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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
  1. Tsutomu Takeuchi1,
  2. Yoshiya Tanaka2,
  3. Satoshi Soen3,
  4. Hisashi Yamanaka4,
  5. Toshiyuki Yoneda5,
  6. Sakae Tanaka6,
  7. Takaya Nitta7,
  8. Naoki Okubo8,
  9. Harry K Genant9,
  10. Désirée van der Heijde10
  1. 1 Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
  2. 2 First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
  3. 3 Department of Orthopedics and Rheumatology, Kindai University Nara Hospital, Ikoma, Japan
  4. 4 Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan
  5. 5 Department of Biochemistry, Osaka University Graduate School of Dentistry, Osaka, Japan
  6. 6 Department of Orthopedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
  7. 7 Clinical Development Department, Daiichi Sankyo Co., Ltd, Shinagawa-ku, Tokyo, Japan
  8. 8 Biostatistics & Data Management Department, Daiichi Sankyo Co., Ltd, Shinagawa-ku, Tokyo, Japan
  9. 9 Department of Radiology, Medicine and Orthopedic Surgery, University of California, San Francisco, California, USA
  10. 10 Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
  1. Correspondence to Dr Tsutomu Takeuchi, Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan; tsutake{at}z5.keio.jp

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.

  • rheumatoid arthritis
  • denosumab
  • joint destruction
  • erosion

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Footnotes

  • TT and YT contributed equally.

  • Handling editor Josef S Smolen

  • Contributors TT and YT contributed equally as first authors. TT, YT, SS and HY provided substantial contributions to the study conception and design. TY diagnosed the oral adverse events. ST diagnosed the atypical femoral fracture events. TN was involved in the design and conduct of the study and in collecting data. NO was involved in the design of the study and data analysis. DvdH supervised scoring of the radiographs. All authors interpreted the data. All authors discussed and agreed on the content of the manuscript before submission.

  • 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.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Deidentified individual patient data and supporting documents pertaining to this study, such as the study protocol, statistical analysis plan and clinical study report, are provided upon request via the data sharing portal (https://vivli.org/ourmember/daiichi-sankyo/) in accordance with the data sharing policy of Daiichi Sankyo Co., Ltd.

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