Efficacy and safety of certolizumab pegol without methotrexate co-administration in Japanese patients with active rheumatoid arthritis: The HIKARI randomized, placebo-controlled trial

Abstract

Objective. This 24-week, placebo-controlled, double-blind, randomized study (NCT00791921) investigated efficacy and safety of certolizumab pegol (CZP) in Japanese rheumatoid arthritis (RA) patients in whom methotrexate (MTX) cannot be administered.

Methods. A total of 230 patients were randomized to subcutaneous CZP 200 mg (induction dosing: 400 mg at Weeks 0, 2 and 4) or placebo every 2 weeks.

Results. ACR20 responses with CZP were rapid and significant versus placebo at Week 1, sustained to Week 12 (67.2% vs. 14.9%) and Week 24 (63.8% vs. 11.4%). Week 24-modified Total Sharp Score (mTSS) change from baseline (CFB) was 0.48 (CZP) versus 2.45 (placebo). CZP treatment was associated with higher Week 12 ACR20 responses versus placebo (with non-MTX disease modifying antirheumatic drugs [DMARDs], 74.2% vs. 20.0%; without [monotherapy], 59.3% vs. 8.2%) and inhibition of radiographic progression at Week 24 (mTSS CFB; with non-MTX DMARDs, 0.24 vs. 1.61; monotherapy, 0.68 vs. 3.65). Incidences of serious adverse events were 11.2% (CZP) and 2.6% (placebo); one CZP patient died of dissecting aortic aneurysm.

Conclusion. CZP treatment with and without non-MTX DMARDs in Japanese patients in whom MTX cannot be administered resulted in rapid, sustained reductions in RA signs and symptoms. Notably, CZP monotherapy showed significant inhibition of radiographic progression.

Keywords:

• Certolizumab pegol
• Monotherapy
• Randomized controlled trial
• Rheumatoid arthritis
• Tumor necrosis factor-alpha inhibitor

Acknowledgements

The authors acknowledge ‘Matladi Ndlovu, PhD, UCB Pharma, Brussels, Belgium, and Yumiko Wada, PhD, UCB Pharma, Tokyo, Japan, for publication management and Costello Medical Consulting for editorial and administrative support. The authors also acknowledge all investigators from the HIKARI study: Hokkaido University Hospital (T. Atsumi), Tomakomai City Hospital (A. Fujisaku), Oki Medical Clinic (I. Oki), Tohoku University Hospital (T. Ishii), Taga General Hospital (S. Ota), Inoue Hospital (H. Inoue), Saitama Medical Center (K. Amano), Jichi Medical University Hospital (T. Yoshio), Tsukuba University Hospital (T. Sumida), Chiba University Hospital (N. Watanabe), Yonemoto Orthopedic Clinic (K. Yonemoto), The University of Tokyo Hospital (K. Kawahata), Tokyo Medical and Dental University Hospital Faculty of Medicine (H. Kohsaka), Institute of Rheumatology Tokyo Women's Medical University (H. Yamanaka), Keio University Hospital (M. Kuwana), Juntendo University Hospital (Y. Takasaki), Toho University Ohashi Medical Center (T. Ogawa), Showa University Hospital (T. Kasama), Kyorin University Hospital (Y. Arimura), Fukuhara Hospital (A. Yamaguchi), Tokyo Metropolitan Ohtsuka Hospital (T. Yamada), Yokohama Rosai Hospital (Y. Kita), Tokai University Hospital (Y. Suzuki), Kitasato University Hospital (S. Hirohata), Gunma University Hospital (Y. Nojima), Nagoya University Hospital (T. Kojima), Nagoya Medical Center (A. Kaneko), Kondo Orthopedic and Rheumatology Clinic (K. Kondo), Ito Orthopedic Clinic (T. Ito), Fujita Health University Hospital (S. Yoshida), Nagoya City University Hospital (Y. Hayami), Toyama University Hospital (H. Taki), Saiseikai Takaoka Hospital (S. Honjo), Niigata Rheumatic Center (A. Murasawa), Tonami General Hospital (H. Yamada), Matsuno Clinic for Rheumatic Diseases (H. Matsuno), Kyoto University Hospital (T. Nojima), Osaka Minami Medical Center (Y. Saeki), Matsubara Mayflower Hospital (T. Matsubara), Sanin Rosai Hospital (H. Kishimoto), Higashi-Hiroshima Memorial Hospital (S. Yamana), Kurashiki Medical Clinic (Y. Yoshinaga), Hiroshima Clinic (K. Amano), Kagawa University Hospital (H. Dobashi), Tokushima University Hospital (J. Kishi), University of Occupational and Environmental Health, Hospital (Y. Tanaka), Kitakyushu Municipal Medical Center (H. Nishizaka), Kyushu University Hospital (T. Horiuchi), Kyushu Medical Center (H. Miyahara), Shono Rheumatism Clinic (E. Shono), Kondo Rheumatology and Orthopedic Clinic (M. Kondo), Kurume University Medical Center (T. Fukuda), Nagasaki University Hospital of Medicine and Dentistry (A. Kawakami), Nagasaki Medical Center (K. Migita), Sasebo Chuo Hospital (Y. Ueki), Nagasaki Medical Hospital of Rheumatology (M. Tsuboi), Nagasaki Atomic Bomb Hospital (M. Nakashima), Saga University Hospital (K. Nagasawa), Oribe Clinic of Rheumatism and Medicine (M. Oribe), Otsuka Clinic of Medicine and Rheumatism (E. Otsuka), Kumamoto Saishunso National Hospital (S. Mori), Kumamoto Orthopaedic Hospital (M. Sakaguchi), Center for Arthritis and Clinical Rheumatology Matsubara Clinic (S. Matsubara), Shimin-No-Mori Hospital (T. Hidaka) and Kagoshima Red Cross Hospital (T. Matsuda).

