Filgotinib versus placebo or adalimumab in patients with rheumatoid arthritis and inadequate response to methotrexate: a phase III randomised clinical trial

Abstract

Objective: To evaluate the efficacy and safety of the Janus kinase-1-preferential inhibitor filgotinib versus placebo or tumour necrosis factor-α inhibitor therapy in patients with active rheumatoid arthritis (RA) despite ongoing treatment with methotrexate (MTX).

Methods: This 52-week, multicentre, double-blind, placebo-controlled and active-controlled phase III trial evaluated once-daily oral filgotinib in patients with RA randomised 3:3:2:3 to filgotinib 200 mg (FIL200) or filgotinib 100 mg (FIL100), subcutaneous adalimumab 40 mg biweekly, or placebo (through week 24), all with stable weekly background MTX. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Additional efficacy outcomes were assessed sequentially. Safety was assessed from adverse events and laboratory abnormalities.

Results: The proportion of patients (n=1755 randomised and treated) achieving ACR20 at week 12 was significantly higher for FIL200 (76.6%) and FIL100 (69.8%) versus placebo (49.9%; treatment difference (95% CI), 26.7% (20.6% to 32.8%) and 19.9% (13.6% to 26.2%), respectively; both p<0.001). Filgotinib was superior to placebo in key secondary endpoints assessing RA signs and symptoms, physical function and structural damage. FIL200 was non-inferior to adalimumab in terms of Disease Activity Score in 28 joints with C reactive protein ≤3.2 at week 12 (p<0.001); FIL100 did not achieve non-inferiority. Adverse events and laboratory abnormalities were comparable among active treatment arms.

Conclusions: Filgotinib improved RA signs and symptoms, improved physical function, inhibited radiographic progression and was well tolerated in patients with RA with inadequate response to MTX. FIL200 was non-inferior to adalimumab.

Trial registration number: NCT02889796.

Keywords: antirheumatic agents; arthritis; rheumatoid; therapeutics.

Figure 1

Patient disposition. *23 (4.8%) patients treated with filgotinib 200 mg, 29 (6.0%) patients treated with filgotinib 100 mg, 13 (4.0%) patients treated with adalimumab, and 41 (8.6%) patients treated with placebo did not have adequate response to treatment per protocol at week 14. ^†3 (0.7%) patients treated with filgotinib 200 mg, 2 (0.5%) patients treated with filgotinib 100 mg, 3 (1.0%) patients treated with adalimumab, 0 patient treated with placebo and rerandomised to filgotinib 200 mg at week 24, and 4 (2.2%) patients treated with placebo and rerandomised to filgotinib 100 mg at week 24 failed to maintain response to treatment per protocol after week 30. ADA, adalimumab; FIL, filgotinib; PBO, placebo; W, week.

Figure 2

Proportions of patients achieving (A) ACR20, (B) ACR50 and (C) ACR70 through week 52. Error bars show 95% CI. Additional statistical details are available in online supplemental table S3 and all response rates in online supplemental table S7. **p<0.01, ***p<0.001 versus PBO, not adjusted for multiplicity and should be considered exploratory except for ACR20 for FIL200 and FIL100 versus PBO at week 12. ⁺p<0.05, ⁺⁺p<0.01,⁺⁺⁺p<0.001 versus ADA, not adjusted for multiplicity and should be considered exploratory. ACR20/50/70, 20%/50%/70% improvement from baseline by the American College of Rheumatology core criteria; ADA, adalimumab; FIL100, filgotinib 100 mg; FIL200, filgotinib 200 mg; PBO, placebo.

Figure 3

Radiographic progression through week 24. (A) mTSS change from baseline, (B) erosion score change from baseline and (C) joint space narrowing change from baseline. Data from campaign A (through week 24) are shown. Supporting data are shown in online supplemental table S4. Patient numbers at each time point in (B) and (C) are the same as for (A). Error bars represent the SE of the LS mean. *p<0.05, **p<0.01, ***p<0.001 versus PBO, not adjusted for multiplicity and should be considered exploratory except for mTSS change from baseline following FIL200 and FIL100 versus PBO at week 24. Difference for mTSS change from baseline at week 24 following treatment with FIL200 or FIL100 versus ADA was explored and was not significant for either dose. ADA, adalimumab; FIL100, filgotinib 100 mg; FIL200, filgotinib 200 mg; LS, least-squares; mTSS, van der Heijde modified total Sharp score; PBO, placebo.

Figure 4

Proportions of patients achieving (A) low disease activity and (B) DAS28(CRP) <2.6 or remission at weeks 12, 24 and 52. Error bars show 95% CI. Additional statistical details are available in online supplemental table S3. *p<0.05, **p<0.01, ***p<0.001 versus placebo, not adjusted for multiplicity and should be considered exploratory except for FIL200 and FIL100 versus placebo for DAS28(CRP) <2.6 at week 12. ^#Non-inferior versus adalimumab. ⁺p<0.05, ⁺⁺p<0.01, ⁺⁺⁺p<0.001 versus ADA, not adjusted for multiplicity and should be considered exploratory. ADA, adalimumab; Boolean, Boolean remission; CDAI, Clinical Disease Activity Index; DAS28(CRP), Disease Activity Score in 28 joints with C reactive protein; FIL100, filgotinib 100 mg; FIL200, filgotinib 200 mg; PBO, placebo; SDAI, Simplified Disease Activity Index.