Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY)

Abstract

Objective: In patients with active rheumatoid arthritis (RA) despite methotrexate, to compare the efficacy of adding tocilizumab to that of switching to tocilizumab monotherapy.

Methods: Double-blind, 2-year study in which adults with active RA (DAS28 >4.4) despite methotrexate were randomly assigned either to continue methotrexate with the addition of tocilizumab (MTX+TCZ) 8 mg/kg every 4 weeks or switch to tocilizumab and placebo (TCZ+PBO). The primary endpoint was the DAS28-erythrocyte sedimentation rate (ESR) remission rate at week 24. Secondary objectives included other symptomatic outcomes, quality of life and progression of structural damage.

Results: Of 556 randomly assigned patients, 512 (92%) completed 24 weeks. DAS28-ESR remission rates were 40.4% for TCZ+MTX and 34.8% for TCZ+PBO (p=0.19); American College of Rheumatology 20/50/70/90 rates were 71.5%/45.5%/24.5%/5.8% (TCZ+MTX) and 70.3%/40.2%/25.4%/5.1% (TCZ+PBO; differences not significant). A significant difference between groups was seen for low DAS28 (61.7% vs 51.4%). Radiographic progression was small and not different between groups (Genant-Sharp score progression ≤ smallest detectable change in 91% (TCZ+MTX) and 87% (TCZ+PBO)). Rates per 100 patient-years of serious adverse events and serious infections were 21 and six, respectively, for TCZ+MTX and 18 and six, respectively, for TCZ+PBO. Alanine aminotransferase elevations greater than threefold the upper limit of normal occurred in 7.8% and 1.2% of TCZ+MTX and TCZ+PBO patients, respectively.

Conclusion: No clinically relevant superiority of the TCZ+MTX add-on strategy over the switch to tocilizumab monotherapy strategy was observed. The combination was more commonly associated with transaminase increases. Meaningful clinical and radiographic responses were achieved with both strategies, suggesting that tocilizumab monotherapy might be a valuable treatment strategy in suitable RA patients.

Figure 1

Patient disposition and study flow chart. ITT, intention-to-treat; MTX, methotrexate; PBO, placebo; TCZ, tocilizumab.

Figure 2

Binary composite indices and radiographic results at week 24 (intent-to-treat population). (A) Patients achieving remission (DAS28 <2.6), (B) low disease activity (DAS28 ≤3.2), (C) good or moderate European League Against Rheumatism responses, (D) ACR responses, (E) patients (%) with no radiographic progression in total GSS, and (F) cumulative distribution of change from baseline in total GSS. Dashed lines indicate smallest detectable change with data falling between these lines representing no change. ACR, American College of Rheumatology; DAS28, disease activity score based on 28 joints; GSS, Genant-modified Sharp Score; MTX, methotrexate; NS, not significant; PBO, placebo; TCZ, tocilizumab.

Figure 3

Changes from baseline in selected American College of Rheumatology core set variables over time (intent-to-treat population). (A) Mean change from baseline for swollen joint counts, (B) tender joint counts, (C) patient's global assessment of pain, (D) HAQ–DI, (E) ESR and (F) CRP. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HAQ–DI, health assessment questionnaire–disability index; MTX methotrexate; TCZ, tocilizumab; VAS, visual analogue scale.