other names: Rixathon;|
| Active Comparator: Tapering of rituximab based on interval prolongation<br>Treatment with fixed dose of rituximab (1 x 1000 mg IV) if DAS28-CRP ≥ 3.2 AND interval of at least 6 months (24 weeks) since previous administration of rituximab. | Drug: Rituximab<br>* IV rituximab<br>* Other names: Rixathon;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of disease impact in both study arms, measured using the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire | RAID questionnaire score range: 0 - 10, with higher scores indicating worse status. | Over 2 years (104 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of disease activity in both study arms, measured using the Disease Activity Score in 28 joints - C-reactive protein (DAS28-CRP) | Main secondary outcome. DAS28-CRP range: 0 - ..., with higher values indicating higher disease activity. | Over 2 years (104 weeks) | 
| Comparison of disease activity in both study arms, measured using the Simplified Disease Activity Index (SDAI) | SDAI range: 0 - ..., with higher values indicating higher disease activity. | Over 2 years (104 weeks) | 
| Comparison of cumulative dose of rituximab in both study arms |  | Over 2 years (104 weeks) | 
| Comparison of cumulative dose of glucocorticoids in both study arms |  | Over 2 years (104 weeks) | 
| Proportion of patients in both study arms achieving a good or moderate European League Against Rheumatism (EULAR) treatment response after administration of rituximab, over a period of 2 years (104 weeks) | A good EULAR response is defined as a decrease in Disease Activity Score in 28 joints - C-reactive protein (DAS28-CRP) > 1.2 and a present DAS-CRP ≤ 3.2. A moderate EULAR response is defined as a decrease in DAS28-CRP > 0.6 to ≤ 1.2 and a present DAS28-CRP ≤ 5.1, or a decrease in DAS28-CRP > 1.2 and a present DAS28-CRP > 3.2. Treatment responses will be evaluated 12 weeks after every administration of rituximab. | Over 2 years (104 weeks) | 
| Comparison of loss of disease control in both study arms | Loss of disease control is defined as achieving a Disease Activity Score in 28 joints - C-reactive protein (DAS28-CRP) > 3.2 with previous DAS28-CRP ≤ 3.2. | Over 2 years (104 weeks) | 
| Comparison of rituximab drug retention rate in both study arms | Defined as the percentage of patients remaining on treatment with rituximab over time. | Over 2 years (104 weeks) | 
| Proportion of patients tapering rituximab below 1000 mg in the experimental arm |  | Over 2 years (104 weeks) | 
| Mean/median interval between rituximab administrations in the active comparator group |  | Over 2 years (104 weeks) | 
| Comparison of serious adverse events/reactions rates in both study arms. | An adverse event or adverse reaction is considered serious if it leads to inpatient hospitalization or prolongation of existing hospitalization, if it results in persistent or significant disability or incapacity, if it results in a life-threatening experience (meaning that the subject was at risk of death), or if it results in death. | Over 2 years (104 weeks) | 
| Comparison of serious infections rate in both study arms. | An infection is considered serious if it leads to inpatient hospitalization or prolongation of existing hospitalization, if it results in persistent or significant disability or incapacity, if it results in a life-threatening experience (meaning that the subject was at risk of death), or if it results in death. | Over 2 years (104 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid arthritis, Rituximab, Tapering, Disease impact