. 2022 Feb 17;51:102271. doi: 10.1016/j.redox.2022.102271

Table 2.

Summary of clinical trials evaluating urate lowering therapies (ULTs).

Year	Author	Trial	n	Population	Intervention (mg)	Duration	Measured Endpoints	Result	P-Value	Ref
2005	Becker et al.	–	153	Gout	Febuxostat (40, 80, or 120) or Placebo	28 days	SUA <6.0 mg/dL	Febuxostat was more effective than placebo	<0.001	[106]
2005	Becker et al.	FACT	762	Gout	Febuxostat (80 or 120) or Allopurinol (300)	52 weeks	SUA <6.0 mg/dL	Febuxostat was more effective than Allopurinol	<0.001	[111]
2006	Siu et al.	–	54	CKD	Allopurinol 100–300 vs. usual therapy	1 year	Reduced BP and slowing serum creatinine increase	No difference in systolic or diastolic blood pressure	N/S	[94]
2006	Siu et al.	–	54	CKD	Allopurinol 100–300 vs. usual therapy	1 year	Reduced BP and slowing serum creatinine increase	Serum creatinine trended lesser with treatment.	N/S	[94]
2008	Schumacher et al.	APEX	1,072	Gout	Febuxostat (80, 120, 240), Allopurinol (100 or 300), or Placebo	28 weeks	SUA <6.0 mg/dL	At all doses, Febuxostat was more effective than Allopurinol or placebo	≤0.05	[112]
2008	Hare et al.	OPT-CHF	405	CHF	Oxypurinol 600 or Placebo	24 weeks	Clinical Improvement of NYHA HF class	Oxypurinol did not produce clinical improvement.	N/S	[102]
2009	Schumacher et al.	FOCUS	116	Gout	Febuxostat [[40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100], [101], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], 115, [116], 117. (, [118], [119], [120]]	5 years	SUA <6.0 mg/dL	Febuxostat resulted in the maintenance of SUA <6.0 mg/dL.	–	[107]
2009	Becker et al.	–	1,086	Gout	Febuxostat (80 or 120) or Allopurinol (300)	31–40 months	SUA <6.0 mg/dL	Better goal SUA maintenance with Febuxostat than Allopurinol	–	[114]
2010	Becker et al.	CONFIRMS	2,269	Gout	Febuxostat (40 or 80) or Allopurinol (200–300)	6 months	SUA <6.0 mg/dL	Greater dose (80 mg) Febuxostat was the most efficacious ULT.	<0.001	[113]
2010	Momeni et al.	–	40	Diabetic Nephropathy	Allopurinol 100 vs. Placebo	4 months	Reduction of proteinuria	24-h protein was lesser in Allopurinol group	<0.049	[97]
2010	Goicoechea et al.	–	113	CKD	Allopurinol 100 vs. continuation of usual therapy	2 years	Renal disease progression, CV events, and hospitalizations.	Allopurinol decreased:		[91]
								Renal Disease Progression	0.018
								CV events	0.039
								Hospitalization risk	0.033
2011	Kao et al.	–	53	CKD + LVH	Allopurinol 300 vs. Placebo	9 months	Change in Left Ventricular Mass Index and Endothelial Function	Allopurinol reduced LVH	0.036	[100]
2011	Kao et al.	–	53	CKD + LVH	Allopurinol 300 vs. Placebo	9 months		Allopurinol improved endothelial function	0.009	[100]
2011	Kanbay et al.	–	97	Asymptomatic Hyperuricemia	Allopurinol 300 vs. No Treatment	4 months	Endothelial Function and eGFR	Allopurinol Improved endothelial function	0.003	[95]
2011	Kanbay et al.	–	97	Asymptomatic Hyperuricemia	Allopurinol 300 vs. No Treatment	4 months	Endothelial Function and eGFR	Allopurinol preserved renal function (eGFR)	0.001	[95]
2012	European Medicines Agency	Studies C0405 and C0406	212	Gout	Placebo x2wks Pegloticase 8 mg × 2wks Pegloticase 8 mg × 4wks	6 months	SUA <6.0 mg/dL	Pegloticase has a dose-dependent response of lowering SUA	<0.001	[133]
2013	Pai et al.	–	183	CKD	Allopurinol 100 vs. No Treatment	2 years	CKD Progression	Allopurinol preserved renal function (eGFR)	0.4*	[93]
2014	Hosoya et al.	–	123	CKD	Topiroxostat 160 vs. Placebo	22 weeks	SUA and eGFR	Topiroxostat decreased SUA	<0.0001	[134]
2014	Hosoya et al.	–	123	CKD	Topiroxostat 160 vs. Placebo	22 weeks	SUA and eGFR	No change in eGFR	N/S	[134]
2015	Goicoechea et al.	–	107	CKD	Allopurinol 100 vs. Placebo	7 years	Renal and CV events	Reduction of Renal Events	0.004	[92]
2015	Goicoechea et al.	–	107	CKD	Allopurinol 100 vs. Placebo	7 years	Renal and CV events	Reduction of CV Events	0.02	[92]
2015	Sircar et al.	–	93	CKD	Febuxostat 40 vs. Placebo	6 months	eGFR	Febuxostat slowed eGFR decline	0.05	[108]
2015	Givertz et al.	EXACT-HF	253	Hyperuricemia + H.F.	Allopurinol 60 vs. Placebo	24 weeks	Change in clinical status	No significant change in the composite clinical endpoints	N/S	[101]
