REDO Trial Will Help Answer Questions About Ultra-Low-Dose Rituximab Therapy

Several small studies have suggested that ultra—low-dose treatment with rituximab leads to good treatment responses in patients with rheumatoid arthritis (RA) compared with standard low-dose schedules of rituximab. Re-treatment with ultra—low-dose rituximab in patients who responded well to rituximab induction treatment is of special interest, as it may lead to shorter infusion duration, lower risk of adverse events, and lower treatment costs.

To this point, however, the effect of ultra—low-dose rituximab has not been investigated using a controlled trial of proper design and dimensions, according to Dutch researchers, led by Alfons A. den Broeder, MD, PhD. The Retreatment with Rituximab in RhEumatoid arthritis: Disease Outcome after Dose Optimisation (REDO) trial shares characteristics of both early dose-finding trials and late pragmatic clinical studies.

REDO is a 6-month, double-blind, randomized, controlled, non-inferiority trial on the effects of ultra—low-dose rituximab (500 mg or 200 mg) compared with standard low-dose rituximab (1000 mg) in patients with RA. REDO is funded by 2 healthcare insurance companies in The Netherlands and is independent of the reference rituximab’s manufacturer, Roche. The description of the REDO trial was published online in the journal Trials.

A total of 140 patients with RA who reached low disease activity—defined as a score of under 2.9 on the Disease Activity Score 28 scale using C-reactive protein values (DAS28-CRP) after the previous rituximab infusion, and DAS28CRP under 3.4 at the moment of retreatment—will be randomized in a ratio of 1:22 to single doses of either 500 mg or 200 mg of rituximab. Patients are eligible for the trial if they were treated at least once with regular low-dose rituximab for RA in the last 18 months, and had received no other biological disease-modifying antirheumatic drugs (DMARDs) after the last rituximab dose. Patients treated with innovator rituximab (MabThera) as well as approved rituximab biosimilars in similar doses to those used for conventional rituximab will also be included.

The primary study objective is testing non-inferiority of the ultra—low-dose versus standard low-dose rituximab by comparing the mean change in DAS28CRP from baseline to 6 months with a non-inferiority margin of 0.6. Secondary outcomes over the same period are function, quality of life, safety, costs, and pharmacokinetics and pharmacodynamics as process measures.

The use of ultra—low-dose rituximab for retreatment of patients with RA could be effective, the researchers believe, because RA is caused by a proliferation of oligoclonal B cells exhibiting malignant behavior by destroying local tissues. Thus, the treatment goal is achieving disease remission by eradicating pathogenic B cells. Because earlier low-dose rituximab studies have shown that B-cell depletion achieved with rituximab can persist throughout the interval between drug infusion, and because lower baseline B-cell counts were associated with complete B-cell depletion following a first 500-mg dose of rituximab, “…the (partially) persisting B-cell depletion induced by an earlier infusion could reduce the dose of rituximab needed for retreatment infusions,” the researchers note. In addition, similar monoclonal antibodies have been shown to be effective well below the authorized doses for rituximab.

The use of ultra—low-dose rituximab could present several advantages over standard low-dose rituximab treatment, the authors say:

• The risk of infection could be lower because rituximab use is associated with a dose-dependent risk of serious infection
• Shorter infusion durations and less administered drug product could lead to less patient burden and perhaps lower risk for infusion reaction
• Costs could decrease, and could therefore improve cost-effectiveness of biological therapy

However, the use of ultra-low doses of rituximab might also lead to increased disease activity in the subset of patients whose minimal effective rituximab dose is 1000 mg. Therefore, prediction of response to ultra—low-dose rituximab would be key to preventing patients from flaring and experiencing accelerated joint damage.

The REDO trial began on December 15, 2016, and is currently recruiting.