Effect of Filgotinib vs Placebo on Clinical Response in Patients With Moderate to Severe Rheumatoid Arthritis Refractory to Disease-Modifying Antirheumatic Drug Therapy: The FINCH 2 Randomized Clinical Trial

Abstract

Importance: Patients with active rheumatoid arthritis (RA) despite treatment with biologic disease-modifying antirheumatic drug (bDMARD) therapy need treatment options.

Objective: To evaluate the effects of filgotinib vs placebo on the signs and symptoms of RA in a treatment-refractory population.

Design, setting, and participants: A 24-week, randomized, placebo-controlled, multinational phase 3 trial conducted from July 2016 to June 2018 at 114 sites internationally, randomizing 449 adult patients (and treating 448) with moderately to severely active RA and inadequate response/intolerance to 1 or more prior bDMARDs.

Interventions: Filgotinib, 200 mg (n = 148); filgotinib, 100 mg (n = 153); or placebo (n = 148) once daily; patients continued concomitant stable conventional synthetic DMARDs (csDMARDs).

Main outcomes and measures: The primary end point was the proportion of patients who achieved 20% improvement in the American College of Rheumatology criteria (ACR20) at week 12. Secondary outcomes included week 12 assessments of low disease activity (disease activity score in 28 joints-C-reactive protein [DAS28-CRP] ≤3.2) and change in Health Assessment Questionnaire-Disability Index, 36-Item Short-Form Health Survey Physical Component, and Functional Assessment of Chronic Illness Therapy-Fatigue scores, as well as week 24 assessment of remission (DAS28-CRP <2.6) and adverse events.

Results: Among 448 patients who were treated (mean [SD] age, 56 [12] years; 360 women [80.4%]; mean [SD] DAS28-CRP score, 5.9 [0.96]; 105 [23.4%] with ≥3 prior bDMARDs), 381 (85%) completed the study. At week 12, more patients receiving filgotinib, 200 mg (66.0%) or 100 mg (57.5%), achieved ACR20 response (placebo, 31.1%; difference vs placebo: 34.9% [95% CI, 23.5%-46.3%] and 26.4% [95% CI, 15.0%-37.9%], respectively; both P < .001), including among patients with prior exposure to 3 or more bDMARDs (70.3%, 58.8%, and 17.6%, respectively; difference vs placebo: 52.6% [95% CI, 30.3%-75.0%] for filgotinib, 200 mg, and 41.2% [95% CI, 17.3%-65.0%] for filgotinib, 100 mg; both P < .001). The most common adverse events were nasopharyngitis (10.2%) for filgotinib, 200 mg; headache, nasopharyngitis, and upper respiratory infection (5.9% each) for filgotinib, 100 mg; and RA (6.1%) for placebo. Four uncomplicated herpes zoster cases and 1 retinal vein occlusion were reported with filgotinib; there were no opportunistic infections, active tuberculosis, malignancies, gastrointestinal perforations, or deaths.

Conclusions and relevance: Among patients with active RA who had an inadequate response or intolerance to 1 or more bDMARDs, filgotinib, 100 mg daily or 200 mg daily, compared with placebo resulted in a significantly greater proportion achieving a clinical response at week 12. However, further research is needed to assess longer-term efficacy and safety.

Trial registration: ClinicalTrials.gov Identifier: NCT02873936.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Genovese reported receiving grants and personal fees from Gilead and grants from Galapagos during the conduct of the study and grants and personal fees from Lilly, AbbVie, Pfizer, Astellas, Vertex, Sanofi, EMD Serono, and Genentech/Roche and personal fees from Incyte outside the submitted work. Dr Kalunian reported receiving grants from Gilead during the conduct of the study. Dr Gottenberg reported receiving personal fees from AbbVie, Pfizer, UCB, Eli Lilly, and Sanofi-Genzyme; grants and personal fees from Bristol-Myers Squibb; and nonfinancial support from Roche outside the submitted work. Drs Mozaffarian, Bartok, Matzkies, Gao, Guo, and Sundy are employees and stockholders of Gilead Sciences. Dr Tasset is an employee and stockholder of Galapagos NV. Dr Walker reported serving on advisory boards and speaking at meetings for Eli Lilly, Pfizer, Novartis, and Gilead. Dr Takeuchi reported receiving grants and personal fees from AbbVie, Astellas Pharma Inc, Chugai Pharmaceutical Co Ltd, Daiichi Sankyo Co, Eisai Co Ltd, Mitsubishi Tanabe Pharma Co, Nipponkayaku Co Ltd, Pfizer Japan Inc, and Takeda Pharmaceutical Co Ltd; personal fees from AstraZeneca, Bristol-Myers Squibb, Eli Lilly Japan, GlaxoSmithKline, Janssen Pharmaceutical, Novartis Pharma, AYUMI Pharmaceutical Corporation, Sanofi, Teijin Pharma Ltd, Taiho Pharmaceutical Co Ltd, Taisho Pharmaceutical Co Ltd, and UCB Japan Co Ltd; and grants from Asahikasei Pharma Corp during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Study Flow and Patient Disposition

aNo additional information was provided by the site investigators. bAdverse events in the filgotinib, 200 mg, group included 1 case each (0.7%) of abnormal blood alkaline phosphatase, gastroesophageal reflux disease, and migraine; in the filgotinib, 100 mg, group included 1 case each (0.7%) of anxiety, herpes zoster, hot flush, myocardial ischemia, and osteitis; and in the placebo group included 2 cases of rheumatoid arthritis (1.4%) and 1 case (0.7%) of decreased lymphocyte count. cA patient in the filgotinib, 100 mg, group reported their partner’s pregnancy at the week 4 visit that resulted in the patient being removed from the study and recorded as a protocol violation. A patient in the placebo group received protocol-prohibited medication on study day 6 due to severe bodily pain caused by rheumatoid arthritis (dexamethasone intra-articular injection and dexamethasone intravenous drip).

Figure 2.. Primary and Secondary Efficacy End Points

Panels A, B, and C show the percentage of patients who had 20% improvement in American College of Rheumatology criteria (ACR20), 50% improvement (ACR50), and 70% improvement (ACR70), respectively, with nonresponder imputation. The vertical line in panel A at 12 weeks indicates the primary efficacy time point. Panel D shows the least square mean change from baseline in the 28-joint disease activity score based on the level of disease activity score in 28 joints using C-reactive protein (DAS28-CRP). A mixed-effects model with repeated measures was used to evaluate treatment effect on change from baseline with treatment, visit, treatment-by-visit interaction, stratification factors, and baseline value included in the model as fixed effects and patient as a random effect. No imputation was used for change from baseline data that were missing. In panels A and D, filgotinib, 200 mg, and filgotinib, 100 mg, vs placebo were significant (P ≤ .001) at all postbaseline time points. In panel B, postbaseline time points were significant (P ≤ .01), with the exception of filgotinib, 200 mg, and filgotinib, 100 mg, at week 2 (P > .05). In panel C, postbaseline time points were significant (P ≤ .01), with the exception of filgotinib, 200 mg, and filgotinib, 100 mg, at week 2 (P > .05); filgotinib, 200 mg, at week 4 (P > .05); and filgotinib, 100 mg, at weeks 4 and 12 (P ≤ .05).