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

Abstract

Objectives: The phase III RADIATE study examined the efficacy and safety of tocilizumab, an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis (RA) refractory to tumour necrosis factor (TNF) antagonist therapy.

Methods: 499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo (control) intravenously every 4 weeks with stable methotrexate for 24 weeks. ACR20 responses, secondary efficacy and safety endpoints were assessed.

Results: ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively (less than p<0.001 both tocilizumab groups versus control). At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls (less than p = 0.001). Patients responded regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 remission (DAS28 <2.6) rates at week 24 were clearly dose related, being achieved by 30.1%, 7.6% and 1.6% of 8 mg/kg, 4 mg/kg and control groups (less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control). Most adverse events were mild or moderate with overall incidences of 84.0%, 87.1% and 80.6%, respectively. The most common adverse events with higher incidence in tocilizumab groups were infections, gastrointestinal symptoms, rash and headache. The incidence of serious adverse events was higher in controls (11.3%) than in the 8 mg/kg (6.3%) and 4 mg/kg (7.4%) groups.

Conclusion: Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile.

Trial registration number: NCT00106522.

Figure 1. Numbers of patients undergoing enrolment, random selection and study completion. *One randomly assigned patient was withdrawn from the study before receiving any study medication because of a latex allergy.

Figure 2. Clinical response to tocilizumab treatment by visit for (A) ACR20 response, (B) ACR50 response, (C) ACR70 response, (D) percentage of patients achieving clinical remission (disease activity score based on 28 joints (DAS28) <2.6). **p<0.001 versus placebo. ***less than p<0.001 versus placebo. MTX, methotrexate; TCZ, tocilizumab.

Figure 3. Changes in haematological and serum proteins per visit for (A) C-reactive protein, (B) erythrocyte sedimentation rate, (C) haemoglobin. *p<0.05 versus placebo; **p<0.001 versus placebo; ***less than p<0.001 versus placebo. LLN, lower limit of normal; MTX, methotrexate; TCZ, tocilizumab; ULN, upper limit of normal.