Background/Purpose: Up to 20% of patients with hyperuricemia (serum urate [sUA] >6.8 mg/dL) and gout have moderate-to-severe renal impairment. Higher sUA (>8.5 mg/dL) may increase the risk for progressive decline in renal function. The objective of this prospective 12-m pilot study was to evaluate the effect of treatment with febuxostat (FEB) vs placebo (PLB) on urate-lowering, renal function, and general safety in gout subjects with moderate-to-severe renal impairment.

Methods: In this multicenter, double-blind, phase 2 study, subjects were randomized 1:1:1 to receive 12 m of daily treatment with either FEB 30 mg BID, FEB 40/80 mg QD (titrated from 40 to 80 mg to achieve sUA <6.0 mg/dL) or PLB. Eligible subjects fulfilled ARA criteria for gout (subjects with tophi were excluded), had sUA >7.0 mg/dL, and had an estimated glomerular filtration rate (eGFR; by MDRD) ≥15 to ≤50 mL/min (severe, eGFR ≥15 to <30 mL/min; moderate, ≥30 to ≤50 mL/min) on d -21. Endpoints at m 12 included the proportion of subjects with sUA <6.0 mg/dL (Cochran-Mantel-Haenszel test) and change from baseline (CFB) in sUA and eGFR (by ANCOVA analysis). Adverse events (AEs) were recorded throughout the study.

Results: Among 96 subjects enrolled, 80% were male with a mean sUA (SD) of 10.5 (1.70) mg/dL; 95 subjects qualified for primary efficacy analysis. At m 1 visit, 20 subjects were titrated from FEB 40 mg to 80 mg QD based on d 14 sUA. At baseline, 28%, 31%, and 53% of subjects in the FEB 30 mg BID, FEB 40/80 mg QD, and PLB groups, respectively, had severe renal impairment. The proportion of subjects with sUA <6.0 mg/dL at m 12 was significantly greater in both FEB groups compared to PLB: 69%, 45%, and 0% for FEB 30 mg BID, FEB 40/80 mg QD, and PLB, respectively (p<0.001). The CFB in sUA at m 6 and m 12 was significantly greater in both FEB groups vs PLB (Table). Mean (SE) baseline eGFR was 34.14 (1.46), 34.08 (1.48), and 29.31 (1.46) mL/min/1.73 m².  Mean eGFR CFB (SE) at m 12 for FEB 30 mg BID and 40/80 mg QD (0.33 [1.17] and -0.86 [1.19] mL/min/1.73 m², respectively) was not significantly different from PLB (-2.05 [1.20] mL/min/1.73 m²; p>0.1). Overall, ≥1 AE was reported by 78%, 88%, and 78% of subjects in the FEB 30mg BID, FEB 40/80 mg QD, and PLB groups, respectively. The majority of AEs were mild to moderate in intensity and not considered to be related to study treatment. Elevated serum creatinine (increase from baseline ≥0.3 mg/dL) was seen in 13/32, 16/32, and 17/32 subjects in the FEB 30mg BID, FEB 40/80 mg QD, and PLB groups, respectively.  

Conclusion: In subjects with moderate-to-severe renal impairment, FEB urate-lowering was efficacious, with no emergent serious safety issues at 12 m. The sUA was significantly reduced in subjects receiving either regimen of FEB compared to PLB. CFB in renal function did not differ significantly between groups. Limitations include small sample size and a baseline imbalance in the distribution of subjects with severe vs moderate renal impairment across the treatment groups.

Table. CFB in serum urate
	FEB 30 mg (N=32)	FEB 40/80 mg (N=31)	PLB (N=32)
	LS mean (SE)
Baseline	10.36 (0.31)	10.35 (0.31)	10.72 (0.31)
CFB at m 6	-5.08 (0.30)*	-4.29 (0.31)*	0.07 (0.30)
CFB at m 12	-4.97 (0.32)*	-4.17 (0.32)*	-0.15 (0.32)
LS = least squares; SE = standard error; FEB = febuxostat; PLB = placebo; CFB = change from baseline; *p <0.001 vs PLB

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effect-of-febuxostat-on-serum-urate-levels-in-gout-subjects-with-hyperuricemia-and-moderate-to-severe-renal-impairment-a-randomized-controlled-trial/