Elsevier

The Lancet

Volume 374, Issue 9685, 18–24 July 2009, Pages 210-221
The Lancet

Articles
Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor α inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial

https://doi.org/10.1016/S0140-6736(09)60506-7Get rights and content

Summary

Background

Tumour necrosis factor α (TNFα) inhibitors are frequently used to treat rheumatoid arthritis, but whether use of a different TNFα inhibitor can improve patient response is unknown. We assess the efficacy and safety of the TNFα inhibitor golimumab in patients with active rheumatoid arthritis who had previously received one or more TNFα inhibitors.

Methods

461 patients with active rheumatoid arthritis from 82 sites in 10 countries were randomly allocated by interactive voice response system, stratified by study site and methotrexate use, to receive subcutaneous injections of placebo (n=155), 50 mg golimumab (n=153), or 100 mg golimumab (n=153) every 4 weeks between Feb 21, 2006, and Sept 26, 2007. Allocation was double-blind. Eligible patients had been treated with at least one dose of a TNFα inhibitor previously. Patients continued stable doses of methotrexate, sulfasalazine, hydroxychloroquine, oral corticosteroids, and non-steroidal anti-inflammatory drugs. The primary endpoint was achievement at week 14 of 20% or higher improvement in American College of Rheumatology criteria for assessment of rheumatoid arthritis (ACR20). At week 16, patients who had less than 20% improvement in tender and swollen joint counts were given rescue therapy and changed treatment from placebo to 50 mg golimumab, or from 50 mg to 100 mg golimumab. Drug efficacy was assessed by intention to treat and safety was assessed according to the study drug given. This study is registered with ClinicalTrials.gov, number NCT00299546.

Findings

Patients had discontinued previous TNFα inhibitors because of lack of effectiveness (269 [58%] patients) or reasons unrelated to effectiveness (246 [53%] patients), such as intolerance and accessibility issues. Patients had active disease, which was indicated by a median of 14·0 (IQR 9·0–22·0) swollen and 26·0 (16·0–41·0) tender joints for the whole group. 28 (18%) patients on placebo, 54 (35%) patients on 50 mg golimumab (odds ratio 2·5 [95% CI 1·5–4·2], p=0·0006), and 58 (38%) patients on 100 mg golimumab (2·8 [1·6–4·7], p=0·0001) achieved ACR20 at week 14. Two patients were never treated, and 57 patients did not complete the study because of adverse events, unsatisfactory treatment effect, loss to follow-up, death, or other reasons. 155 patients on placebo, 153 on 50 mg golimumab, and 153 on 100 mg golimumab were assessed for drug efficacy. For weeks 1–16, serious adverse events were recorded in 11 (7%) patients on placebo, 8 (5%) on 50 mg golimumab, and 4 (3%) on 100 mg golimumab. For weeks 1–24, after some patients were given rescue therapy, serious adverse events were recorded in 15 (10%) patients on placebo, 14 (5%) on 50 mg golimumab, and 8 (4%) on 100 mg golimumab.

Interpretation

Golimumab reduced the signs and symptoms of rheumatoid arthritis in patients with active disease who had previously received one or more TNFα inhibitors.

Funding

Centocor Research and Development and Schering-Plough Research Institute.

Introduction

Development of drugs to target tumour necrosis factor α (TNFα) has been one of the most impressive advances for the treatment of inflammatory diseases, including rheumatoid arthritis, in the past decade. However, some patients do not tolerate or respond adequately to available TNFα inhibitors. Thus, increased use of TNFα inhibitors to manage rheumatoid arthritis is likely to be accompanied by increased occurrence of patients who have previously received TNFα inhibitors. Such patients are frequently treated with more than one TNFα inhibitor, according to observational studies and registries.1, 2, 3, 4 However, no prospective, controlled clinical trial has been done to establish whether patients who discontinued treatment with one TNFα inhibitor would respond to treatment with another TNFα inhibitor. The decision to treat with an alternative TNXα inhibitor is based on retrospective analyses of registry data or non-blinded observational studies with small numbers of patients.1, 2, 3, 4, 5 By contrast, the efficacy of other biologically derived drugs, such as the B-cell depleting chimeric antibody rituximab or the T-cell co-stimulation inhibitor abatacept, have been assessed in well designed, controlled studies of patients who did not respond to a TNFα inhibitor.6, 7

