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

TLDR

Tocilizumab blocks IL‑6 signalling, a key cytokine in rheumatoid arthritis pathogenesis. The study aimed to compare the efficacy and safety of tocilizumab monotherapy with methotrexate monotherapy in patients with active RA who had not previously failed methotrexate or biologic therapy. A 24‑week, double‑blind, double‑dummy, parallel‑group trial randomized 673 patients to tocilizumab 8 mg/kg every 4 weeks, methotrexate titrated to 20 mg/week, or placebo followed by tocilizumab, with the primary endpoint being the proportion achieving an ACR20 response at week 24. Tocilizumab produced a higher ACR20 response (69.9 % vs 52.5 %) and DAS28 < 2.6 rate (33.6 % vs 12.1 %) at week 24, normalised hs‑CRP from week 12, and had a comparable serious adverse event rate but higher neutropenia and hypercholesterolaemia, indicating a favourable benefit‑risk profile. Trial registration number: NCT00109408.

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&lt;0.001), and 28-joint Disease Activity Score (DAS28) &lt;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 ⩾240 mg/dl (13.2% vs 0.4%), and a lower incidence of alanine aminotransferase elevations &gt;3×–&lt;5× 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 number: NCT00109408