EFFICACY AND SAFETY OF ADALIMUMAB WITH LOW AND HIGH DOSE-METHOTREXATE IN PATIENTS WITH RHEUMATOID ARTHRITIS WITH INADEQUATE RESPONSE TO METHOTREXATE: THE RANDOMISED CONTROLLED MIRACLE STUDY

Background Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes not only joint pain but also bone destruction resulting in impairment of quality of life. Tumor necrosis factor inhibitors have improved prognosis of patients with rheumatoid arthritis dramatically, especially in combination with methotrexate, however, the optimal dose of the concomitant methotrexate is unclear. Objectives To evaluate the efficacy and safety of adalimumab in combination with reduced dose of methotrexate in patients with early RA with inadequate response to methotrexate. Methods The MIRACLE study was a multinational, randomized, open-label study in patients with RA with inadequate response to methotrexate conducted in Asia. It compared low dose and high dose methotrexate upon starting adalimumab. Methotrexate-naive patients with RA with a disease duration of less than two years started methotrexate at 6 to 8 mg/week and increased it to the maximum tolerable dose by week 12. Patients who have not achieved remission according to simplified disease activity index (SDAI) despite methotrexate ≥ 10 mg/week at week 24 were randomised to the maximum tolerable dose of methotrexate group (10 to 25 mg/week) or the reduced dose group (6 to 8 mg/week) and started to receive subcutaneous adalimumab 40 mg every other week. The primary endpoint was non-inferiority in the achievement of SDAI remission at week 48 in the reduced dose group compared with the maximum tolerable dose group with a non-inferiority margin of -15% based on two-sided 90% confidence interval. ( NCT03505008 ) Results A total of 300 patients were enrolled in the study. Among them, 291 started methotrexate and were included in the analysis. The mean age was 57.7±15.2 years, female was 74.6%, and the mean disease duration from the diagnosis of RA was 21.1±56.2 days. Anti-CCP antibody was positive in 211 (73.0%) and the mean SDAI at study enrollment was 26.5±12.4. At week 24, with the mean dose of methotrexate of 12.6±2.9 mg/week, 108 patients (37.1%) achieved remission according to SDAI and continued MTX monotherapy. 134 patients (46.0%) were randomised and started adalimumab with 68 patients in the maximum tolerable dose group and 66 patients in the reduced dose group. At week 48, the remission achievement rates were 38.4 % and 44.8 %, respectively, with the adjusted risk difference of the reduced dose group to the maximum tolerable dose group of 6.4% (-7.0% to 19.8%, 90% CI), which met the criterion for noninferiority. No significant difference was found in health assessment questionnaire disability index ≤0.5 (59.1% vs 62.0%, respectively, p=0.72) and in radiological remission rates (Δmodified total Sharp score ≤0.5, 66.3% vs 62.0 %, respectively, p=0.59). Adverse drug reactions tended to be more frequent in the maximum tolerable dose group than in the reduced dose group (22.1% vs 9.1%, respectively, p=0.06). Conclusion The MIRACLE randomised study demonstrated that, in patients with inadequate response to methotrexate, the efficacy of adalimumab with reduced dose of concomitant methotrexate was not inferior to that with maximum tolerable dose of methotrexate with better safety profile. Disclosure of Interests Hiroya Tamai Speakers bureau: