Efficacy and safety of febuxostat extended release and immediate release in patients with gout and moderate renal impairment: phase II placebo-controlled study

Abstract

Background: Febuxostat immediate release (IR), a xanthine oxidase inhibitor, is indicated for the management of hyperuricemia in patients with gout by lowering urate levels. An extended release (XR) formulation of febuxostat was developed to provide equal or superior efficacy on urate lowering compared with the IR formulation and potentially lower the risk of treatment-initiated gout flares due to an altered pattern of drug exposure. The present study evaluated the efficacy and safety of febuxostat XR and IR formulations in patients with gout and moderate renal impairment (estimated glomerular filtrate rate ≥ 30 and < 60 ml/min).

Methods: This was an exploratory, 3-month, phase II, multicenter, placebo-controlled, double-blind proof-of-concept study. Patients (n = 189) were randomized 1:1:1:1:1 to receive placebo or febuxostat IR 40 mg, XR 40 mg, IR 80 mg, or XR 80 mg once daily. Endpoints included: proportion of patients with serum uric acid (sUA) < 5.0 mg/dl at month 3 (primary endpoint), proportion of patients with sUA < 6.0 mg/dl at month 3, and proportion of patients with ≥ 1 gout flare requiring treatment over 3 months.

Results: At month 3, all febuxostat treatment groups were associated with greater proportions of patients achieving sUA < 5.0 mg/dl (p < 0.05 vs placebo). A greater proportion of patients receiving XR 40 mg achieved sUA < 5.0 mg/dl versus those receiving IR 40 mg (p = 0.034); proportions were similar in the IR 80 mg and XR 80 mg groups. Higher proportions of febuxostat-treated patients achieved sUA < 6.0 mg/dl at month 3 (p < 0.05 vs placebo) and experienced ≥ 1 gout flare (significant for all comparisons, except XR 40 mg). Incidences of treatment-related adverse events were low across all treatment groups; the majority were mild or moderate with no apparent trends correlating with IR or XR doses. The most common treatment-emergent adverse event was hypertension. One death (unrelated to the study drug) was reported.

Conclusions: These exploratory data demonstrate that febuxostat (XR and IR) formulations were effective and well tolerated in patients with gout and moderate renal impairment.

Trial registration: ClinicalTrials.gov, NCT02128490 Registered on 29 April 2014.

Keywords: Extended release; Febuxostat; Hyperuricemia; Renal impairment; Serum uric acid.

Conflict of interest statement

Ethics approval and consent to participate

Each investigator conducted the study according to the Declaration of Helsinki and the International Conference on Harmonisation’s Harmonised Tripartite Guideline for good clinical practices, and in compliance with applicable local or regional regulatory requirements. All patients enrolled in the study provided written informed consent in the manner deemed appropriate by the institutional review board or the independent ethics committees. For the full list of review boards and ethics committees providing approval, please see Additional file 2.

Competing interests

LG is an employee of and owns stocks/stock options in Takeda Pharmaceuticals USA, Inc. MAB has received research grants from Ardea/AstraZeneca, Horizon, and Takeda and consultancy/other remuneration from Ardea/AstraZeneca, CymaBay, Horizon, Ironwood, and Takeda (total remuneration: Ardea/AstraZeneca, > $10,000; CymaBay, < $10,000; Horizon, < $10,000; Ironwood, < $10,000; and Takeda, > $10,000). AW is a consultant for Takeda (< $10,000). BH and MC are employees of Takeda Pharmaceuticals USA, Inc. KS has received research grants from Ardea/AstraZeneca, Horizon, SOBI and Takeda (> $10,000 from each company) and consultancy/other remuneration from Ardea/AstraZeneca (> $10,000), Horizon, Ironwood, SOBI, and Takeda (< $10,000 from each company).

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Study design. FBX febuxostat, IR immediate release, QD once daily, XR extended release

Fig. 2

Disposition of patients. (a) Percentage is based on number of patients with early D/C for the treatment group. (b) If a patient had a gout flare that caused W/D from the study, it was recorded as ‘Wishes to withdraw from study drug due to gout flare’ instead of adverse event. Note: 38.7% (261 patients) were excluded at screening, and 33.3% (225 patients) were excluded at washout. Most patients who were not enrolled (249/261, 95.4%) had failed to meet the screening criteria. AE adverse event, D/C discontinuation of study drug, IR immediate release, Maj prot dev major protocol deviation, PTE pretreatment event, W/D withdrawal, XR extended release

Fig. 3

Percentage of patients who achieved primary and secondary outcomes (full analysis set*). p < 0.05 versus placebo for all active treatment groups for all three endpoints, with the exception of ‘≥ 1 flare’, where there was no statistically significant difference between FBX XR 40 mg and placebo. †p < 0.05 versus equivalent-dose IR formulation. FBX febuxostat, IR immediate release, sUA serum uric acid, XR extended release