Abstract
BackgroundA standard low-dosing schedule of rituximab (RTX; 2 × 500 mg or 1 × 1000 mg) is as effective for active rheumatoid arthritis (RA) as the registered dose (2 × 1000 mg). Moreover, several small uncontrolled studies suggest that even lower-dosed treatment with RTX also leads to good treatment response in patients with RA. Retreatment with such an ‘ultra-low’ dose RTX in patients who responded well to RTX induction treatment is of special interest, as long-term use of lower RTX doses may lead to shorter infusion duration, lower risk of adverse events and lower costs. However, the effect of ultra-low dose of RTX has not been investigated using a controlled trial of proper design and dimensions.Methods/DesignREDO is an investigator driven six-month pragmatic, double-blind, randomised controlled non-inferiority trial on the effects of ultra-low-dose RTX (1 × 500 or 1 × 200 mg) compared to standard low dose (1 × 1000 mg) in RA patients who are being retreated with RTX. A total of 140 RA patients, having reached low disease activity (DAS28CRP < 2.9) after the previous RTX infusion and DAS28CRP < 3.5 at moment of retreatment, are randomised in a ratio of 1:2:2 to 1 × 1000 mg, 1 × 500 mg or 1 × 200 mg. The primary objective is testing non-inferiority of the ultra-low-dose vs. standard low-dose RTX, by comparing mean change in DAS28CRP from baseline to six months to the non-inferiority margin of 0.6. Secondary outcomes over the same period are: function; quality of life; safety; costs; and pharmacokinetics and dynamics as process measures.DiscussionThis study protocol shares characteristics of both early dose finding trials as well as late pragmatic clinical studies. Several choices in the design of this trial are described and possible consequences for RA treatment and expected biosimilar introduction are discussed.Trial registrationDutch Trial Register, NTR6117. Registered on 15 November 2016 (CMO NL57520.091.16, 8 November 2016)
Highlights
A standard low-dosing schedule of rituximab (RTX; 2 × 500 mg or 1 × 1000 mg) is as effective for active rheumatoid arthritis (RA) as the registered dose (2 × 1000 mg)
Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody authorised for use in patients with severe active rheumatoid arthritis (RA) in combination with methotrexate (MTX) when patients have an inadequate response or intolerance to other disease-modifying antirheumatic drugs (DMARDs), including one or more tumour necrosis factor inhibitors (TNFi)
No formal dose-finding efforts were done, Leandro et al concluded in their uncontrolled study of 22 RA patients that doses below 600 mg/m2 were less effective, but this conclusion was based on only four patients
Summary
A standard low-dosing schedule of rituximab (RTX; 2 × 500 mg or 1 × 1000 mg) is as effective for active rheumatoid arthritis (RA) as the registered dose (2 × 1000 mg). It was reasoned that RA could be seen as a low-grade lymphoma of synovial tissue, caused by an oligoclonal (instead of monoclonal) proliferation of B cells exhibiting malignant behaviour by destroying local tissues Using this comparison, patients were treated with a single remission-induction treatment course, identical to that for non-Hodgkin’s lymphoma, combining four weekly RTX infusions of 750 mg/m2 with prednisone and cyclophosphamide. Adriamycin was omitted as co-medication to decrease the chance on treatment-related side toxicity These two open-label case series showed that a single RTX-based treatment course could induce disease remission in a proportion of patients with RA. The first randomised controlled trial (RCT) to examine the efficacy of RTX in RA patients aimed at obtaining a treatment regimen without cyclophosphamide instead of dosefinding and used a simplified RTX dosing regimen of 1000 mg on treatment days 1 and 15 [8]. This dose is the registered dose for treatment of RA patients
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