91. Methotrexate dose has Minimal Effect on Methotrexate-Related Toxicity in Patients with Early Rheumatoid Arthritis Treated in Combination with Adalimumab: Results of Concerto Trial

Abstract

Background/Purpose: Adalimumab is usually used in combination with 15-20 mg methotrexate (MTX) weekly in early rheumatoid arthritis (RA). Lower doses of MTX in combination with biologics have not been evaluated in controlled clinical trials. The objective of this study was to evaluate the MTX dose-response of MTX-related toxicities in patients (pts) with early RA receiving ADA in combination with MTX. Methods: CONCERTO was a 26-week (wk), phase 3, double-blind, parallel-arm study in MTX-naive pts with active RA < 1 year in duration. Pts were randomized 1:1:1:1 to open-label ADA 40 mg every other wk + blinded weekly oral MTX doses of 2.5, 5, 10, or 20 mg. All pts took 5 mg folic acid weekly throughout the study. Pts in the 20 mg arm started with 10 mg MTX, with bi-weekly increases of 2.5 mg through wk 8. MTX-toxicity related adverse events (AEs) were defined according to MTX prescribing information and recorded as AEs at each visit through wk 26. Laboratory data were summarized through wk 26. Results: Of the 395 randomized pts, 358 (91%) completed 26 wks. The safety population included 98, 100, 99, and 98 pts in the 2.5, 5, 10, and 20 mg arms, respectively. 9 pts (2.3%) discontinued study drug due to an AE that was not necessarily MTX-related. Of the total population, the percentage of pts with any AE was 62, 59, 67, and 69%, any serious AE was 5, 2, 3 and 7%, and any infection was 20, 17, 24, and 35% in the 2.5, 5, 10, and 20 mg arms, respectively. Two infections in the 5 mg arm were serious AEs, appendicitis and sepsis, but did not result in study discontinuation and were not associated with MTX. The overall incidence of MTX-related AEs was low (Table). Infection and abnormal hair loss appeared to have a MTX dose relationship. No differences in mean change from baseline in hematocrit, neutrophil count, platelet count, ALT, or AST values were observed at wk 26 among the 4 doses of MTX. The percentage of pts with ALT values > upper limit of normal (ULN) that were associated with MTX at wk 26 were 3, 1, 6, and 6% in the 2.5, 5, 10, and 20 mg arms, respectively. Regarding AST, 4, 0, 3, and 3% in the 2.5, 5, 10, and 20 mg arms, respectively, had AST values > ULN. (Table Presented) Conclusion: Overall, the combination of ADA plus varying doses of MTX was well tolerated, and MTX-related AEs were infrequent. The frequency of infections and abnormal hair loss appeared to have a MTX-dose relationship. Serious infections were very rare and had no relationship to MTX. No differences in mean change from baseline in blood cell counts or transaminases were observed at wk 26 among the 4 doses of MTX. (Table Presented).