Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study

Abstract

Background: The anti-interleukin (IL) 6 receptor antibody tocilizumab inhibits signalling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis.

Objective: To evaluate through the AMBITION study the efficacy and safety of tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed.

Methods: This 24-week, double-blind, double-dummy, parallel-group study, randomised 673 patients to either tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by tocilizumab 8 mg/kg. The primary end point was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 24.

Results: The intention-to-treat analysis demonstrated that tocilizumab was better than methotrexate treatment with a higher ACR20 response (69.9 vs 52.5%; p<0.001), and 28-joint Disease Activity Score (DAS28) <2.6 rate (33.6 vs 12.1%) at week 24. Mean high-sensitivity C-reactive protein was within the normal range from week 12 with tocilizumab, whereas levels remained elevated with methotrexate. The incidence of serious adverse events with tocilizumab was 3.8% versus 2.8% with methotrexate (p = 0.50), and of serious infections, 1.4% versus 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1% vs 0.4%) and increased total cholesterol > or =240 mg/dl (13.2% vs 0.4%), and a lower incidence of alanine aminotransferase elevations >3x-<5x upper limit of normal (1.0% vs 2.5%), respectively.

Conclusion: Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit-risk, in patients for whom treatment with methotrexate or biological agents has not previously failed.

Trial registration: ClinicalTrials.gov NCT00109408.

Conflict of interest statement

Competing interests: GJ has received consulting fees from Merck, Roche, Genzyme, Novartis and Servier and has been paid lecture fees by Merck, Roche, Sanofi-Aventis, Servier, Pfizer and Novartis. ASe has received consulting fees from Amgen, Merck, Novartis and Roche, and has been paid lecture fees by Merck, Novartis, Roche, Glaxo Smith Kline and Lilly. AC has received lecture fees from Deutsche Pharma, Farmindustria, Schering Plough and Pfizer, has been paid lecture fees by Bristol-Myers Squibb and Merck, and has received grant support from Bristol-Myers Squibb, Merck and Roche. JJG-R has received consulting fees from Roche, Schering Plough, Wyeth and Bristol-Myers Squibb, and has been paid lecture fees by Roche, Wyeth and Bristol-Myers Squibb. ASi has received consulting fees from Roche. MT has received consulting fees from Roche and Schering Plough. TW and EA are employees of Roche. MCG has received consulting fees from Roche, Genentech, Biogen-Idec and Bristol-Myers Squibb, has been paid lecture fees by Genentech and Bristol-Myers Squibb and has received grant support from Roche, Genentech, Biogen-Idec, Bristol-Myers Squibb and Pfizer.

Figures

Figure 1

Study enrolment, randomisation and study completion. aIncludes one patient who did not complete 24 weeks of treatment and therefore should have been counted as having withdrawn prematurely; bincludes one patient who missed the first dose of intravenous study drug, but received 24 weeks of the oral study drug and therefore should have been considered a completer; conly patients enrolled in the placebo controlled substudy could receive rescue treatment with tocilizumab 8 mg/kg within the first 8 weeks of double-blind treatment; ITT, intention to treat; PP, per-protocol.

Figure 2

Improvement in signs and symptoms of disease. (A) Proportion of patients achieving ACR20, ACR50 and ACR70 responses at week 24 (ITT population). Results demonstrate that treatment with tocilizumab is significantly better than treatment with methotrexate (*p

Figure 3

(A) Proportion of patients experiencing reduced neutrophil counts during the 24-week study (Safety population). (B) Patients with elevations in liver aminotransferases and total bilirubin levels from normal levels at baseline (AST