2016	Xiao et al.	–	125	Normouricemic patients with chronic HF.	Allopurinol 300 vs. Control	6 months	Cardiac Function	Allopurinol improved parameters of cardiac function	<0.01	[99]
2016	Weng et al.	–	2,460	CKD	• Febuxostat “ab initio” (n = 40) • Other ULT to Febuxostat (n = 206) • Other ULT (n = 2,214)	1 year	eGFR	Febuxostat preserved renal function (eGFR)	<0.001	[109]
2016	Saag et al.	CLEAR 1	603	Gout	Lesinurad 200/400 + Allopurinol vs. Placebo + Allopurinol	12 months	SUA <6.0 mg/dL at 6 months	Combination of Lesinurad + Allopurinol was more efficacious	<0.0001	[128]
2016	Bardin et al.	CLEAR 2	610	Gout	Lesinurad 200/400 + Allopurinol vs. Placebo + Allopurinol	12 months	SUA <6.0 mg/dL at 6 months	Combination of Lesinurad + Allopurinol was more efficacious	<0.001	[129]
2017	Krishnamurthy et al.	–	100	Hyperuricemic Males	Allopurinol 200 vs. No Treatment	3.4 years	eGFR	Allopurinol preserved renal function (eGFR)	<0.01	[96]
2017	Jalal et al.	–	80	CKD	Allopurinol 300 vs. Placebo	12 weeks	Endothelial Function	Allopurinol did not improve endothelial function	N/S	[98]
2017	Stamp et al.	–	183	Gout	Constant dose (269 mg/day)of Allopurinol (n = 93) or Allopurinol dose-escalation (n = 90)	12 months	Reduction in SUA and TEAE	Dose-escalation was more efficacious in lowering SUA	<0.001	[105]
2017	Tausche et al.	LIGHT	214	Gout	Lesinurad 400 vs. Placebo	6 months	SUA <6.0 mg/dL	Lesinurad was more effective than placebo	<0.0001	[130]
2017	Dalbeth et al.	CRYSTAL	324	Gout	Lesinurad 200/400 + Febuxostat vs. Placebo + Febuxostat	12 months	SUA <5.0 mg/dL at month 6	Combination of Lesinurad 400 + Febuxostat was most efficacious	<0.0001	[131]
2018	Kimura et al.	FEATHER	443	CKD	Febuxostat dose escala tion to 40 mg/day vs. Placebo	108 weeks	eGFR	No difference in eGFR decline	N/S	[110]
2018	Coburn et al.	–	12,856	Gout	Current dose of Allopurinol (n = 6,428) or Allopurinol dose-escalation (n = 6,428)	10 years	All-Cause Mortality	Increase mortality associated with Allopurinol dose-escalation	HR 1.08⁺	[104]
2018	Wada et al.	UPWARD	65	Hyperuricemia and Diabetic Nephropathy	Topiroxostat 160 vs. Placebo	28 weeks	Change in urinary Albumin:Creatinine and eGFR.	Topiroxostat preserved renal function (eGFR).	0.0303	[135]
2018	Wada et al.	UPWARD	65	Hyperuricemia and Diabetic Nephropathy	Topiroxostat 160 vs. Placebo	28 weeks	Change in urinary Albumin:Creatinine and eGFR.	No change in urinary Albumin: Creatinine	N/S	[135]
2018	White et al.	CARES	6,190	Gout + CVD	Allopurinol (200–600) vs. Febuxostat [[40], [41], [42], [43], [44], [45], [46], [47], [48], [49], [50], [51], [52], [53], [54], [55], [56], [57], [58], [59], [60], [61], [62], [63], [64], [65], [66], [67], [68], [69], [70], [71], [72], [73], [74], [75], [76], [77], [78], [79], [80]]	32 months	First occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization for unstable angina	Increase mortality and Cardiovascular events associated with Febuxostat	0.047	[116]
								Nonfatal Myocardial Infarction	N/S
								Nonfatal Stroke
								Urgent Revascularization for Unstable Angina
2020	MacDonald et al.	FAST	6,142	Hyperuricemia, with ≥1 additional CV risk factor	Febuxostat [[80], [81], [82], [83], [84], [85], [86], [87], [88], [89], [90], [91], [92], [93], [94], [95], [96], [97], [98], [99], [100], [101], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], 115, [116], 117. (, [118], [119], [120]] vs. Allopurinol (100–900)	36 months	First occurrence of the Anti-Platelet Trialists’ Collaboration (APTC) cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death	Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol.	<0·0001	[118]
2019	Kojima et al.	FREED	1,070	Hyperuricemia, with ≥1 additional CV risk factor	Febuxostat 10–40 vs. Allopurinol 100 (If SUA elevated)	36 months	Development of cerebral or cardiorenovascular events and all deaths	Febuxostat lowers uric acid and delays the progression of renal dysfunction.	0.041	[122]

*P-value indicates no significant change from baseline, indicating no disease progression.

⁺Study calculated hazard ratios (HR) instead of p-values.

TEAE: Treatment-Emergent Adverse Event; N/S: Non-Significant; NYHA: Ney York Heart Association; LVH: Left Ventricular Hypertrophy; ALT: Alanine Aminotransferase.