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)
Thomas Bardin, Robert T Keenan, Puja P Khanna, Jeff Kopicko, Maple Fung, Nihar Bhakta, Scott Adler, Chris Storgard, Scott Baumgartner, Alexander So, Thomas Bardin, Robert T Keenan, Puja P Khanna, Jeff Kopicko, Maple Fung, Nihar Bhakta, Scott Adler, Chris Storgard, Scott Baumgartner, Alexander So
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.
Conflict of interest statement
Competing interests: TB: grant/research support from Ipsen, Menarini and consultant for AstraZeneca, Ipsen, Menarini, Novartis, Savient, Sobi, Takeda and Cymabay. RTK: consultant for AstraZeneca, Crealta Pharmaceuticals and Takeda. PPK: research grant: AstraZeneca. JK (former employee), MF, NB, CS (former employee) and SB: full-time employees of Ardea Biosciences, a member of the AstraZeneca Group. SA: full-time employee of AstraZeneca Pharmaceuticals. AS: consultant for Novartis, AstraZeneca, Menarini.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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