Eisai, Grant/research support from: Eisai, Kei Ikeda Speakers bureau: AbbVie, Eisai, Eli Lilly, Novartis, Gilead, Asahi-Kasei, Grant/research support from: Mitsubishi-Tanabe, Toshiaki Miyamoto: None declared, Hiroaki Taguchi: None declared, Chang-Fu Kuo: None declared, Kichul Shin: None declared, Shintaro Hirata Speakers bureau: AbbVie, Asahi-Kasei, Astellas, Ayumi, Bristol Myers Squibb, Celgene, Chugai, Eisai, Eli Lilly, Gilead, Glaxo SmithKline, Janssen, Kyorin, Novartis, Pfizer, Sanofi, Tanabe-Mitsubishi, UCB, Paid instructor for: AbbVie, Mitsubishi-Tanabe, Consultant of: AbbVie, Astellas, Bristol Myers Squibb, Eisai, Gilead, Ily Lilly, Grant/research support from: AbbVie, Asahi-Kasei, Eisai, Otsuka, Sanofi, Shionogi, Chugai, Pfizer, Tanabe-Mitsubishi, Eli Lilly, UCB, yutaka okano: None declared, Shinji Sato Speakers bureau: AbbVie, Eisai, Grant/research support from: AbbVie, Eisai, Hidekata Yasuoka Speakers bureau: AbbVie, Asahi Kasei Pharma, Astellas, Daiichi-Sankyo, Eisai, Kissei, Takeda, Mitsubishi-Tanabe, Chugai, Novartis, Eli Lilly, Pfizer, Janssen, Sanofi, Teijin, Boehringer-Ingelheim, Bayer, Glaxo Smith Kline, Paid instructor for: AbbVie, Consultant of: AbbVie, Asahi Kasei, Grant/research support from: Mitsubishi-Tanabe, Takeda, Daiichi-Sankyo, Chugai, Bristol-Myers, MSD, Astellas, In Ah Choi Speakers bureau: Abbvie, Eisai, Sung-Hwan Park: None declared, Meng-Yu Weng Paid instructor for: Novartis, Eli Lilly, ChuGai, Abbvie, Consultant of: Abbvie, Masataka Kuwana Speakers bureau: Astellas, Asahi Kasei Pharma, Boehringer-Ingelheim, Chugai, Eisai, Janssen, Mochida, Nippon Shinyaku, Ono Pharmaceuticals, Pfizer, Mitsubishi-Tanabe, Consultant of: Boehringer-Ingelheim, Kissei, Mochida, Grant/research support from: AbbVie, Asahi Kasei Pharma, Boehringer-Ingelheim, Chugai, Eisai, MBL, Nippon Shinyaku, Ono Pharmaceuticals, Mitsubishi-Tanabe, Yun Jong Lee Grant/research support from: Yuhan, Tomonori Ishii Speakers bureau: Chugai, Mitsubishi-Tanabe, Glaxo Smith Kline, Pfizer, Eli Lilly, Janssen, AbbVie, Eisai, Astellas, Jinhyun Kim: None declared, Hideto Kameda Speakers bureau: AbbVie, Pfizer, Consultant of: AbbVie, Grant/research support from: AbbVie, Eisai, Toshihisa Kojima Speakers bureau: AbbVie, Pfizer, Eisai, Grant/research support from: AbbVie, Han Joo Baek: None declared, Ping-Ning Hsu: None declared, Chun-Ming Huang Paid instructor for: Abbvie, Pfizer, Tien-Tsai Cheng Paid instructor for: Abbvie, Grant/research support from: Abbvie, Wan-Yu Sung: None declared, Takehiro Taninaga Shareholder of: Eisai.co.,Ltd., Employee of: Eisai.co.,Ltd., Masahiko Mori Shareholder of: Eisai.co.,Ltd., Employee of: Eisai.co.,Ltd., Hideaki Miyagishi Shareholder of: Eisai.co.,Ltd., Employee of: Eisai.co.,Ltd., Yasunori Sato Speakers bureau: Eisai Co., Ltd. Kowa Company, Ltd., Consultant of: MOCHIDA PHARMACEUTICAL CO., LTD, Tsutomu Takeuchi Speakers bureau: Astellas, AbbVie, Ayumi, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Glaxo Smith Kline, Janssen, Mitsubishi-Tanabe, Nippon-kayaku, Novartis, Pfizer, Sanofi, UCB, Grant/research support from: Asahi Kasei, AbbVie, Ayumi, Boehringer-Ingelheim, Chugai, Eisai, Eli Lilly, Mitsubishi-Tanabe, Sanofi, UCB, Yuko Kaneko Speakers bureau: Asahi Kasei, Astellas, Ayumi, Bristol Myers Squibb, Chugai, Eisai, Elli Lilly, Mitsubishi-Tanabe, Novartis, UCB, Grant/research support from: AbbVie, Chugai, Eisai, Mitsubishi-Tanabe, UCB.