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 + leflunomide in patients with rheumatoid arthritis (RA). Methods In this investigator-initiated, randomised, double-blind, placebo-controlled phase 3 trial, patients with an inadequate response to leflunomide who had failed ≥1 disease-modifying antirheumatic drug were randomly assigned 2:1 to intravenous rituximab 1000 mg or placebo on day 1 and 15 plus ongoing oral leflunomide. The primary efficacy outcome was the difference between ≥50% improvement in American College of Rheumatology 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 August 13, 2010 and January 28, 2015 140 patients received rituximab (n = 93) or placebo (n = 47) plus ongoing leflunomide. Rituximab + leflunomide resulted in an increase in the ACR50 response rate which was significant at week 16 (32% vs 15%; p = 0.020), but not week 24 (27% vs 15%;] p = 0.081), the primary end point. Significant differences favoring the rituximab + leflunomide arm were observed in some secondary endpoints, including ACR20 rates from weeks 12–24. 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 end point was not reached, but rituximab + leflunomide demonstrated clinical benefits vs leflunomide 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.

Efficacy of synthetic and biological DMARDs: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis

“…AMARA was an RCT investigating rituximab (RTX) combination therapy with LEF in patients who showed IR to LEF alone. Although numerical results were in favour of RTX+LEF, the primary endpoint (ACR 50 response at week 24) was not met (RTX+LEF: 25/68 (27%) vs PBO+LEF: 7/40 (15%); p=0.081) 14…”

“…In total eight trials investigating bDMARDs with or without concomitant csDMARD were included (six with low RoB, one with high RoB, one conference abstract). Primary results are summarised in table 2 13–21…”

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)

“…The Addition of MabThera to Arava in the RA (AMARA) study was an investigatorinitiated prospective, randomized, double-blind, placebo-controlled, phase 3 clinical trial conducted at 33 clinical centers in Germany between 8 August 2010 and 28 January 2015 (Supplementary Section S1) [15]. The AMARA study was registered with the European Union Drug Regulating Authorities Clinical Trials Database (EudraCT 2009-015950-39) on 28 December 2009, prior to submission to ethical committees and to inclusion of the first subject; subsequently it was additionally registered with ClinicalTrials.gov (NCT01244958) to provide broader access to the protocol.…”

“…As previously reported [15], we investigated the efficacy and safety of rituximab + leflunomide compared with placebo + leflunomide in patients with active RA and an inadequate response to leflunomide. In the rituximab arm, patients received the approved standard induction dose of rituximab (two doses of rituximab 1000 mg two weeks apart).…”

Dynamics of patient reported outcomes during the use various biological disease-modifying antirheumatic drugs for rheumatoid arthritis

“…Через 6 мес. было отмечено преимущество РТМ в отношении физической и ментальной составляющей SF-36, но не динамики HAQ (0,16 и 0,16 соответственно) и FACIT-F (12,3 и 5,26 соответственно) (р=0,11) соответственно [54]. Научно-практическая ревматология.…”