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.

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 ^aIncludes one patient who did not complete 24 weeks of treatment and therefore should have been counted as having withdrawn prematurely; ^bincludes one patient who missed the first dose of intravenous study drug, but received 24 weeks of the oral study drug and therefore should have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<0.001; **p = 0.002; ***p<0.001). (B) Proportion of methotrexate-naïve patients achieving ACR20, ACR50 and ACR70 responses at week 24 (ITT population); *Weighted difference between groups 0.15 (95% CI 0.05 to 0.25), p<0.004; **weighted difference between groups 0.14 (95% CI 0.03 to 0.24), p = 0.01; ***weighted difference between groups 0.15 (95% CI 0.04 to 0.25), p = 0.005. (C) Time course for achievement of ACR20, ACR50 and ACR70 responses during 24 weeks of treatment with tocilizumab or methotrexate (ITT population). (D) Proportion of patients in clinical remission (DAS28 <2.6) and proportion of patients with good/moderate EULAR response at week 24 (ITT population). (E) CRP levels at each post-baseline visit during the 24-week study (ITT population); (F) Haemoglobin levels at each post-baseline visit during the 24-week study (safety population). CRP, C-reactive protein; DAS28, 28-joint Disease Activity Score; ITT, intention to treat; LLN, lower limit of normal; ULN, upper limit of normal.

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 <40 U/L, ALT <55 U/L, total bilirubin <17 μmol/L; safety population). (C) Patients experiencing elevations in total and LDL cholesterol from <200 mg/dl and <100 mg/dl at baseline, respectively (Safety population). ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDL, low-density lipoprotein; ULN, upper limit of normal.