Background Adalimumab is usually used in combination with 15-20 mg methotrexate (MTX) weekly in early rheumatoid arthritis (RA). Lower doses of MTX have not been evaluated in controlled clinical trials.
Objectives 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. The percentage of pts with any AE was 62%, 59%, 67%, and 69% in the 2.5, 5, 10, and 20 mg arms, respectively. The overall incidence of MTX-related AEs was low. MTX-related AEs are shown in the table. Two infections in the 5 mg arm were serious AEs, appendicitis and sepsis, but did not result in study discontinuation. 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 number (percentage) of pts with ALT values >upper limit of normal (ULN) at wk 26 were 3(3%), 1(1%), 6(6%) and 6(6%) in the 2.5, 5, 10, and 20 mg arms, respectively. Regarding AST, 4(4%), 0, 3(3%), and 3(3%) in the 2.5, 5, 10, and 20 mg arms, respectively, had AST values >ULN.
Conclusions Overall, MTX-related AEs were infrequent. The frequency of some AEs appeared to increase with MTX dose, suggesting the lowest effective MTX dose in combination with ADA might be used.
Acknowledgements AbbVie Inc funded the study (NCT01185301). AbbVie was responsible for the study design, research, analysis, data collection, interpretation of data, and writing, reviewing, and approving of the publication. Medical writing support was provided by Kathleen V. Kastenholz, PharmD, MS, of AbbVie.
Disclosure of Interest G. Burmester Grant/research support from: AbbVie, Essex/Schering-Plough, Novartis, Roche, Wyeth, Consultant for: AbbVie, Essex/Schering-Plough, Novartis, Roche, Wyeth, Speakers bureau: AbbVie, Essex/Schering-Plough, Novartis, Roche, Wyeth, A. Kivitz Grant/research support from: AbbVie, Amgen, AstraZeneca, BMS, Celgene, Genentech, Janssen, Pfizer, UCB, Consultant for: BMS, Genentech, UCB, Speakers bureau: BMS, R. van Vollenhoven Grant/research support from: AbbVie, BMS, GSK, Human Genome Sciences, Merck, Pfizer, Roche, UCB, Consultant for: AbbVie, BMS, GSK, Human Genome Sciences, Merck, Pfizer, Roche, UCB, S. Florentinus Shareholder of: AbbVie, Employee of: AbbVie, P. Karunaratne Shareholder of: AbbVie, Employee of: AbbVie Inc, H. Kupper Shareholder of: AbbVie, Employee of: AbbVie Deutschland GmbH & Co., M. Dougados Grant/research support from: AbbVie, BMS, Merck, Novartis, Pfizer, Sanofi-Aventis, UCB, Consultant for: AbbVie, BMS, Merck, Novartis, Pfizer, Sanofi-Aventis, UCB, R. Fleischmann Grant/research support from: AbbVie, Pfizer, Merck, Roche, UCB, Celgene, Amgen, Astra-Zeneca, BMS, Janssen, Lilly, Novartis, Consultant for: AbbVie, Pfizer, Merck, Roche, UCB, Celgene, Amgen, Astra-Zeneca, BMS, Janssen, Lilly, Novartis
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