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Lesinurad in combination with allopurinol: results of a phase 2, randomised, double-blind study in patients with gout with an inadequate response to allopurinol.

ABSTRACT: OBJECTIVES:To assess the efficacy and tolerability of lesinurad, an oral selective uric acid reabsorption inhibitor, in combination with allopurinol versus allopurinol alone in patients with gout and an inadequate response to allopurinol. METHODS:Patients (N=227) with an inadequate response to allopurinol, defined as serum urate (sUA) ?6?mg/dL on ?2 occasions ?2?weeks apart despite ?6?weeks of allopurinol, were randomised 2:1 to 4?weeks of double-blind treatment with lesinurad (200, 400 or 600?mg/day) or matching placebo in combination with their prestudy allopurinol dose (200-600?mg/day). Colchicine prophylaxis for gout flares was required. The primary end point was percent reduction from baseline sUA levels at 4?weeks. A pharmacokinetic substudy was also conducted. Safety was assessed throughout. RESULTS:Patients (n=208) received ?1 dose of blinded medication. Lesinurad 200, 400 and 600?mg in combination with allopurinol produced significant mean percent reductions from baseline sUA of 16%, 22% and 30%, respectively, versus a mean 3% increase with placebo (p<0.0001, all doses vs placebo). Similar results were observed in patients with mild or moderate renal insufficiency (estimated creatinine clearance 30 to <90?mL/min). The incidence of ?1 treatment-emergent adverse event was 46%, 48% and 54% with lesinurad 200, 400 and 600?mg, respectively, and 46% with placebo (most frequent, gout flares, arthralgia, headache and nasopharyngitis), with no deaths or serious adverse events. CONCLUSIONS:Lesinurad achieves clinically relevant and statistically significant reductions in sUA in combination with allopurinol in patients who warrant additional therapy on allopurinol alone. TRIAL REGISTRATION NUMBER:NCT01001338.

SUBMITTER: Perez-Ruiz F

PROVIDER: S-EPMC4893096 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Lesinurad in combination with allopurinol: results of a phase 2, randomised, double-blind study in patients with gout with an inadequate response to allopurinol.

Perez-Ruiz Fernando F Sundy John S JS Miner Jeffrey N JN Cravets Matthew M Storgard Chris C

Annals of the rheumatic diseases 20160107 6

<h4>Objectives</h4>To assess the efficacy and tolerability of lesinurad, an oral selective uric acid reabsorption inhibitor, in combination with allopurinol versus allopurinol alone in patients with gout and an inadequate response to allopurinol.<h4>Methods</h4>Patients (N=227) with an inadequate response to allopurinol, defined as serum urate (sUA) ≥6 mg/dL on ≥2 occasions ≥2 weeks apart despite ≥6 weeks of allopurinol, were randomised 2:1 to 4 weeks of double-blind treatment with lesinurad (20 ...[more]

PMID: 26742777

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Project description:OBJECTIVES:Determine the efficacy and safety of daily lesinurad (200 or 400?mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial. METHODS:Patients on allopurinol ?300?mg (?200?mg in moderate renal impairment) had sUA level of ?6.5?mg/dL (?387?µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6.0?mg/dL (<357?µmol/L) (month 6). Key secondary end points were mean gout flare rate requiring treatment (months 7 through 12) and proportions of patients with complete resolution of one or more target tophi (month 12). Safety assessments included adverse events and laboratory data. RESULTS:Patients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90?years, gout duration 11.5±9.26?years and baseline sUA of 6.9±1.2?mg/dL (410±71?µmol/L). Lesinurad at 200 and 400?mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p<0.0001 both lesinurad+allopurinol groups). In key secondary end points, there were no statistically significant treatment-group differences favouring lesinurad. Lesinurad was generally well tolerated; the 200?mg dose had a safety profile comparable with allopurinol-alone therapy. Renal-related adverse events occurred in 5.9% of lesinurad 200?mg+allopurinol, 15.0% of lesinurad 400?mg+allopurinol and 4.9% of allopurinol-alone groups, with serum creatinine elevation of ?1.5× baseline in 5.9%, 15.0% and 3.4%, respectively. Serious treatment-emergent adverse events occurred in 4.4% of lesinurad 200?mg+allopurinol, in 9.5% of lesinurad 400?mg+allopurinol and in 3.9% of allopurinol-alone groups, respectively. CONCLUSION:Lesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200?mg was generally well tolerated in patients with gout warranting additional therapy. TRIAL REGISTRATION NUMBER:NCT01493531.

Project description:IntroductionThis 24-week randomized, double-blind, non-inferiority study compared the efficacy and safety of febuxostat, a xanthine oxidase inhibitor, with allopurinol using an up-titration method in hyperuricemic Chinese subjects with or without gout.MethodsEligible adults (serum uric acid [SUA] > 7.0 mg/dl with a history of gout, SUA ≥ 8.0 mg/dl with complications or SUA ≥ 9.0 mg/dl without complications) were randomized (1:1:1) to febuxostat 40 mg/day, 80 mg/day, or allopurinol 300 mg/day. Starting doses of febuxostat 20 mg/day and allopurinol 100 mg/day were up-titrated, up to 16 weeks, to the randomized doses and maintained to week 24. Primary endpoint was non-inferiority of febuxostat 40 mg/day versus allopurinol 300 mg/day based on the percentage of subjects with SUA ≤ 6.0 mg/dl at week 24. The same comparison was made between febuxostat 60 mg/day or 80 mg/day versus allopurinol 300 mg/day. Safety assessments included measurement of treatment-emergent adverse events (TEAEs).ResultsThe per-protocol population comprised 472 subjects. Non-inferiority of febuxostat 40 mg/day versus allopurinol 300 mg/day was not demonstrated based on the protocol-defined margin of - 10% (44.7 vs. 50.0%; - 5.3% difference; 95% confidence interval [CI]: - 16.4%, 5.8%); however, superiority over allopurinol 300 mg/day was demonstrated for febuxostat 60 mg/day at week 16 (66.3 vs. 51.2%; a 15.0% difference; 95% CI: 4.2%, 25.9%) and febuxostat 80 mg/day at week 24 (70.0 vs. 50.0%; a 20.0% difference; 95% CI: 9.3%, 30.7%). The frequency of TEAEs was similar across groups, with gout flares occurring frequently.ConclusionsUsing a novel dose-titration method, although the primary endpoint of non-inferiority of febuxostat 40 mg/day versus allopurinol 300 mg/day was not reached, non-inferiority and superiority of febuxostat 60 mg/day and 80 mg/day versus allopurinol 300 mg/day was demonstrated at weeks 16 and 24, respectively. Febuxostat demonstrated an acceptable tolerability profile in the treatment of hyperuricemia in Chinese subjects with or without gout.Trial registrationJapicCTI-132106.FundingAstellas Pharma Global Development, Inc.

Dataset Information

Lesinurad in combination with allopurinol: results of a phase 2, randomised, double-blind study in patients with gout with an inadequate response to allopurinol.

Publications

Lesinurad in combination with allopurinol: results of a phase 2, randomised, double-blind study in patients with gout with an inadequate response to allopurinol.

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