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TAKT

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)

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Year of Publication: 2018

Authors: Yoshikazu Nakaoka, Mitsuaki Isobe, Syuji Takei, ..., Norihiro Nishimoto

Journal: Annals of the Rheumatic Diseases

Citation: Ann Rheum Dis 2018;77:348–354

Link: https://doi.org/10.1136/annrheumdis-2017-211878

PDF: https://ard.bmj.com/content/annrheumdis/77/3/348.full.pdf

Clinical Question

Does tocilizumab treatment enable glucocorticoid tapering and prevent relapse in patients with refractory Takayasu arteritis?

Study Overview

Objective

To investigate the efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis

Study Summary

Primary endpoint not met: HR 0.41 (95.41% CI 0.15-1.10; p=0.0596) for time to relapse
Per-protocol analysis showed significant benefit: HR 0.34 (95.41% CI 0.11-1.00; p=0.0345)
Results suggest favor for tocilizumab over placebo without new safety concerns

Intervention

Weekly subcutaneous tocilizumab 162mg vs placebo with mandatory glucocorticoid tapering

Patients per Arm

18 per arm

Bottom Line

Although the primary endpoint was not met, tocilizumab showed numerical favor over placebo for preventing relapse of Takayasu arteritis, with significant benefit in per-protocol analysis and no new safety concerns.

        Major Points
        First randomized, double-blind, placebo-controlled trial of anti-cytokine therapy in Takayasu arteritis
Primary endpoint (time to relapse) narrowly missed statistical significance in ITT population (HR 0.41, p=0.0596)
Per-protocol sensitivity analysis showed significant benefit for tocilizumab (HR 0.34, p=0.0345)
Weekly subcutaneous tocilizumab 162mg was used with mandatory 10% weekly glucocorticoid tapering
No serious infections or deaths occurred; safety profile was comparable to other tocilizumab indications
Study ended when 19 relapse events occurred as per protocol

      

Design

Study Type: Randomized, double-blind, placebo-controlled, phase 3 trial

Randomization: 1

Blinding: Patients, investigators, and study personnel were masked to treatment assignment

Enrollment Period: October 2014 - August 2015

Follow-up Duration: Until 19 patients relapsed

Countries: Japan

Sample Size: 36

Analysis: Intent-to-treat and per-protocol analysis using Kaplan-Meier analysis and Cox regression stratified by age category, log-rank test, SAS V.9.2

Inclusion Criteria

Patients 12 years of age or older at time of informed consent
Diagnosis of Takayasu arteritis based on Japanese Guidelines for Management of Vasculitis Syndrome 2008
Relapse of Takayasu arteritis within 12 weeks before enrollment
Previous treatment with oral glucocorticoid at prednisolone-equivalent dose of at least 0.2mg/kg/day

Exclusion Criteria

Details provided in online supplementary appendix

Baseline Characteristics

Characteristic	Control	Active
Female	83.3%	88.9%
Age at consent (years)	30.8±13.1 (median 27.0)	31.1±18.1 (median 26.5)
Age <18 years	11.1%	22.2%
Age 18-<65 years	83.3%	66.7%
Age ≥65 years	5.6%	11.1%
GC dose at baseline (mg/kg)	0.52±0.16 (median 0.45)	0.57±0.19 (median 0.50)
Disease duration (years)	3.57±4.03 (median 2.89)	6.46±7.37 (median 3.33)
HLA-B52 positive	72.2%	38.9%

Arms

Field	Control	Tocilizumab
Intervention	Weekly subcutaneous placebo injections with mandatory glucocorticoid tapering 10% per week from week 4 to minimum 0.1mg/kg/day	Weekly subcutaneous tocilizumab 162mg with mandatory glucocorticoid tapering 10% per week from week 4 to minimum 0.1mg/kg/day
Duration	Until relapse or study completion	Until relapse or study completion

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Time to relapse of Takayasu arteritis defined as ≥2 of five categories: objective systemic symptoms, subjective systemic symptoms, elevated inflammation markers, vascular signs and symptoms, ischemic symptoms	Primary	11 patients relapsed (61.1%); median time to relapse 12.1 weeks (95% CI 10.7 to 16.0); median treatment duration 12.86 weeks	8 patients relapsed (44.4%); median time to relapse not evaluable (95% CI 12.1 to NE); median treatment duration 19.00 weeks	0.41	0.0596
Time to relapse according to Kerr's definition	Secondary	11 patients relapsed (61.1%)	8 patients relapsed (44.4%)	0.41	0.0596
Time to relapse based on clinical symptoms only	Secondary	11 patients relapsed (61.1%)	11 patients relapsed (61.1%)	0.7	0.4224
Per-protocol analysis - time to relapse	Secondary	11/17 patients relapsed (64.7%)	7/16 patients relapsed (43.8%)	0.34	0.0345
Any adverse event	Adverse	11 patients (61.1%)	14 patients (77.8%)
Serious adverse events	Adverse	2 patients (11.1%)	1 patient (5.6%)
Infections and infestations	Adverse	6 patients (33.3%)	9 patients (50.0%)
Deaths	Adverse	0	0

Subgroup Analysis

Exploratory subgroup analysis showed consistent results for tocilizumab across all subgroups regardless of sex, glucocorticoid dose, disease duration, HLA-B52 status, and previous DMARD/immunosuppressant treatment

Criticisms

Primary endpoint was not met in intent-to-treat analysis
Small sample size may have been insufficient based on potentially overoptimistic efficacy estimates
Study was designed with mandatory glucocorticoid tapering rather than physician discretion
Short exposure duration limits long-term safety assessment
Efficacy in combination with other immunosuppressants was not investigated
Limited power for individual symptom categories and imaging studies

Funding

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

Based on: TAKT (Annals of the Rheumatic Diseases, 2018)