Comparison of topiroxostat and allopurinol in Japanese hyperuricemic patients with or without gout: a phase 3, multicentre, randomized, double‐blind, double‐dummy, active‐controlled, parallel‐group study

Abstract

What is known and objective: There are no clinical reports that have compared topiroxostat, a selective xanthine oxidase inhibitor, with allopurinol in serum urate-lowering efficacy. The aim of this study was to compare the efficacy and safety of topiroxostat and allopurinol in Japanese hyperuricemic patients with or without gout. Methods: A phase 3, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study conducted in Japan. Patients who had inadequate serum urate levels (a gout patient: serum urate level ≥416Á4 lmol/L; an asymptomatic hyperuricemic patient with specific complications (urinary lithi-asis, hypertension, hyperlipidemia and/or diabetes): serum urate level ≥475Á8 lmol/L; and an asymptomatic hyperuricemic patient with no specific complications: serum urate level ≥535Á3 lmol/L) were randomized to topiroxostat 120 mg/day or allopurinol 200 mg/day, with an equal allocation ratio, for 16 weeks. To prevent the onset of gouty arthritis by rapid serum urate reduction, these doses were increased in a stepwise manner. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit. Results and discussion: Overall, 206 patients were randomly assigned to topiroxostat and allopurinol. Two hundred and three patients (allopurinol: n = 105, topiroxostat: n = 98) received at least one dose of the study drug and had their serum urate level assessed at least once. The baseline characteristics were comparable between groups. The mean age of patients was 53Á0 AE 11Á4 years and 99% of patients were male. The primary efficacy endpoint was À34Á3 AE 11Á1% in the allopurinol group (n = 105) and À36Á3 AE 12Á7% in the topiroxostat group (n = 98). Non-inferiority of the serum urate-lowering efficacy of topirox-ostat to allopurinol was proved by the predefined non-inferiority margin (95% confidence interval, À5Á3 to 1Á3%). The overall incidences of adverse events and adverse drug reactions were similar between both groups. What is new and conclusion: Topiroxostat 120 mg/day provides non-inferior serum urate reduction compared with allopurinol 200 mg/day and is well tolerated in Japanese hyperuricemic patients with or without gout. WHAT IS KNOWN AND OBJECTIVE Gout is a common disease in adult males, and its acute symptom, the so-called gout attack, causes impaired quality of life. 1 Because gout is related to monosodium urate crystal deposition, a causative disease of gout is hyperuricemia, which is defined as a serum urate level >416Á4 lmol/L in Japan. 2 Therefore, it is essential to control hype-ruricemia in order to treat gout and its related disorders such as gouty arthritis. Surprisingly, the prevalence of hyperuricemia in male was approximately 20% in United States and 15-20% in Japan. 3,4 Recent clinical reports have suggested a link between high serum urate levels and life-threatening diseases such as cardio-vascular disease, chronic kidney disease (CKD) and hyperten-sion. 5-10 Therefore, the management of hyperuricemia has become increasingl...

Cross-Over Trial of Febuxostat and Topiroxostat for Hyperuricemia With Cardiovascular Disease (TROFEO Trial)

“…It has been reported that febuxostat reduces UA more effectively than allopurinol, 7 while the reduction of UA by topiroxostat and allopurinol is reported to be similar. 8 In our previous study, febuxostat not only reduced UA more rapidly than allopurinol, but also achieved significantly lower s-Cr, eGFR, urinary albumin, cystatin-C, O-LDL, and hs-CRP compared with allopurinol. 5, 6 Given that the patient demographic profile differed between our previous study and the present study, head-to-head comparison is not appropriate.…”

“…8 No study, however, has compared febuxostat with topiroxostat. Accordingly, a clinical study was conducted to compare febuxostat with topiroxostat and assess potential differences in efficacy (TopiROxostat and FEbuxostat in a randomized, Open-label, cross-over trial for hyperuricemia with cardiovascular disease (TROFEO trial).…”

Comparison of Clinical Advantage between Topiroxostat and Febuxostat in Hemodialysis Patients

“…Hosoya et al 5) reported similar overall incidence of adverse events and drug reactions between topiroxostat and allopurinol groups from baseline to 4 months. Topiroxostat was well tolerated in our study and was continued over 16 months.…”

“…4) In a multicenter, double-blind randomized controlled trial comparing the XO inhibitors topiroxostat 120 mg/d and allopurinol 200 mg/d in Japanese hyperuricemic patients with or without gout, topiroxostat showed a non-inferior decrease in serum UA levels compared with allopurinol and was well tolerated (change in serum urate levels of −36.3 vs. −34.3%, respectively). 5) In another study involving hyperuricemic stage 3 CKD patients with or without gout, topiroxostat 160 mg reduced serum UA levels (−45.3%) and urinary albumin-to-creatinine ratio (−33.0%) over 22 weeks. 6) Also, in HD patients receiving topiroxostat therapy, serum UA levels were reduced from 9 to 5 mg/dL and the serum concentrations of topiroxostat were 25 ng/mL before HD sessions.…”

Uric acid-lowering and renoprotective effects of topiroxostat, a selective xanthine oxidoreductase inhibitor, in patients with diabetic nephropathy and hyperuricemia: a randomized, double-blind, placebo-controlled, parallel-group study (UPWARD study)

“…vascular injury and renal dysfunction [7,8]. Topiroxostat, a selective xanthine oxidoreductase inhibitor, is used for the management of hyperuricemia in patients with or without gout in Japan [9][10][11]. Topiroxostat not only effectively reduced SUA levels, but also had a urinary albumin-to-creatinine ratio (UACR)-lowering effect in hyperuricemic stage 3 chronic kidney disease patients [12].…”