Efficacy and Safety of Febuxostat Extended and Immediate Release in Patients With Gout and Renal Impairment: A Phase III Placebo-Controlled Study

Abstract

Objective: To assess the efficacy and safety of febuxostat extended release (XR) and immediate release (IR) in patients with gout and normal or impaired renal function.

Methods: This was a 3-month, phase III, multicenter, double-blind, placebo-controlled study. Patients (n = 1,790) with a history of gout and normal or impaired (mild-to-severe) renal function were randomized to receive placebo, febuxostat IR 40 or 80 mg, or febuxostat XR 40 or 80 mg once daily (1:1:1:1:1 ratio). End points included proportions of patients with a serum urate (UA) level of <5.0 mg/dl at month 3 (primary end point), a serum UA level of <6.0 mg/dl at month 3, and ≥1 gout flare requiring treatment over 3 months (secondary end points).

Results: Both febuxostat formulations led to significantly greater proportions of patients achieving a serum UA level of <5.0 mg/dl or <6.0 mg/dl at month 3 (P < 0.001 for all comparisons versus placebo). Equivalent doses of febuxostat XR and IR had similar treatment effects on serum UA level end points; however, a significantly greater proportion of patients achieved a serum UA level of <5.0 mg/dl with XR 40 mg versus IR 40 mg. Similar proportions of patients experienced ≥1 gout flare across treatment groups. Rates of treatment-emergent adverse events were low and evenly distributed between treatment arms. A preplanned subgroup analysis demonstrated that febuxostat formulations were well tolerated and generally effective on serum UA level end points (versus placebo) across all renal function subgroups.

Conclusion: Both formulations of febuxostat (XR and IR) were well tolerated and effective in patients with gout and normal or impaired renal function, including patients with severe renal impairment.

Trial registration: ClinicalTrials.gov NCT02139046.

© 2018 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.

Figures

Figure 1

Study design. Subgroup numbers are from the full analysis set. In the safety analysis set, 1 patient was randomized to receive placebo but received febuxostat (FBX) immediate release (IR) 40 mg and so was included in the FBX IR 40 mg group. All patients received prophylaxis for gout flares over the 3‐month double‐blind treatment period. QD = once daily; XR = extended release.

Figure 2

Percentage of patients (in full analysis set) who achieved primary and secondary outcomes. Based on multiplicity adjustment, the level of significance was set at P < 0.025 for primary comparisons. * = P < 0.001 versus placebo. † = P = 0.001 versus equivalent‐dose immediate release (IR) formulation. FBX = febuxostat; XR = extended release.

Figure 3

Renal subgroup analysis, with treatment group comparisons were based on the Cui, Hung, and Wang Z test statistic. A, Percentage of patients who achieved a serum urate (sUA) level of <5.0 mg/dl (primary end point) at month 3. * = P < 0.05 versus placebo; † = P < 0.05 versus equivalent‐dose immediate release (IR) formulation. B, Percentage of patients who achieved a serum UA level of <6.0 mg/dl at month 3. * = P ≤ 0.001 versus placebo; † = P < 0.05 versus equivalent‐dose IR formulation. C, Percentage of patients who experienced ≥1 gout flare that required treatment over the 3‐month study period. * = P < 0.05 versus placebo. Patients were stratified by baseline renal function; normal renal function was defined as an estimated glomerular filtration rate (eGFR) of ≥90 ml/minute, mild renal impairment as an eGFR of ≥60–89 ml/minute, moderate renal impairment as an eGFR of ≥30–59 ml/minute, and severe renal impairment as an eGFR of ≥15–29 ml/minute. FBX = febuxostat; XR = extended release.