Conflicts of interest

The competing interests of all authors are provided below.

• KY has served as a consultant for UCB Pharma, Pfizer, Abbott, BMS, Roche, Chugai, Mitsubishi-Tanabe and Eisai and has received research funding from UCB Pharma, Pfizer, Abbott, Santen, Mitsubishi-Tanabe and Eisai.

• TT has served as a consultant for AstraZeneca, Eli Lilly, Novartis, Mitsubishi-Tanabe and Asahi Kasei, has received research support from Abott, Astellas, BMS, Chugai, Daiichi-Sankyo, Eisai, Janssen, Mitsubishi-Tanabe, Nippon Shinyaku, Otsuka, Pfizer, Sanofi-Aventis, Santen, Takeda and Teijin, and has served on speaker bureaus for Abbott, BMS, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer and Takeda.

• HY has served as a consultant for, and received research funding from, UCB Pharma, Abbott, Astellas, BMS, Chugai, Eisai, Janssen, Mitsubishi-Tanabe, Pfizer and Takeda.

• NI has received research funding from Takeda, Mitsubishi-Tanabe, Astellas, Chugai, Abbott, BMS, Eisai, Janssen, Kaken and Pfizer and has served on speaker bureaus for Takeda, Mitsubishi-Tanabe, Astellas, Chugai, Abbott, BMS, Eisai, Janssen, Kaken, Pfizer, Taisho-Toyama and Otsuka.

• YT has received research funding from BMS, MSD, Chugai, Mitsubishi-Tanabe, Astellas, Abbott, Eisai and Janssen and has served on speaker bureaus for UCB Pharma, Mitsubishi-Tanabe, Abbott, Eisai, Chugai, Janssen, Santen, Pfizer, Astellas, Daiichi-Sankyo, GSK, AstraZeneca, Otsuka, Actelion, Eli Lilly, Nippon Kayaku, Quintiles Transnational and Ono.

• KE has served as a consultant for UCB Pharma.

• AW has received research support from Astellas, Daiichi-Sankyo, Kyorin, Shionogi, Taisho, Dainippon-Sumitomo, Taiho, Toyama Chemical and Meiji Seika and has served on speaker bureaus for Abott, MSD, Otsuka, GSK, Shionogi, Daiichi-Sankyo, Taisho-Toyama, Dainippon-Sumitomo, Mitsubishi-Tanabe, Toyama Chemical, Bayer and Pfizer.

• HO has served as a consultant for UCB Pharma and Astellas.

• KI is an employe of Otsuka.

• YS is an employee of UCB Pharma.

• DvH has served as a consultant for, and received research support from, AbbVie, Amgen, AstraZeneca, BMS, Centocor, Chugai, Daiichi, Eli Lilly, GSK, Janssen, Merck, Novartis, Novo-Nordisk, Otsuka, Pfizer, Roche, Sanofi-Aventis, Schering-Plough, UCB Pharma and Vertex. DvH is also director of Imaging Rheumatology bv.

• NM has received research support from Pfizer, Takeda, Mitsubishi-Tanabe, Chugai, Abbott, Eisai and Astellas.

• TK has served on speaker bureaus for UCB Pharma, Pfizer, Chugai, Abbott, Mitsubishi-Tanabe, Takeda, Eisai, Santen, Astellas, Taisho-Toyama, BMS, Teijin and Daiichi-Sankyo.

Funding

This study has been funded by UCB Pharma.

Notice of correction

The original version of this article published on 11 November contained an error in the caption of Figure 3. “Cumulative probability plot of the change from BL in mTSS at Week 24 (FAS-linear population)” should have read “Cumulative probability plot of the change from BL in mTSS at Week 24 (FAS-linear extrapolation). This error has been corrected in this version.