Elsevier

The Lancet

Volume 381, Issue 9877, 4–10 May 2013, Pages 1541-1550
The Lancet

Articles
Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial

https://doi.org/10.1016/S0140-6736(13)60250-0Get rights and content

Summary

Background

Roughly a third of patients with rheumatoid arthritis treated with biological treatments receive them as monotherapy. Tocilizumab—an inhibitor of interleukin 6 receptor signalling—has been studied as monotherapy in several clinical trials. We assessed the efficacy and safety of tocilizumab monotherapy compared with adalimumab monotherapy for patients with rheumatoid arthritis.

Methods

We did this randomised, double-blind, parallel-group, phase 4 superiority study in 76 centres in 15 countries in North and South America, Australasia, and Europe. We enrolled patients who were aged at least 18 years, had severe rheumatoid arthritis for 6 months or more, and were intolerant to methotrexate or were inappropriate for continued methotrexate treatment. Patients were randomly assigned (1:1; block size of four) to receive tocilizumab 8 mg per kg bodyweight intravenously every 4 weeks plus placebo subcutaneously every 2 weeks or adalimumab 40 mg subcutaneously every 2 weeks plus placebo intravenously every 4 weeks for 24 weeks. Investigators, patients, and sponsor personnel were masked to assignment. The primary endpoint was change in disease activity score using 28 joints (DAS28) from baseline to week 24. This trial is registered with ClinicalTrials.gov, number NCT01119859.

Findings

We screened 452 patients and enrolled 326 patients. The intention-to-treat population contained 325 patients (163 assigned to tocilizumab, 162 assigned to adalimumab). Week 24 mean change from baseline in DAS28 was significantly greater in the tocilizumab group (–3·3) than in the adalimumab group (−1·8) patients (difference −1·5, 95% CI −1·8 to −1·1; p<0·0001). 16 of 162 (10%) patients in the adalimumab group versus 19 of 162 (12%) in the tocilizumab group had serious adverse events. More patients in the tocilizumab group than in the adalimumab group had increased LDL-cholesterol, increased alanine aminotransferase concentrations, and reduced platelet and neutrophil counts.

Interpretation

Tocilizumab monotherapy was superior to adalimumab monotherapy for reduction of signs and symptoms of rheumatoid arthritis in patients for whom methotrexate was deemed inappropriate. The adverse event profiles of tocilizumab and adalimumab were consistent with previous findings.

Funding

F Hoffmann-La Roche.

Introduction

The introduction and uptake of biological disease-modifying antirheumatic drugs has substantially advanced the standard of care of patients with rheumatoid arthritis. Although most patients who are clinically eligible for such drugs also maintain current treatment with methotrexate (or another synthetic disease-modifying antirheumatic drug) as standard of care, up to 40% discontinue or are noncompliant with methotrexate because of toxic effects1, 2 or preference.3, 4, 5 Data from registries of biological drugs6, 7, 8, 9, 10, 11 and a US claims database12 suggest that roughly a third of patients take biological disease-modifying antirheumatic drugs as monotherapy.

Interleukin 6 is a key cytokine involved in the pathogenesis of rheumatoid arthritis,13 and increased concentrations of interleukin 6 correlate with disease activity in patients with rheumatoid arthritis.14, 15 Tocilizumab is a humanised monoclonal antibody that binds to membrane-bound and soluble forms of human interleukin 6 receptor,16 inhibiting signalling mediated by interleukin 6 and its inflammatory effects.17 Randomised, double-blind, controlled phase 3 studies have shown that combination treatment with tocilizumab and methotrexate or other synthetic disease-modifying antirheumatic drugs results in rapid and sustained improvement in the signs and symptoms of rheumatoid arthritis in several different patient populations.18, 19, 20, 21 Studies have also shown the efficacy and safety of tocilizumab as monotherapy.22, 23, 24, 25, 26

We compared the efficacy and safety of tocilizumab monotherapy with adalimumab monotherapy in patients with rheumatoid arthritis who were intolerant to methotrexate or for whom continuation of methotrexate was deemed inappropriate. This study is the first randomised controlled trial specifically designed to test the superiority of one biological disease-modifying antirheumatic monotherapy compared with another. Adalimumab is a fully human monoclonal antibody against TNFα that was chosen as a comparator to tocilizumab because of its status as a globally adopted, first-line biological therapy (in combination with methotrexate and as a monotherapy) in patients with rheumatoid arthritis who are refractory to non-biological disease-modifying antirheumatic drugs.

