NPC Archive Item: Tocilizumab plus methotrexate studied in refractory RA (RADIATE)

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Emery P et al. Annals of the Rheumatic Diseases 2008;67:1516–1523

Tocilizumab with methotrexate was more effective than placebo and methotrexate at increasing ACR20 response rates in patients with moderate to severe rheumatoid arthritis (RA) who had responded inadequately, or been intolerant, to at least one anti-TNF agent.

NICE guidance on a number of established treatments is already available and it is awaited for the possible sequential use of adalimumab, etanercept and infliximab. As tocilizumab is likely to be on the market before NICE guidance on the product is available, Area Prescribing Committees and local specialists will need to decide where tocilizumab fits in the management of RA based on published evidence.

What is the background to this?
As reported in “On the Horizon, Future Medicines” (NHSnet connection required), tocilizumab is a humanised anti-interleukin 6 monoclonal antibody which is in development for the management of active RA. Tocilizumab is part of the 18th wave of NICE technology appraisals. A NICE clinical guideline on RA is due to be published in February 2009. Further information on the management of RA is available from the pain management/RA section of NPC.

What does this study claim?
The primary outcome was a 20% improvement in disease criteria as measured by the ACR20 at week 24. This was seen in 50.0% of tocilizumab 8mg/kg patients (n=170), 30.4% of the 4mg/kg group (n=159) and 10.1% of the placebo patients (n=158); P<0.0001 for both tocilizumab doses vs. placebo. No confidence intervals were quoted in the paper. Remission, a secondary outcome measured by DAS28 scores of less than 2.6, occurred in significantly more patients who received 8mg/kg doses of tocilizumab compared to placebo (30.1% vs. 1.6%, P=0.0001).

How does this relate to other studies?
The OPTION and TOWARD trials of tocilizumab have already been published. OPTION included patients who were already receiving methotrexate. The ACR20 response rate at 24 weeks was 59% in the tocilizumab 8mg/kg group (n=205), 48% in the 4mg/kg group  (n=214) and 26% in the placebo patients (n=204), odds ratio (OR) 4·0 (95% confidence interval [CI] 2·6 to 6·1), P<0·0001 for 8mg/kg vs. placebo, and OR 2·6 (95% CI 1·7 to 3·9), P<0·0001 for 4mg/kg vs. placebo). The TOWARD trial assessed tocilizumab in combination with conventional disease-modifying anti-rheumatic drugs (DMARDs). After 24 weeks, the ACR20 response rate was 61% in the tocilizumab plus DMARD group vs. 25% in the placebo group (P<0.0001).

So what?
ACR20 is considered to be the minimum response to distinguish active treatment from placebo in clinical trials. ACR50, 70 and 90 indicate greater improvement. However, the aim in treating RA is achievement of the lowest disease activity possible and ideally, remission should be achieved in a considerable proportion of patients in trials and practice.

As in other published studies, increases in lipid levels were seen in patients given tocilizumab. Longer term studies are required to establish if this may lead to adverse cardiovascular (CV) outcomes. Patients should be assessed to determine if lipid lowering drugs and other measures to reduce CV risk are necessary.

Study details
Design: phase III, randomised, double-blind, placebo-controlled parallel group trial.

Patients: adults with moderate to severe active RA who had failed to respond, or were intolerant, to one or more anti-TNF drugs within the last year.

Intervention: tocilizumab 8mg/kg or 4mg/kg intravenously over 1 hour every 4 weeks for 24 weeks.

Comparison: placebo infusion every 4 weeks.

All patients were treated with stable doses of methotrexate (10 to 25mg weekly) and folate. At week 16, patients who had failed to respond were offered rescue therapy with 8mg/kg tocilizumab and methotrexate.

Outcomes and Results: Randomisation involved 499 patients and efficacy was assessed in all those who had received at least one dose of the study drug. The primary end point was ACR20 response. This is an American College of Rheumatology criterion for assessing response to treatment, based on improvements in key measures of disease activity (e.g. tender joint count).

Secondary outcomes were ACR50, ACR70, DAS28 and EULAR responses. ACR50 and ACR70 are more stringent response rates than ACR20; a DAS28 score of less than 2.6 equates to remission and EULAR criteria were developed from the DAS measure by the European League Against Rheumatism.

Adverse events: overall 84.0%, 87.1% and 80.6% of patients on tocilizumab 8mg/kg, 4mg/kg and placebo, respectively, experienced adverse events. Serious infections occurred in 4.6%, 1.8% and 3.1% of patients, respectively. Transient neutropenia was seen in patients on tocilizumab but no patients had associated serious infections or fever. Gastro-intestinal, skin and eye adverse events were more common in patients who received tocilizumab. Total cholesterol levels were raised in tocilizumab patients but not in those who received placebo.

Sponsorship: F. Hoffman-La Roche Ltd and Chugai Pharma KK.

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