Tofacitinib in Combination With Methotrexate in Patients With Rheumatoid Arthritis: Clinical Efficacy, Radiographic, and Safety Outcomes From a Twenty-Four-Month, Phase III Study

Abstract

Objective: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). The phase III, 24-month, placebo-controlled Oral Rheumatoid Arthritis (ORAL) Scan trial was undertaken to evaluate the efficacy, including inhibition of structural progression, and safety of tofacitinib in patients with active RA and an inadequate response to methotrexate (MTX). Month 24 data from the completed study are reported here.

Methods: Patients were randomized 4:4:1:1 to receive tofacitinib 5 mg or 10 mg twice daily, or placebo, switched to tofacitinib 5 mg or 10 mg twice daily, with stable background MTX. Patients receiving placebo switched to tofacitinib at month 3 (nonresponders) or month 6 (remaining patients). Clinical efficacy, structural progression, and treatment-emergent adverse events were evaluated. Analyses were performed on the full analysis set with observed data or nonresponder imputation with no advancement penalty for clinical efficacy, and imputation by linear extrapolation for structural progression.

Results: Overall, 797 patients were treated; 539 (67.6%) completed 24 months of treatment. Responses according to the American College of Rheumatology criteria for 20% improvement (ACR20), ACR50, and ACR70; the proportion of patients in whom remission or low disease activity was achieved according to the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate, Clinical Disease Activity Index, or Simplified Disease Activity Index; Boolean remission; and Health Assessment Questionnaire disability index scores were maintained from month 12 to 24 and were similar between tofacitinib dosages. Limited structural damage was observed at months 12 and 24. Safety events were similar in type and frequency for both tofacitinib dosages, and were consistent with those previously reported.

Conclusion: Our findings indicate that clinical and radiographic treatment effects are sustained in months 12-24 in patients with RA receiving tofacitinib 5 mg or 10 mg twice daily plus MTX. The safety profile is consistent with that of other tofacitinib studies.

Trial registration: ClinicalTrials.gov NCT00847613.

Figure 1

Disposition of the patients from baseline to month 24. Patients were randomized to receive tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg twice daily, or placebo. All patients received background methotrexate, including those in the placebo groups. For patients in the placebo groups, treatment was switched in a blinded manner to tofacitinib 5 mg twice daily or tofacitinib 10 mg twice daily at either 3 months (for nonresponders) or 6 months (for all remaining patients in the placebo groups). Patients with <20% improvement in swollen and tender joint counts were considered nonresponders. At month 3, a <20% improvement in swollen and tender joint counts from baseline was found in 84 (26%) of the patients receiving tofacitinib 5 mg twice daily, 56 (18%) of the patients receiving tofacitinib 10 mg twice daily, 42 (52%) of the patients receiving placebo who switched to tofacitinib 5 mg twice daily, and 37 (47%) of the patients receiving placebo who switched to to tofacitinib 10 mg twice daily. Only deaths that occurred during study treatment are included. See Table 3 for details on deaths that occurred after the last dose of study drug. AE = adverse event.

Figure 2

Actual values, change from baseline to months 12 and 24, and change from month 12 to month 24 in A, modified Sharp/van der Heijde score (SHS), B, erosion score, and C, joint space narrowing score in rheumatoid arthritis (RA) patients receiving tofacitinib 5 mg twice daily (BID) and RA patients receiving tofacitinib 10 mg twice daily (as observed in the full analysis set). All patients received background methotrexate. Patients who did not have valid postbaseline radiographs were not included. Data are shown for patients who completed month 12, as observed. Values are the mean ± SEM (n = 287 at baseline, n = 252 at month 12, and n = 210 at month 24 [n = 208 for change from month 12] for tofacitinib 5 mg twice daily; n = 298 at baseline, n = 261 at month 12, and n = 216 at month 24 [n = 214 for change from month 12] for tofacitinib 10 mg twice daily).