Background:Iguratimod (IGU) has demonstrated efficacy and safety for active rheumatoid arthritis (RA) patients in double-blind clinical trials in China and Japan as a new disease-modifying anti-rheumatic drug (DMARD). There are no studies evaluating the radiographic progression of structural joint damage of IGU for the treatment of RA using the mTSS as the primary endpoint.Objectives:Our study was to evaluate the efficacy and safety of IGU monotherapy and IGU combined methotrexate (MTX) compared with MTX monotherapy, including the inhibitory effects of joint destruction.Methods:This randomized, double-blind, parallel-controlled, multicenter study in patients with active RA who have not previously used MTX and biological DMARDs (bDMARDs) (ClinicalTrials.gov Identifier NCT01548001) was carried out in China. Patients were randomized 1:1:1 to receive IGU 25 mg twice a day (bid), MTX 10mg once a week(qw) for the first 4 weeks and 15 mg once a week(qw) for week 5 to 52, or IGU combined MTX (IGU+MTX) for 52 weeks. The primary endpoints were to assess and compare American College of Rheumatology 20% (ACR20) response and the change of modified total Sharp scoring (mTSS) score over 52 weeks (Intention-to-treat, ITT analysis). The non-inferiority test was used to analyze the difference of ACR20 response at 52 weeks between the IGU monotherapy and the MTX monotherapy arms, and the non-inferiority limit value was 10%. The difference test was used for the comparison between the IGU+MTX and MTX monotherapy arms. Two-way ANOVA was used to analyze the difference of the changes of mTSS score of each arm compared with baseline value (0 week).Results:A total of 895 patients were randomized to IGU 25mg bid (n =297), MTX 10-15mg qw(n=293), and IGU+MTX (n=305). Baseline characteristics were comparable between the arms (Table 1).Table 1.Demographic and Other Baseline Characteristics (SAS)IGUMTXIGU+MTXNumber of Subjects297293305Age, mean (SD) years46.87(10.67)47.63(10.70)48.37(10.69)Female/male, %77.44/22.5679.18/20.8278.03/21.97Duration of RA, mean(SD) years11.67±7.1611.60±7.9811.67±7.27CRP, mean(SD) mg/L222.32±35.4720.67±26.6119.74±31.38Tender joint count, mean (SD)14.59±9.1614.83±9.3014.93±9.88Swollen joint count, mean (SD)9.81±6.639.73±7.209.51±6.22DAS28-CRP, mean (SD)5.084±0.9945.102±0.9795.103±0.956HAQ score, mean (SD)15.82±11.2515.24±10.9316.06±10.92SAS: Safety Analysis Set; CRP: C-reactive protein;DAS28: disease activity score; HAQ: Health Assessment QuestionnaireThe study met its primary endpoints. More concretely, IGU monotherapy and IGU+MTX were found to be superior to MTX at week 52 with a higher ACR20 response of 77.44%(230/297, P=0.0019) and 77.05%(235/305, P=0.0028) versus 65.87%(193/293) (fig 1). As shown in fig 1, the structural remission (ΔmTSS≤0.5) was statistically significant for IGU monotherapy (57.4%, P=0.0308) but not for IGU+MTX arm (55%) versus MTX monotherapy (47.8%).Overall incidence of the adverse events (AEs) leading to study discontinuation were reported in 13.8% (41/297) in IGU monotherapy arm, 11.26% (33/293) in MTX monotherapy arm and 11.51% (35/305) patients in IGU+MTX arm. The incidence of adverse drug reactions (ADR) leading to study discontinuation were 11.45% (34/297), 8.53% (25/293) and 9.21% (28/305), respectively. There was no one death and no significant difference in all the safety indicators among the three arms.Conclusion:Iguratimod alone or in combination with MTX demonstrated superior efficacy with acceptable safety compared to MTX for patients with active RA who have not previously used MTX bDMARDs.Disclosure of Interests:None declared