Long-Term Efficacy and Safety of Tocilizumab in Refractory Takayasu Arteritis

Final Results of the Randomized Controlled Phase 3 TAKT Study

Yoshikazu Nakaoka; Mitsuaki Isobe; Yoshiya Tanaka; Tomonori Ishii; Seido Ooka; Hiroaki Niiro; Naoto Tamura; Shogo Banno; Hajime Yoshifuji; Yasushi Sakata; Atsushi Kawakami; Tatsuya Atsumi; Shunsuke Furuta; Hitoshi Kohsaka; Katsuya Suzuki; Ryoki Hara; Yasuhiro Maejima; Hiroshi Tsukamoto; Yoshinari Takasaki; Katsuhisa Yamashita; Norihiro Okada; Shinji Yamakido; Syuji Takei; Shumpei Yokota; Norihiro Nishimoto

Disclosures

Rheumatology. 2020;59(9):2427-2434. 

In This Article

Abstract and Introduction

Abstract

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

Methods: Patients completing the randomized, double-blind, placebo-controlled period of the TAKT (Takayasu arteritis Treated with Tocilizumab) trial were followed up during open-label extended treatment with weekly s.c. tocilizumab 162 mg for up to 96 weeks or longer, with oral glucocorticoid tapering performed at the investigators' discretion. Endpoints of the extension analysis included steroid-sparing effects of tocilizumab, imaging data, patient-reported outcomes (36-Item Short Form Health Survey) and safety.

Results: All 36 patients enrolled in the double-blind period entered the open-label extension; 28 patients received tocilizumab for 96 weeks. The median glucocorticoid dose was 0.223 mg/kg/day at the time of relapse before study entry, 0.131 mg/kg/day (interquartile range 0.099, 0.207) after 48 weeks and 0.105 mg/kg/day (interquartile range 0.039, 0.153) after 96 weeks. Overall, 46.4% of patients reduced their dose to <0.1 mg/kg/day, which was less than half the dose administered at relapse before study entry (mean difference –0.120 mg/kg/day; 95% CI −0.154, −0.087). Imaging evaluations indicated that most patients' disease was improved (17.9%) or stable (67.9%) after 96 weeks compared with baseline. Mean 36-Item Short Form Health Survey physical and mental component summary scores and 7 of 8 domain scores were clinically improved from baseline and maintained over 96 weeks of tocilizumab treatment. No unexpected safety issues were reported.

Conclusion: These results in patients with Takayasu arteritis provide evidence of a steroid-sparing effect and improvements in well-being during long-term treatment with once-weekly tocilizumab 162 mg, with no new safety concerns.

Trial registration: JAPIC Clinical Trials Information, http://www.clinicaltrials.jp/user/cteSearch_e.jsp, JapicCTI-142616.

Introduction

Takayasu arteritis (TAK) is a rare disease characterized by inflammation of large blood vessels, resulting in vascular occlusion and aneurysm formation.[1,2] The classic pathological feature of TAK is granulomatous inflammation in the adventitia and media of the involved arteries; typical changes are inflammatory cell infiltration with granulomatosis formation, resulting in thickening of the adventitia and intima or disruption of elastic fibres, often accompanied by thrombus formation.[1]

TAK occurs most frequently in females, with a peak onset around 20 years of age;[3] globally, the estimated annual incidence is 1–3 cases/million,[4] but the prevalence may be higher in Japan (~60 cases/million).[2] Disease manifestations include systemic symptoms (fever, malaise), head and neck symptoms (neck pain, dizziness, headache), upper limb problems (pulselessness, fatigue) and body pain.[2] In addition, patients with TAK experience impaired health-related quality of life (HRQoL) compared with healthy controls.[5]

For many years, the first-line treatment for TAK has been glucocorticoids (GCs);[6] however, long-term use is associated with adverse events (AEs), and patients with TAK frequently experience relapse during GC tapering.[4] Elevated IL-6 levels are detectable in the peripheral blood and aortic tissue of patients with TAK and correlate with disease activity.[7] Clinical responses and a steroid-sparing effect in patients with TAK treated with the recombinant, humanized, anti-IL-6 receptor mAb tocilizumab were demonstrated in case studies.[8–10] In the randomized, double-blind, placebo-controlled, phase 3 Japanese TAKT (Takayasu arteritis Treated with Tocilizumab) study, the primary endpoint of time to relapse was not met for tocilizumab vs placebo (hazard ratio 0.41; 95.41% CI 0.15, 1.10; P = 0.0596), while background GC dose was tapered.[11]

Results of the double-blind period of the TAKT study were based on a short observation period and mandatory GC tapering of 10% per week. The TAKT extension evaluated long-term efficacy and safety of tocilizumab during which GC doses could be adjusted at the investigators' discretion, as in a real-life clinical setting. This article reports final results from the TAKT study, including the open-label extension, and describes the steroid-sparing effects, HRQoL outcomes, imaging data and safety associated with long-term tocilizumab treatment.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....