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Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis: results from a randomised, double-blind, placebo-controlled, phase 3 trial in Japan (the TAKT study)
  1. Yoshikazu Nakaoka1,
  2. Mitsuaki Isobe2,
  3. Syuji Takei3,
  4. Yoshiya Tanaka4,
  5. Tomonori Ishii5,
  6. Shumpei Yokota6,
  7. Akira Nomura7,
  8. Seitaro Yoshida7,
  9. Norihiro Nishimoto8
  1. 1 Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
  2. 2 Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan
  3. 3 Faculty of Medicine, School of Health Sciences, Kagoshima University, Kagoshima, Japan
  4. 4 First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
  5. 5 Clinical Research, Innovation and Education Center, Tohoku University Hospital, Sendai, Japan
  6. 6 Laboratory of Pediatric Research, Institute of Tokyo Medical School, Tokyo, Japan
  7. 7 Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
  8. 8 Department of Molecular Regulation for Intractable Disease, Institute of Medical Science, Tokyo Medical University, Tokyo, Japan
  1. Correspondence to Dr Yoshikazu Nakaoka, Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute, Osaka 565-8565, Japan; ynakaoka{at}ncvc.go.jp

Abstract

Objective To investigate the efficacy and safety of the interleukin-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK).

Methods Patients with TAK who had relapsed within the previous 12 weeks were induced into remission with oral glucocorticoid therapy. In this double-blind, placebo-controlled trial, patients were randomly assigned 1:1 to receive weekly tocilizumab 162 mg or placebo subcutaneously, and oral glucocorticoids were tapered 10 %/week from week 4 to a minimum of 0.1 mg/kg/day until 19 patients relapsed. The primary endpoint was time to relapse of TAK, defined as ≥2 of the following: objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular signs and symptoms or ischaemic symptoms.

Results The intent-to-treat and safety populations included 18 tocilizumab-treated and 18 placebo-treated patients. The per-protocol set (PPS) included 16 tocilizumab-treated and 17 placebo-treated patients. HRs for time to relapse of TAK were 0.41 (95.41% CI 0.15 to 1.10; p=0.0596) in the intent-to-treat population (primary endpoint) based on relapse in eight tocilizumab-treated and 11 placebo-treated patients and 0.34 (95.41% CI 0.11 to 1.00; p=0.0345) in the PPS. The secondary endpoints, time to relapse assessed by Kerr’s definition and clinical symptoms only, were consistent with the primary endpoint. Serious adverse events were reported in one tocilizumab-treated and two placebo-treated patients. There were no serious infections and no deaths.

Conclusion Although the primary endpoint was not met, the results suggest favour for tocilizumab over placebo for time to relapse of TAK without new safety concerns. Further investigation is warranted to confirm the efficacy of tocilizumab in patients with refractory TAK.

Trial registration number JapicCTI-142616.

  • corticosteroids

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Footnotes

  • Handling editor Tore K Kvien

  • Contributors YN was involved in conception and design, acquisition of data, analysis and interpretation of data, drafting the article and revising it critically for important intellectual content. NN was involved in conception and design, analysis and interpretation of data, drafting the article and revising it critically for important intellectual content. MI, YT, ST and TI were involved in conception and design, acquisition of data, interpretation of data and revising the article critically for important intellectual content. SY was involved in conception and design, interpretation of data and revising the article critically for important intellectual content. SY and AN were involved in conception and design, analysis and interpretation of data and drafting the article. YN, AN and SY had full access to all the data in the study and take responsibility for its integrity and the data analysis.

  • Funding This study was funded by Chugai Pharmaceutical Co. Funding for manuscript preparation was provided by F. Hoffmann-La Roche.

  • Competing interests YN reports personal fees from Chugai as a consultant of the sponsor-initiated clinical trial (Chugai Pharmaceutical Co.) using tocilizumab for Takayasu arteritis; grants and personal fees from Chugai; grants and personal fees from Astellas, Pfizer, and MSD outside the submitted work; grants from Takeda, Otsuka, Bayer outside the submitted work; and personal fees from Daiichi Sankyo and Kowa Pharmaceutical Co. outside the submitted work. MI reports personal fees from Chugai during the conduct of the study; personal fees from Chugai; and grants and personal fees from Ono, Mitsubishi Tanabe, Daiichi Sankyo, Otsuka and Teijin Pharma outside the submitted work. ST reports grants and personal fees from Chugai during the conduct of the study; grants and personal fees from Eisai, Takeda, Bristol-Myers Squibb and Tanabe-Mitsubishi; and personal fees from Pfizer, Ayumi, Asahi Kasei Pharma, AbbVie, Santen, Nihon Pharmaceutical, Japan Blood Products Organization, Teijin and UCB Japan outside the submitted work. YT reports grants and personal fees from Chugai during the conduct of the study; grants and personal fees from Daiichi Sankyo, Astellas, Pfizer, Mitsubishi-Tanabe and Bristol-Myers Squibb outside the submitted work; grants from MSD, Takeda, AbbVie, Kyowa-Kirin, Eisai and Ono outside the submitted work; and personal fees from YL Biologics, Eli Lilly, Sanofi, Janssen and UCB outside the submitted work. TI reports personal fees from Chugai during the conduct of the study and personal fees from Chugai, Ono, Pfizer, Mitsubishi-Tanabe and Astellas outside the submitted work. SY reports personal fees from Chugai during the conduct of the study and personal fees from Chugai outside the submitted work. AN reports personal fees from Chugai during the conduct of the study. SY reports personal fees from Chugai during the conduct of the study. NN reports personal fees from Chugai during the conduct of the study and grants and personal fees from Chugai outside the submitted work and has a patent for tocilizumab with royalties paid by Chugai. S Ooka reports personal fees from Chugai during the conduct of the study and a grant from Chugai outside the submitted work. H Yamada reports personal fees from Chugai during the conduct of the study and personal fees from Chugai, Teijin, Asahi Kasei, Astellas, Ono, Bristol-Myers Squibb, Pfizer, Eisai, Mitsubishi Tanabe, Janssen, AbbVie, Actelion, Nippon Shinyaku, GlaxoSmithKline and Bayer outside the submitted work. H Niiro reports personal fees from Chugai during the conduct of the study; grants and personal fees from Chugai, Mitsubishi Tanabe, Astellas, Bristol-Myers Squibb and Takeda outside the submitted work; and personal fees from Pfizer and Eisai outside the submitted work. H. Tsukamoto reports personal fees from Chugai during the conduct of the study and personal fees from Chugai, Astellas, Takeda, Pfizer, AbbVie, Eisai, Mitsubishi-Tanabe, Bristol-Myers Squibb, Ayumi, Mylan, Asahi Kasei Pharma, Actelion, Daiichi Sankyo, Nippon Kayaku, Thermo Fisher Diagnostics, Kissei and Eli Lilly outside the submitted work. S Banno reports personal fees from Chugai during the conduct of the study; personal fees from Kissei outside the submitted work; and grants from Chugai, Teijin, Kissei, Mitsubishi Tanabe, Takeda, Pfizer, Eisai, AbbVie, Bristol-Myers Squibb, Ono, Astellas, Janssen and UCB outside the submitted work. N Tamura reports personal fees from Chugai during the conduct of the study; grants and personal fees from Janssen, Astellas, Eisai, AbbVie, Pfizer and Daiichi Sankyo outside the submitted work; and personal fees from UCB, Bristol-Myers Squibb and Novartis outside the submitted work. Y Takasaki reports personal fees from Chugai during the conduct of the study and grants and personal fees from Santen, Daiichi Sankyo, Mitsubishi Tanabe, Bristol-Myers Squibb, AstraZeneca, Astellas, MSD, Chugai, Asahi Kasei, Eisai and Janssen outside the submitted work. H Yoshifuji reports personal fees from Chugai during the conduct of the study. A Kawakami reports personal fees from Chugai during the conduct of the study; grants and personal fees from Ono, Mitsubishi Tanabe, Takeda, Astellas, AbbVie, MSD, AstraZeneca, Actelion, Eisai, Kissei, Santen, Daiichi Sankyo, Pfizer, Sanofi, Asahi Kasei, Taisho Toyama, Teijin, Sumitomo Dainippon, Eli Lilly, Bristol-Myers Squibb and Janssen outside the submitted work; grants from Mochida, Boehringer Ingelheim, Otsuka and Kowa outside the submitted work; and personal fees from Novartis outside the submitted work. S Furuta reports personal fees from Chugai during the conduct of the study. T Atsumi reports personal fees from Chugai, Eli Lilly, GlaxoSmithKline, Pfizer and UCB Japan during the conduct of the study; grants and personal fees from Astellas, Takeda, Mitsubishi Tanabe, Chugai, Pfizer, Daiichi Sankyo, Eisai and AbbVie outside the submitted work; grants from Otsuka outside the submitted work; personal fees from Bristol-Myers Squibb outside the submitted work. K Suzuki reports personal fees from Chugai during the conduct of the study; grants and personal fees from Eisai, Bristol-Myers Squibb and Kissei outside the submitted work; grants from Daiichi Sankyo outside the submitted work; personal fees from AbbVie, Astellas, Chugai, Fuji Film, Janssen, Mitsubishi Tanabe, Pfizer, Shionogi, Takeda and UCB Japan outside the submitted work. R Hara reports personal fees from Chugai during the conduct of the study and personal fees from Chugai, Eisai and Toshiba Medical outside the submitted work.

  • Patient consent Obtained.

  • Ethics approval The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice and was approved by the Institutional Review Board.

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

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