Pos0664 a Multicenter Randomized Study in Rheumatoid Arthritis to Compare Iguratimod, Methotrexate, or Combination: 52 Week Efficacy and Safety Results of the Smile Trial

Abstract

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

Effectiveness and Safety of Iguratimod Monotherapy or Combined With Methotrexate in Treating Rheumatoid Arthritis: A Systematic Review and Meta-Analysis

“…IGU + MTX does not increase the risk of leukopenia, but it can decrease the risk of LFTs. Recently, a multicenter, randomized, double-blind, parallel controlled trial of rheumatoid arthritis showed no significant difference in the incidence of adverse events after weeks of treatment with IGU alone or in combination with MTX compared to MTX (Du et al, 2021). Another study showed that IGU combined with MTX is safer than LEF combined with MTX (Tian et al, 2020).…”

“…IGU is a new type of small-molecule compound, which mainly regulates the immune system, inhibits T-cell and B-cell differentiation, reduces inflammatory factors, improves the function of joint swelling, and is widely used in China and Japan (Jiang et al, 2020). Multiple studies have demonstrated the superior efficacy of IGU alone or in combination with MTX in treating RA with acceptable safety (Ishiguro et al, 2013;Shi et al, 2015;Du et al, 2021).…”

“…Hu et al (2021) conducted a systematic review and meta-analysis of IGU alone or IGU + MTX treatment, but only 23 RCTs were included. Furthermore, RCTs from additional clinical research centers demonstrated the effectiveness and safety of IGU alone or in combination with MTX in treating RA (Du et al, 2021;Niu et al, 2021;Zhao, 2021). As a result, for the first time, this study could conduct a systematic review and meta-analysis of the efficacy and safety of IGU alone or combined with MTX, providing an evidence-based foundation, new direction for clinical treatment, and new research direction for RCTs in the future.…”