Background/Purpose: 24- and 52- week data from ACT-RAY comparing an add-on strategy (tocilizumab [TCZ] + methotrexate [MTX]) with a switch strategy (TCZ + placebo [PBO]) in MTX-IR pts have been previously reported, demonstrating relevant clinical and radiographic benefit without clinically meaningful between-arm differences for most endpoints. During year 2, the study included a step-down strategy with the goal of achieving drug free remission (discontinuation of study drugs with DAS28 <2.6). The objective here is to further assess the efficacy and safety of TCZ-based treatment strategies and to determine the ability to discontinue study drugs in year 2 after sustained clinical remission (DAS28 <2.6 at 2 consecutive visits 12 weeks apart).

Methods: ACT-RAY is a phase 3b trial. Pts on stable doses of MTX were randomized to either add TCZ 8 mg/kg IV every 4 weeks (q4w; add-on) or switch to TCZ 8 mg/kg IV with oral PBO (switch). Utilizing a treat to target (T2T) approach, OL DMARDs other than MTX were added from week 24 usually if DAS28 was >3.2, while maintaining MTX/PBO blinding. In year 2, if sustained clinical remission was achieved, first TCZ and then OL DMARDs and MTX/PBO were discontinued. In case of flare, the last effective treatment or TCZ with blinded MTX/PBO was restarted.

Results: Pt baseline (BL) data were similar between treatment arms (mean disease duration 8.2 y, BL DAS28 6.4) except for higher Genant-Sharp Scores (GSS) in the switch group (41.2 vs 36.9 for add-on pts). 76% of 556 randomized pts (277 add-on and 276 switch) completed year 2. Reasons for withdrawal included lack of efficacy (1.8% add-on, 4.7% switch) and adverse events (AEs; 9.7% add-on, 11.2% switch, including 3 and 6 deaths, respectively). Of pts entering into year 2,~50% discontinued TCZ after achieving sustained remission, and 86% of these pts experienced flare before the end of year 2 (flares can still occur in year 3). For pts who restarted TCZ and had a DAS28 assessment (n = 164), mean DAS28 at flare was 4.46. The effects of restarting TCZ were rapid with mean DAS28 dropping to 2.99, 2.18 and 2.02 within 4, 12 and 20 weeks, respectively. See table for additional results. Despite many pts stopping TCZ for some period, radiographic progression was minimal in both arms (table). Safety was consistent with previous findings. SAEs and serious infections per 100 PY were 11.9 and 4.2, respectively, for the add-on and 14.6 and 3.8, respectively, for the switch arm. In pts with normal BL values, ALT elevations >3x ULN were observed in 13.5% of add-on and 4.9% of switch pts.

Conclusion: Previous clinical improvements were largely maintained in year 2 of ACT-RAY. Year 2 results suggest that T2T strategies can be successfully utilized in MTX-IR pts (whether or not currently on MTX) to achieve sustained remission. However, stopping TCZ in this established RA pt population was associated with a high flare risk. Pts who restarted TCZ achieved improvements in DAS28.