Rituximab plus leflunomide in rheumatoid arthritis: a randomized, placebo-controlled, investigator-initiated clinical trial (AMARA study)

Abstract

Objective: To investigate the efficacy and safety of rituximab + LEF in patients with RA.

Methods: In this investigator-initiated, randomized, double-blind, placebo-controlled phase 3 trial, patients with an inadequate response to LEF who had failed one or more DMARD were randomly assigned 2:1 to i.v. rituximab 1000 mg or placebo on day 1 and 15 plus ongoing oral LEF. The primary efficacy outcome was the difference between ≥50% improvement in ACR criteria (ACR50 response) rates at week 24 (P ≤ 0.025). Secondary endpoints included ACR20/70 responses, ACR50 responses at earlier timepoints and adverse event (AE) rates. The planned sample size was not achieved due to events beyond the investigators' control.

Results: Between 13 August 2010 and 28 January 2015, 140 patients received rituximab (n = 93) or placebo (n = 47) plus ongoing LEF. Rituximab + LEF resulted in an increase in the ACR50 response rate that was significant at week 16 (32 vs 15%; P = 0.020), but not week 24 (27 vs 15%; P = 0.081), the primary endpoint. Significant differences favouring the rituximab + LEF arm were observed in some secondary endpoints, including ACR20 rates from weeks 12 to 24. The rituximab and placebo arms had similar AE rates (71 vs 70%), but the rituximab arm had a higher rate of serious AEs (SAEs 20 vs 2%), primarily infections and musculoskeletal disorders.

Conclusion: The primary endpoint was not reached, but rituximab + LEF demonstrated clinical benefits vs LEF in secondary endpoints. Although generally well tolerated, the combination was associated with additional SAEs and requires monitoring.

Trial registration: EudraCT: 2009-015950-39; ClinicalTrials.gov: NCT01244958.

Keywords: investigator-initiated research; leflunomide; randomized clinical trial; rheumatoid arthritis; rituximab.

Fig. 1

Patient disposition through week 24 AE: adverse event; RTX: rituximab.

Fig. 2

ACR response rates The red box indicates the primary end point of ACR50 response at week 24. *P < 0.025 for rituximab + LEF vs placebo + LEF as assessed by one-sided Fisher’s exact test. ACR20/50/70: ACR criteria for 20/50/70% improvement.

Fig. 3

Mean DAS28 values; horizontal bars indicate 95% CIs Stated P-values for rituximab + LEF vs placebo + LEF are two-sided values as determined by t-test (significance level of 0.05).

Fig. 4

Dimensions of SF-36, HAQ-DI and FACIT scores at baseline and week 24 Higher scores are better for SF-36 and FACIT (dimensions F7 and F8 were rescaled so that higher levels were better for all dimensions) and worse for HAQ-DI. *P-value ≤0.05 for rituximab + LEF vs placebo + LEF. Data for mean change from baseline to week 24 are presented in supplementary Table S1, available at Rheumatology online. FACIT: Functional Assessment of Chronic Illness-Therapy fatigue scale; HAQ-DI: HAQ Disability Index; SF-36: Short Form-36.