Purpose: To report results of a 2-yr planned analysis of a double-blind, randomized controlled, phase 3 trial of TCZ in pts with moderate to severe RA who remained on MTX despite inadequate response.
Method: Pts were randomized (1:1:1) to receive TCZ + MTX (4 mg/kg [TCZ4] or 8 mg/kg [TCZ8]) or placebo + MTX (control [CON]) every 4 wks. Stepwise rescue therapy starting at wk 16 was allowed if pts did not respond (<20% improvement in SJC and TJC). At wk 52, all pts were required to initiate open-label TCZ8 for yr 2, unless they had achieved ≥ 70% improvement in SJC and TJC, allowing them to continue the blinded therapy they were receiving at the end of yr 1 to wk 104. Primary 2-yr end points were change from baseline in Genant-modified Total Sharp Score (GmTSS) and physical function (AUC of change from baseline in HAQ-DI). Linear extrapolation (GmTSS) or standardization (change in HAQ-DI) was used for missing data (post-rescue data set to missing). To examine impact of 2 yrs of treatment, efficacy end points were assessed over time for pts randomized to TCZ8, with LOCF for SJC and TJC for pts who received rescue therapy or withdrew from that time point.
Results: The ITT population consisted of 398 TCZ8, 399 TCZ4, and 393 CON pts. At 2 yrs, exposure rate per pt-yrs (PY) were 1320, 521.9, and 284.8 in TCZ8, TCZ4, and CON pts. More CON pts required rescue vs TCZ pts, and more TCZ pts remained on initial randomized therapy (Table A). At yr 2, pts in the TCZ8 group had significantly less radiographic progression (81% inhibition) vs CON pts (based on linear extrapolation of mean change in GmTSS on initial treatment for post-rescue data). Significantly more TCZ8 pts had no radiographic progression vs CON pts (p≤0.0001). AUC of change from baseline in HAQ-DI showed significant improvement in physical function in TCZ4 and TCZ8 vs CON pts (Table A). In pts initially randomized to TCZ8, low disease activity score (LDAS; DAS28 £3.2) was seen in >60%, and DAS28 remission (DAS28 <2.6) rates were ~50% at wk 52 and continued to increase to wk 104 (Table B). By wk 52, in pts treated with TCZ8, clinically significant improvements in SJC occurred (–10) that were maintained through wk 104. Rates/100PY for adverse events (AEs) were higher in TCZ8 and TCZ4 (263.6, 275.4) vs CON pts (251.4) while rates for serious AEs were comparable (11.4, 12.1, 10.9). Rates per 100PY of AEs leading to withdrawal and treatment modification were higher in TCZ8 and TCZ4 (7.4 and 32.5; 8.4 and 30.7) vs CON pts (4.8 and 20.4) and rates for death were comparable (0.6, 0.2, 0.4).
Conclusion: TCZ + MTX continues to inhibit radiographic progression and improve physical function with a clinical effect, as evidenced by improving DAS28 remission, LDAS, and SJC at 2 yrs and with a manageable safety profile.