Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study)

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 mu mol/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 mu mol/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 mmol/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 >= 1.5x 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 allopurinolalone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy.