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Clinical Trial
. 2018 Mar;77(3):348-354.
doi: 10.1136/annrheumdis-2017-211878. Epub 2017 Nov 30.

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)

Yoshikazu Nakaoka  1 , Mitsuaki Isobe  2 , Syuji Takei  3 , Yoshiya Tanaka  4 , Tomonori Ishii  5 , Shumpei Yokota  6 , Akira Nomura  7 , Seitaro Yoshida  7 , Norihiro Nishimoto  8
Affiliations
Clinical Trial

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)

Yoshikazu Nakaoka et al. Ann Rheum Dis. 2018 Mar.

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.

Keywords: corticosteroids.

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Conflict of interest statement

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.

Figures

Figure 1
Figure 1
Kaplan-Meier curves showing time to relapse* in the intent-to-treat population (primary endpoint, A) and per-protocol set (sensitivity analysis, B) according to the protocol definition. *Two or more of five signs of relapse present: objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular signs and symptoms, ischaemic symptoms. SC, subcutaneous; TCZ, tocilizumab.
Figure 2
Figure 2
Forest plot showing the HR for each symptom in the protocol-based definition of relapse (intent-to-treat population). Data are based on Cox regression analysis and stratified by age (<18, 18–<65, ≥65 years). HRs and 95% CIs are shown in the plot. NE, not evaluable; SC, subcutaneous; TCZ, tocilizumab.
See this image and copyright information in PMC

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