Background/Purpose: Although methotrexate (MTX) is often administered in combination with biologics for the treatment of rheumatoid arthritis (RA), it may be discontinued due to intolerance or to reduce medication burden. This study evaluated whether tocilizumab-monotherapy (TCZ-MONO) is non-inferior to TCZ + MTX in maintaining clinical response in patients who achieve low disease activity with TCZ + MTX in the COMP-ACT trial.

Methods: US patients with RA who were inadequate responders to MTX initially received MTX (≥ 15 mg/week orally) plus TCZ 162 mg subcutaneous (SC) either weekly (patients ≥ 100 kg) or every 2 weeks (patients < 100 kg). Patients who had not achieved low disease activity (DAS28 ≤ 3.2) at week 12 could escalate from q2w to qw dosing. Patients who achieved DAS28-ESR ≤ 3.2 at week 24 were randomized 1:1 to receive TCZ-MONO or TCZ + MTX until week 52 (double-blind). The primary outcome measured was the comparison of mean change in DAS28-ESR score from weeks 24 to 40 between the TCZ-MONO and TCZ + MTX arms (non-inferiority margin of 0.6). Secondary outcomes included the proportion of patients achieving DAS28 < 2.6, DAS28 ≤ 3.2 and American College of Rheumatology 20%/50%/70% (ACR20/50/70) responses at weeks 40 and 52, and safety. Trial registration number: NCT01855789.

Results: Of 718 patients enrolled, 296 were randomized at week 24 (TCZ-MONO, n = 148; TCZ + MTX, n = 148). Early discontinuation in the randomized cohort occurred in 12.2% of patients in the TCZ-MONO group and 10.2% in the TCZ + MTX group. Baseline characteristics were balanced between treatment groups (mean age, 55.5 years; 74.8% female; mean RA duration, 6.8 years; mean DAS28-ESR, 6.3). At week 24, DAS28 scores were similar in both groups, but ACR responses were ≈8% to 11% lower in the TCZ-MONO group prior to MTX withdrawal (randomization). The mean change in DAS28 was similar between the randomized treatment groups (Table 1). For the primary efficacy analysis, the mean changes in DAS28 from weeks 24 to 40 were 0.46 and 0.14 in the TCZ-MONO and TCZ + MTX groups, respectively (95% CI, 0.045-0.592). This study met the primary endpoint by demonstrating that discontinuing MTX in TCZ responders was noninferior to continuing MTX. The safety of TCZ-SC in this study was consistent with the known safety profile, with no new safety signals observed (Table 2). The most common SAE was infection, occurring in 4.1% of patients. TCZ + MTX had greater frequency of AEs, SAEs and serious infections than TCZ-MONO.

Conclusion: These results demonstrate that patients receiving TCZ + MTX who achieve low disease activity can discontinue MTX and maintain disease control.