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.

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).