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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

Clinical Question

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

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

Arms

FieldControlTocilizumab
InterventionWeekly subcutaneous placebo injections with mandatory glucocorticoid tapering 10% per week from week 4 to minimum 0.1mg/kg/dayWeekly subcutaneous tocilizumab 162mg with mandatory glucocorticoid tapering 10% per week from week 4 to minimum 0.1mg/kg/day
DurationUntil relapse or study completionUntil relapse or study completion

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-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 symptomsPrimary11 patients relapsed (61.1%), median time 12.1 weeks8 patients relapsed (44.4%), median time 19.00 weeks0.410.0596
Time to relapse according to Kerr's definitionSecondary11 patients relapsed (61.1%)8 patients relapsed (44.4%)0.410.0596
Time to relapse based on clinical symptoms onlySecondary11 patients relapsed (61.1%)11 patients relapsed (61.1%)0.70.4224
Per-protocol analysis - time to relapseSecondary11/17 patients relapsed (64.7%)7/16 patients relapsed (43.8%)0.340.0345
Any adverse eventAdverse11 patients (61.1%)14 patients (77.8%)
Serious adverse eventsAdverse2 patients (11.1%)1 patient (5.6%)
Infections and infestationsAdverse6 patients (33.3%)9 patients (50.0%)
DeathsAdverse00

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

Chugai Pharmaceutical Co. and F. Hoffmann-La Roche

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

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

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

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