Clinical trial NCT06906549: Evaluation of 200 Mg of Rituximab Every 6 Months As Maintenance Treatment of Rituximab-treated Patients with Rheumatoid Arthritis
Official title: Evaluation of 200 Mg of Rituximab Every 6 Months As Maintenance Treatment of Rituximab-treated Patients with Rheumatoid Arthritis: a Non-inferiority Prospective Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Rheumatoid Arthritis (RA)
Rituximab (RTx)
Keywords: Dose reduction
Low dose Rituximab
Lead sponsor: University Hospital, Strasbourg, France
Sponsor class: OTHER
First posted: 2025-04-02
Enrollment: 260
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting joints and causing progressive disability. Current treatment strategies involve conventional disease-modifying anti-rheumatic drugs (csDMARDs) and, in more resistant cases, biologic DMARDs (bDMARDs) such as Rituximab. Rituximab, a monoclonal antibody targeting CD20-positive B cells, is administered as an induction dose followed by maintenance therapy every six months. Standard maintenance dosing consists of 1g infusions, but lower doses may provide equivalent efficacy with fewer side effects.

The RADAR trial is a multicenter, prospective, randomized, double-blinded, non-inferiority controlled trial designed to evaluate whether a 200 mg maintenance dose of Rituximab every six months is non-inferior to the standard 1g dose in patients with RA who are in low disease activity. The study will assess disease activity using the DAS28-CRP score over 12 months, alongside various secondary endpoints, including treatment failure rates, immune responses, and adverse events.

By determining the minimum effective Rituximab dose, the study aims to optimize patient safety, reduce the risk of infections, and lower healthcare costs. This trial is particularly relevant as Rituximab has lost patent protection, making cost-effective treatment crucial, especially in low-resource settings. Findings from this study could lead to updated treatment guidelines, benefiting RA patients worldwide.

Detailed description: Rheumatoid arthritis (RA) is the most prevalent chronic inflammatory rheumatic disease in Europe, affecting 0.3%-0.5% of the population. Treatment follows a Treat-to-Target (T2T) approach, where patients are initially managed with conventional synthetic DMARDs (csDMARDs), such as methotrexate, and if necessary, escalated to biologic DMARDs (bDMARDs) like Rituximab, a monoclonal antibody that depletes CD20-positive B cells.

The current standard maintenance therapy for RA patients receiving Rituximab consists of 1g infusions every six months. However, concerns about long-term safety, immune suppression, and cost have led researchers to explore lower doses. Studies suggest that 200 mg of Rituximab may be sufficient to maintain disease control while potentially reducing the risks associated with B-cell depletion, such as hypogammaglobulinemia and serious infections.

Study Rationale and Objectives The RADAR trial aims to provide definitive evidence on the feasibility of reducing Rituximab doses without compromising efficacy. A previous randomized trial indicated that a 500 mg dose was non-inferior to 1g, but the 200 mg arm lacked sufficient statistical power. Subsequent long-term follow-up data suggest that 200 mg may also be effective, warranting further investigation.

The primary objective of this study is to demonstrate that the 200 mg Rituximab maintenance dose is non-inferior to 1g in terms of disease activity, measured by DAS28-CRP at 12 months.

Secondary objectives include:

* Comparing disease activity at 6 and 12 months
* Evaluating treatment failure rates (need for additional Rituximab doses, switching to other bDMARDs, corticosteroid use)
* Assessing flare occurrence and patient-reported outcomes (quality of life, disability index)
* Investigating B and T lymphocyte subpopulations and immunoglobulin levels (IgG, IgA, IgM)
* Analyzing vaccine responses and Human Anti-Chimeric Antibody (HACA) levels
* Monitoring immunosuppression markers, such as Torque Teno Virus (TTV) viral load
* Documenting adverse and serious adverse events Study Design

This is a multicenter, double-blinded, non-inferiority, randomized controlled trial (RCT). Patients will be randomized 1:1 to receive either:

1. 200 mg of Rituximab (experimental group)
2. 1g of Rituximab (control group) Participants will receive two infusions: one at baseline (Month 0) and one at 6 months, with follow-up visits at 4, 6, 10, and 12 months. The primary endpoint is the mean reduction in DAS28-CRP between baseline and 12 months.

Blinding Procedure:

* Infusions will be prepared in the central pharmacy to ensure identical appearance in both groups.
* Neither patients nor clinicians will know the assigned dosage.

Inclusion criteria:

* Adults (≥18 years) with RA (EULAR/ACR 2010 criteria)
* Low disease activity (DAS28-CRP \<3.2) on Rituximab
* Prior treatment with Rituximab (at least one infusion in the past year)
* Stable on csDMARDs (if applicable)
* Corticosteroid dose ≤10 mg/day

Non-inclusion criteria:

* Autoimmune diseases other than RA
* Severe infections, immunodeficiency, or uncontrolled disease
* Active or untreated tuberculosis, hepatitis B/C
* Pregnancy, breastfeeding, or planned pregnancy
* Drug/alcohol addiction
* Patients unable to give informed consent Study Assessments and Data Collection

The study will include clinical, biological, and immunological assessments:

* DAS28-CRP scores at baseline, 6, and 12 months
* Immunological assays (B/T cell phenotyping, immunoglobulin levels, HACA)
* Vaccine serologies (Diphtheria, Pneumococcus, Tetanus, Haemophilus, SARS-CoV-2)
* Quality-of-life surveys (EQ-5D-5L, SF-36, RAPID-3)
* Adverse event monitoring

Sample Size Calculation:

The trial requires 260 patients to achieve 92% power to detect non-inferiority, using a linear mixed model with a non-inferiority margin of -0.3 on DAS28-CRP.