Three TNFα inhibitors are licensed to treat rheumatoid arthritis: adalimumab, a human monoclonal antibody that is given subcutaneously every 2 weeks; etanercept, a TNF-receptor fusion protein that is given subcutaneously once or twice per week; and infliximab, a chimeric monoclonal antibody that is given intravenously every 4–8 weeks. Golimumab is a human monoclonal antibody to TNFα. The drug was derived from hybridomas generated from a transgenic mouse containing activated human immunoglobulin genes and inactivated mouse immunoglobulin genes for heavy chain and κ light chain.8 Results from a phase II study showed golimumab injections every 4 weeks effectively reduced the signs and symptoms of rheumatoid arthritis and improved physical function in patients with active disease on methotrexate.9

Development of a TNFα inhibitor with a more convenient dosing schedule than that of available drugs might be beneficial. Patients who do not respond to one TNFα inhibitor might benefit from switching to another. In the GO-AFTER (GOlimulab After Former anti-tumour necrosis factor α Therapy Evaluated in Rheumatoid arthritis) trial, we assessed the efficacy and safety of golimumab for patients with active rheumatoid arthritis who had previously received one or more TNFα inhibitors.

Section snippets

Patients

Patients from 82 sites in ten countries (Austria, Australia, Canada, Finland, Germany, Netherlands, New Zealand, Spain, UK, and USA) were monitored as outpatients in clinics or hospitals between Feb 21, 2006, and Sept 26, 2007. Eligible patients (webappendix pp 1–2) were aged 18 years or older, and had been diagnosed with active rheumatoid arthritis (persistent disease activity with at least four swollen and four tender joints), according to the criteria of the American College of Rheumatology

Results

Figure 1 shows the trial profile. 461 patients were randomised, of whom 331 (72%) were enrolled in the USA and Canada, and 130 (28%) in Europe, Australia, or New Zealand. One patient on each of 50 mg and 100 mg golimumab was assigned but never received treatment; these patients were judged to have not achieved the primary efficacy endpoint. Table 1 shows the demographic and baseline disease characteristics of participants. Only eight (2%) patients had disease duration of less than 1 year.

Discussion

Our study shows that golimumab reduced the signs and symptoms of active rheumatoid arthritis and improved physical function in patients who had previously received TNFα inhibitors, which suggests that switching patients from one TNFα inhibitor to golimumab is effective and generally well tolerated.

The proportion of patients achieving ACR20 was maintained or increased slightly at each time point from week 4 to the primary endpoint at week 14, and further increased or stabilised during the

References (39)

  • SB Cohen et al.

    Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks

    Arthritis Rheum

    (2006)
  • MC Genovese et al.

    Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition

    N Engl J Med

    (2005)
  • DM Fishwild et al.

    High-avidity human IgG kappa monoclonal antibodies from a novel strain of minilocus transgenic mice

    Nat Biotechnol

    (1996)
  • J Kay et al.

    Golimumab in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, placebo-controlled, dose-ranging study

    Arthritis Rheum

    (2008)
  • FC Arnett et al.

    The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis

    Arthritis Rheum

    (1988)
  • DT Felson et al.

    American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis

    Arthritis Rheum

    (1995)
  • JF Fries et al.

    Measurement of patient outcome in arthritis

    Arthritis Rheum

    (1980)
  • D Aletaha et al.

    Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations

    Arthritis Rheum

    (2008)
  • ML Prevoo et al.

    Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis

    Arthritis Rheum

    (1995)
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