Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a Phase III randomized study (MIRROR)

Abstract

Objective: To evaluate the efficacy and safety of three dosing and repeat treatment regimens of rituximab (RTX) plus MTX in patients with active RA.

Methods: Patients with active RA despite stable MTX (10-25 mg/week) were randomly assigned to one of the three treatment regimens comprising two courses of RTX given 24 weeks apart: 2 x 500 and 2 x 500 mg; 2 x 500 and 2 x 1000 mg (dose escalation); and 2 x 1000 and 2 x 1000 mg. The primary endpoint was proportion of patients achieving ACR20 at Week 48.

Results: At Week 48, ACR20 responses were not statistically significantly different between the dose regimens. Compared with RTX 2 x 500 mg (n = 134) or dose escalation (n = 119), ACR and European League Against Rheumatism (EULAR) outcomes in the RTX 2 x 1000 mg group (n = 93) were consistently higher, with significantly more patients achieving EULAR responses (P = 0.0495). At Week 48, rituximab 2 x 1000 mg was associated with a higher proportion of patients who, following retreatment, maintained or improved their Week 24 responses. Dose escalation from 2 x 500 to 2 x 1000 mg did not appear to be associated with improved outcomes compared with continual 2 x 500 mg. All RTX regimens demonstrated comparable safety.

Conclusions: RTX 2 x 500 and 2 x 1000 mg could not be clearly differentiated, although some efficacy outcomes suggest improved outcomes in the rituximab 2 x 1000 mg group. Retreatment from Week 24 resulted in a sustained suppression of disease activity through to Week 48.

Trial registration: ClinicalTrials.gov NCT00422383.

Fig. 1

Overview of study design.

Fig. 2

Disposition of patients up to Week 48. ^aFourteen patients were randomly assigned to rituximab (RTX) 2 × 1000 mg, placebo. ^bSome patients received a treatment regimen other than that to which they were randomly assigned. ^cSix patients received placebo and 25 patients received RTX 2 × 500 mg for their second course (data on these 31 patients treated with non-protocol-specified regimens not shown). ^dOne patient did not receive a second course of treatment, but completed 25 weeks of follow-up.

Fig. 3

Number of patients achieving an improvement in ACR criteria at Week 48 (mITT population). *P = 0.8156. **P = 0.2419 for RTX (2 × 500 and 2 × 500 mg) vs RTX (2 × 500 mg, 2 × 1000 mg) and RTX (2 × 1000 and 2 × 1000 mg), respectively.

Fig. 4

Summary of clinical efficacy at Week 48. ^aDAS-28-ESR <2.6. *P = 0.0495 for RTX (2 × 500 and 2 × 500 mg) vs RTX (2 × 500 and 2 × 1000 mg). LDA: low disease activity.

Fig. 5

Plot of mean change from baseline in DAS-28-ESR score by visit, last observation carried forward (LOCF) imputation (mITT population).