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)

Abstract

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.

Keywords: Gout; Inflammation; Outcomes research.

Figure 1

CLEAR 2 trial design is shown. *200 mg permitted for renally impaired. Maximum allopurinol dose: 800 or 900 mg, according to local label. Randomisation was stratified at day −7 by renal function (ie, estimated eCrCl ≥60 vs <60 mL/min, calculated by the Cockcroft-Gault formula using ideal body weight) and by tophus status during screening (ie, one or more tophus versus no tophi). eCrCl, estimated creatinine clearance; sUA, serum uric acid.

Figure 2

Patient disposition is shown. ^aScreened was defined as signing an informed consent form; ^b2 deaths reported for non-randomised patients during screening and ^ccompleted the study with or without completing randomised study medication. One additional death occurred in the LESU 400 mg+ALLO group. The subject experienced a serious adverse event and withdrew from the study. The primary reason for study withdrawal was reported as ‘adverse event’. Of the 1538 screen failures, 1183 were related to inclusion criteria, 252 to exclusion criteria, 94 to both inclusion and exclusion criteria and 9 to other. ALLO, allopurinol; LESU, lesinurad.

Figure 3

Proportions of patients achieving sUA target of <6.0 mg/dL (<357 µmol/L), <5.0 mg/dL (<297 µmol/L) and <4.0 mg/dL (<238 µmol/L), by months 6 and 12 (ITT population) are shown. Primary end point: proportion of patients achieving sUA target of <6.0 mg/dL (<357 µmol/L) by month 6. *p<0.0001. Note: Subjects missing sUA results were treated as non-responders. All comparisons used a two-sided Cochran-Mantel-Haenszel test stratified by day −7 renal function and tophus status during screening (randomised stratification factor values), with non-responder imputation and adjustment for multiple comparisons for the primary end point (Bonferroni correction). ALLO, allopurinol; ITT, intention to treat; LESU, lesinurad; sUA, serum uric acid.

Figure 4

Graph showing the mean (SE) sUA levels by visit (observed cases, intent-to-treat population). Mean change from baseline for each active treatment group was compared with the ALLO-alone group using analysis of covariance, with p<0.001 at each time point. ALLO, allopurinol; LESU, lesinurad; sUA, serum uric acid.