Section snippets

Study design and participants

This randomised, parallel-group, double-blind, phase 4 study was done at 76 centres in 15 countries in North and South America, Australasia, and Europe.

Eligible patients were aged 18 years or older at baseline and had had rheumatoid arthritis for 6 months or more. Patients had to be taking methotrexate or have done previously, be unable to tolerate methotrexate, or be inappropriate candidates for continued methotrexate treatment in the judgment of the investigator. Patients previously treated

Results

Patients were enrolled between May 19, 2010 and June 21, 2011. 326 patients were enrolled in the study (163 in each group; figure 1). The intention-to-treat population consisted of 325 patients (163 in the tocilizumab group and 162 in the adalimumab group). One enrolled patient did not receive an adalimumab dose. The safety population consisted of 324 patients (162 in each group). One patient in the tocilizumab group had no safety assessments done after baseline. Baseline patient

Discussion

Comparison between biological monotherapies with different mechanisms of action is important because roughly a third of patients receive biological disease-modifying antirheumatic drugs as monotherapy.6, 7, 8, 9, 10, 11 Treatment with tocilizumab monotherapy led to a significantly and clinically meaningful greater improvement in DAS28 from baseline to week 24 compared with adalimumab monotherapy. Response rates were also significantly higher for tocilizumab for all secondary endpoints.

References (39)

  • M Mihara et al.

    Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family

    Int Immunopharmacol

    (2005)
  • JS Smolen et al.

    Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial

    Lancet

    (2008)
  • C Salliot et al.

    Long term safety of methotrexate monotherapy in rheumatoid arthritis patients: a systematic literature research

    Ann Rheum Dis

    (2009)
  • CT Goudie et al.

    How well do patients with rheumatoid and psoriatic arthritis tolerate methotrexate? A retrospective review of discontinuation data from a large UK cohort

    Arthritis Rheum

    (2012)
  • GW Cannon et al.

    Merging Veterans Affairs rheumatoid arthritis registry and pharmacy data to assess methotrexate adherence and disease activity in clinical practice

    Arthritis Care Res

    (2011)
  • A de Thurah et al.

    Compliance with methotrexate treatment in patients with rheumatoid arthritis: influence of patients' beliefs about the medicine: a prospective cohort study

    Rheumatol Int

    (2010)
  • CG Grijalva et al.

    Adherence to disease-modifying antirheumatic drugs and the effects of exposure misclassification on the risk of hospital admission

    Arthritis Care Res

    (2010)
  • MS Heiberg et al.

    The comparative one-year performance of anti-tumor necrosis factor alpha drugs in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: results from a longitudinal, observational, multicenter study

    Arthritis Rheum

    (2008)
  • MM Soliman et al.

    Impact of concomitant use of DMARDs on the persistence with anti-TNF therapies in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register

    Ann Rheum Dis

    (2011)
  • J Listing et al.

    Clinical and functional remission: even though biologics are superior to conventional DMARDs overall success rates remain low—results from RABBIT, the German biologics register

    Arthritis Res Ther

    (2006)
  • J Askling et al.

    Time-dependent increase in risk of hospitalisation with infection among Swedish RA patients treated with TNF antagonists

    Ann Rheum Dis

    (2007)
  • X Mariette et al.

    Registries in rheumatoid arthritis and autoimmune diseases: data from the French registries

    Rheumatology

    (2011)
  • SJ Lee et al.

    Utilization trends of tumor necrosis factor inhibitors among patients with rheumatoid arthritis in a United States observational cohort study

    J Rheumatol

    (2009)
  • Y Yazici et al.

    Utilization of biologic agents in rheumatoid arthritis in the United States: analysis of prescribing patterns in 16,752 newly diagnosed patients and patients new to biologic therapy

    Bull NYU Hosp Joint Dis

    (2008)
  • JM Dayer et al.

    Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor

    Rheumatology

    (2010)
  • JE Gottenberg et al.

    Serum IL-6 and IL-21 are associated with markers of B cell activation and structural progression in early rheumatoid arthritis: results from the ESPOIR cohort

    Ann Rheum Dis

    (2012)
  • PP Tak et al.

    Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity

    Arthritis Rheum

    (1997)
  • N Nishimoto et al.

    Humanized antihuman IL-6 receptor antibody, tocilizumab

    Handb Exp Pharmacol

    (2008)
  • P Emery et al.

    IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial

    Ann Rheum Dis

    (2008)
  • Cited by (0)

    Lead authors, contributed equally

    View full text