Expected Impact

If 200 mg of Rituximab proves non-inferior to 1g, this study could redefine maintenance therapy guidelines, reducing:

* Drug exposure and immune suppression risks
* Serious infections and adverse events
* Healthcare costs, improving access in resource-limited settings By providing definitive clinical and immunological data, the RADAR trial has the potential to influence global RA management and enhance long-term treatment safety.

Eligibility criteria: Inclusion Criteria:

* Age ≥ 18 years
* Diagnosis of rheumatoid arthritis (RA) according to EULAR/ACR 2010 classification criteria
* DAS28 ≤ 5.1
* Current maintenance treatment with Rituximab regardless of dose and/or duration of Rituximab treatment and with at least first cycle of Rituximab ended (2 initial infusions)
* Last Rituximab infusion between 6 and 18 months prior to inclusion
* Corticosteroids ≤10 mg/day within 4 weeks prior to inclusion
* Affiliation to a social insurance system or beneficiary
* Written informed consent to participate in the study, dated and signed before starting the trial
* Effective method of birth control during the study

Exclusion Criteria:

* Rheumatic autoimmune disease other than RA (except associated Sjogren's disease, which is allowed)
* Concurrent treatment with any other targeted therapy than Rituximab
* Any contraindication to Rituximab or to NaCl 0.9%
* Significant uncontrolled associated disease or comorbidity
* Known active infection or history of serious recurrent or chronic infection
* Laboratory findings: active or untreated latent tuberculosis, hepatitis B positive, hepatitis C positive, haemoglobin \<8 g/dL, neutropenia \< 1.5G/L, IgM \<0.4 g/L and/or IgG \<5 g/L
* Pregnancy, breastfeeding, or planned pregnancy during the study (on subject declaration)
* Drug addiction, alcohol addiction
* Patients who cannot be followed for the 12 month-duration
* Patients over the age of legal majority who are protected, or deprived of liberty by judicial or administrative decision
* Subject in exclusion period (determined by a previous or ongoing study)
* Patients unable to give informed consent (e.g., patients in a situation of medical emergency, patients who have difficulty comprehending the essential details of the trial...)
* Patients who have difficulty reading or understanding French, or who have an inability to understand the delivered information

Primary outcomes:
measure: Mean reduction of rheumatoid arthritis activity score (DAS28-CRP)
timeFrame: 12 Months
Secondary outcomes:
measure: Compare the disease activity measured by DAS28-CRP between the two arms
timeFrame: at inclusion, 6 and 12 months
measure: DAS28 categories
timeFrame: at inclusion, 6 months and 12 months
measure: Number of Rituximab infusions
timeFrame: 12 Months
measure: Number of patients switching or initiating a cDMARD or switching from Rituximab to another bDMARD
timeFrame: 12 Months
measure: Number of patients using oral corticosteroids at a dose greater than 10 mg/day
timeFrame: 12 Months
measure: Number of flares throughout study period
timeFrame: 12 Months
measure: FLARE questionnaire (FLARE ASSESSMENT IN RHEUMATOID ARTHRITIS)
timeFrame: at 6 and 12 months
measure: RAPID-3 score (ROUTINE ASSESSMENT OF PATIENT INDEX DATA 3)
timeFrame: at inclusion, 6 and 12 months
measure: RAID score (RHEUMATOID ARTHRITIS IMPACT OF DISEASE)
timeFrame: at inclusion, 6 and 12 months
measure: EQ5D-5L (EUROQOL GROUP)
timeFrame: at inclusion, 6 and 12 months
measure: SF-36 to compare the patient quality of life
timeFrame: at inclusion, 6 and 12 months
measure: B, T and NK cell phenotyping to compare cell subpopulations
timeFrame: at inclusion, 6 and 12 months
measure: Compare change in IgG, IgA and IgM levels
timeFrame: at inclusion, 6 and 12 months
measure: Vaccinal serologies to compare vaccine response
timeFrame: at inclusion, 6 and 12 months
measure: Compare HACA (Human antichimeric antibody) levels
timeFrame: at inclusion and 12 months
measure: Evolution of Torque Teno Virus (TTV) viral load in the serum of patients
timeFrame: between inclusion and 12 months
measure: Number of infections
timeFrame: 12 Months
measure: Number of serious infections
timeFrame: 12 Months
measure: Number of adverse events
timeFrame: 12 Months
measure: Number ofserious adverse events
timeFrame: 12 Months
Other outcomes:
Locations:
Study officials:
References: