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.

Conflict of interest statement

Competing interests: MD has participated in symposia and advisory boards organised by Roche and received consulting fees and his department has received research grants from Roche for conducting clinical trials and/or clinical epidemiological studies. KK is an employee of F Hoffmann-La Roche. TS received consulting fees and research grants from Roche. PPT's department has received Roche funds as grants and consulting fees or honorarium. PPT is an employee of and has stock/stock options for GlaxoSmithKline. PGC has received research grants from Centocor Inc and Roche and has been a speaker for Astra Zeneca, Bioberica, Bristol-Myers Squibb, Centocor Inc, Merck Pharmaceuticals, Novartis Pharmaceutical Corporation, Pfizer and Roche. EMM has received consulting fees and been an educational lecturer for Abbott Immunology, Roche MSD, Pfizer and UCB. GS received consulting fees from Roche. FNS has consulted for Pfizer, UCB, Abbott and Roche and has been a speaker for Roche, Pfizer, Abbott and MSD, and his department has received research grants from Roche, Pfizer and Abbott. AH has no competing interests to report. CB is a contractor of F Hoffmann-La Roche. TWJH has received consulting fees and has been a speaker for Abbott Immunology, Axis Shield Diagnostics, Biotest AG, Bristol-Myers Squibb, Crescendo Bioscience, Roche, Novartis Pharmaceuticals, Schering-Plough, UCB and Wyeth-Pfizer.

Figures

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

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.