Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial

Abstract

Objective: To evaluate the efficacy of denosumab in suppressing joint destruction when added to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy in patients with rheumatoid arthritis (RA).

Methods: This was a multi-centre, randomised, double-blind, parallel-group, placebo-controlled phase 3 study in Japan. Patients with RA aged ≥20 years receiving csDMARDs were randomly assigned (1:1:1) to denosumab 60 mg every 3 months (Q3M), denosumab 60 mg every 6 months (Q6M) or placebo. The change in the modified total Sharp score (mTSS) and effect on bone mineral density (BMD) at 12 months was evaluated.

Results: In total, 654 patients received the trial drugs. Denosumab groups showed significantly less progression of joint destruction. The mean changes in the mTSS at 12 months were 1.49 (95% CI 0.99 to 1.99) in the placebo group, 0.99 (95% CI 0.49 to 1.49) in the Q6M group (p=0.0235) and 0.72 (95% CI 0.41 to 1.03) in the Q3M group (p=0.0055). The mean changes in bone erosion score were 0.98 (95% CI 0.65 to 1.31) in the placebo group, 0.51 (95% CI 0.22 to 0.80) in the Q6M group (p=0.0104) and 0.22 (95% CI 0.09 to 0.34) in the Q3M group (p=0.0001). No significant between-group difference was observed in the joint space narrowing score. The per cent change in lumbar spine (L1-L4) BMD in the placebo, Q6M and Q3M groups were -1.03%, 3.99% (p<0.0001) and 4.88% (p<0.0001). No major differences were observed among safety profiles.

Conclusions: Denosumab inhibits the progression of joint destruction, increases BMD and is well tolerated in patients with RA taking csDMARD.

Keywords: denosumab; erosion; joint destruction; rheumatoid arthritis.

Conflict of interest statement

Competing interests: TT has received research grants from AbbVie, Asahi Kasei, Astellas, AYUMI, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer and Takeda and has received personal fees from AbbVie, Astellas, Astra Zeneca, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer, Sanofi, Taiho, Taisho Toyama, Takeda, Teijin and UCB. YT has received research grants from AbbVie, Astellas, Chugai, Bristol-Myers Squibb, Daiichi Sankyo, Eisai, Kyowa Hakko Kirin, Mitsubishi Tanabe, MSD, Ono, Pfizer and Takeda and has received personal fees from Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, Janssen, Mitsubishi Tanabe, Pfizer, Sanofi, UCB and YL Biologics. SS has received grant/research support from Chugai and Daiichi Sankyo and has received personal fees from Asahi-Kasei Pharma, Astellas, MSD, Chugai, Daiichi Sankyo, Eli Lilly, Mitsubishi-Tanabe, Pfizer, Takeda and Teijin. HY has received research grants from AbbVie, Astellas, AYUMI, BMS, Chugai, Daiichi Sankyo, Eisai, Kaken, Mitsubishi Tanabe, MSD, Nippon Shinyaku, Ono, Pfizer, Takeda, Teijin, Torii and UCB and has received consulting fees from Astellas, BMS, Chugai, Daiichi Sankyo, Mitsubishi Tanabe, Nippon Kayaku, Pfizer, Takeda, Teijin and YL Biologics. TY has received Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT #17H04377) and has received consulting fees from Daiichi Sankyo. ST has acted as a consultant for AbbVie, Asahi Kasei Pharma, Amgen, Astellas, Daiichi Sankyo, Eli Lilly, MSD, Ono and Teijin Pharma. TN is an employee of Daiichi Sankyo. NO is a shareholder and employee of Daiichi Sankyo. HKG has received consulting fees from Amgen, Agnovos, Bioclinica, Biomarin, Clementia, Daiichi Sanyo, Eli Lilly, Janssen, Medimmune, Merck, Novartis, Pfizer, Regeneron, Servier and Takeda. DvdH has received consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda and UCB and is the director of Imaging Rheumatology BV.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Trial profile. *As one patient assigned to denosumab Q6M was administered placebo by mistake, the patient was included in the placebo group for safety analysis. †No mTSS measurements available at baseline or after the first administration of treatment. §207 (per-protocol set). ¶202 (per-protocol set). ǂ200 (per-protocol set). mTSS, modified total Sharp score; PRT, protocol; Q3M, every 3 months; Q6M, every 6 months.

Figure 2

Mean changes from the baseline in the radiographic scores by the van der Heijde-modified Sharp method. (A) Modified total Sharp score, (B) modified Sharp erosion score and (C) modified Sharp joint space narrowing score. Missing values were imputed using linear extrapolation/interpolation. Mean and 95% CIs are presented. P values were calculated by two-sided van Elteren stratified rank test adjusting for baseline use of glucocorticoid. BL, baseline; n, number of patients who received ≥1 dose of investigational product and had a baseline and at least one postbaseline measurement of the radiograph score; Q3M, every 3 months; Q6M, every 6 months.

Figure 3

Cumulative probability plots of changes from the baseline in the radiographic score at 12 months. (A) Modified total Sharp score, (B) modified Sharp erosion score and (C) modified Sharp joint space narrowing score. n, number of patients who received ≥1 dose of investigational product and had a baseline and at least one postbaseline measurement of the radiograph score; Q3M, every 3 months; Q6M, every 6 months.

Figure 4

Per cent change in lumbar spinal bone mineral density (BMD) at 12 months from baseline in all patients (A), patients stratified by baseline use of glucocorticoid (B) and patients stratified by osteoporosis status (C). Data are for full analysis set (observed data). Coloured bars show least square mean values. P values are calculated using the analysis of covariance model after adjusting for treatment, baseline value, machine type, baseline value-by-machine type interaction and baseline use of glucocorticoid. Q3M, every 3 months; Q6M, every 6 months.