Effectiveness of Different Rituximab Doses Combined with Leflunomide in the Treatment or Retreatment of Rheumatoid Arthritis: Part 2 of a Randomized, Placebo-Controlled, Investigator-Initiated Clinical Trial (AMARA)

Abstract

Background: The optimal dose of rituximab in combination with leflunomide in patients with rheumatoid arthritis (RA) is not known.

Methods: In Part 1 (previously reported) of the investigator-initiated AMARA study (EudraCT 2009-015950-39; ClinicalTrials.gov NCT01244958), improvements at week (W)24 were observed in patients randomized to rituximab + leflunomide compared with placebo + leflunomide. In the study reported here (Part 2), Part 1 responders received rituximab 500 or 1000 mg at W24/26 plus ongoing leflunomide. Patients were randomized at baseline to their eventual W24 treatment group. The Part 2 primary outcome was the mean Disease Activity Score-28 joints (DAS28) at W52, based on the last observation carried forward (LOCF) analyses and a two-sided analysis of variance. Patient-reported outcomes (PROs) and adverse events were evaluated.

Results: Eighty-three patients received rituximab at W24/26 (31 rituximab→rituximab 1000 mg; 29 rituximab→rituximab 500 mg; 10 placebo→rituximab 1000 mg; 13 placebo→rituximab 500 mg). At W52, there were no significant differences in DAS28 between rituximab doses in patients originally treated with rituximab or those originally treated with placebo. In the Part 1 placebo group, the higher rituximab dose was associated with greater improvements in ACR response rates and some PROs. Adverse events were similar regardless of rituximab dose.

Conclusions: Retreatment with rituximab 500 mg and 1000 mg showed comparable efficacy, whereas an initial dose of rituximab 500 mg was associated with lower response rates versus 1000 mg. Reduced treatment response with the lower dose in patients initially treated with placebo may have been influenced by small numbers and baseline disease activity.

Keywords: clinical trial; dosing; leflunomide; rheumatoid arthritis; rituximab.

Figure 1

Patient disposition in part 2 of the AMARA study. Randomizations to re-treatment groups occurred at baseline. LEF, leflunomide; PBO, placebo; RTX, rituximab; W, week.

Figure 2

DAS28 outcomes during Part 2 of the AMARA study. (A) Mean DAS28 at week 52 in LOCF analyses. (B) Mean DAS28 over time from week 24 to week 52. For both (A) and (B), vertical lines indicate 95% CI. DAS28, Disease Activity Score based on 28 joints; NS, not significant; PBO, placebo; RTX, rituximab.

Figure 3

Percent of patients with ACR responses following rituximab treatment/retreatment based on observed data. (A) ACR20 responses; (B) ACR50 responses; (C) ACR70 responses. Data for week 52 are based on the number of patients with ACR responses divided by the number of patients with ACR data. Fisher’s exact p-values (2-tail) are shown. Week 52 data were missing for 3 patients in the RTX→RTX 2 × 1000 mg group, 1 patient in the PBO→RTX 2 × 1000 mg group, and 3 patients in the PBO→RTX 2 × 500 mg group. * Stepdown Bonferroni adjusted p value = 0.051. ACR, American College of Rheumatology; PBO, placebo; RTX, rituximab.

Figure 4

Patient-reported outcomes at week 52. Mean values for (A) SF-36 domains; (B) Patient global assessment (PtGA), Health Assessment Questionnaire-Disability Index (HAQ-DI), and FACIT-fatigue (FACIT-F) scores. For SF-36 and FACIT-F, higher scores indicate better status. For PtGA and HAQ-DI, lower scores indicate better status. PBO, placebo; RTX, rituximab.