Current guidelines for the long-term management of gout recommend a combination of lifestyle management and/or pharmacotherapy to lower serum UA levels to <6.0 mg/dL in most patients or <5.0 mg/dL in patients with more severe disease. Allopurinol is the most widely used xanthine oxidase inhibitor and is recommended in treatment guidelines as a first-line urate-lowering therapy in patients with gout, with a maximum daily dose of 800 mg. As an inhibitor of xanthine oxidase, allopurinol reduces uric acid production and lowers serum UA levels. However, many patients––more than 50% in clinical trials––do not achieve the serum UA target of <6.0 mg/dL at the most commonly used allopurinol dosage of 300 mg/day. In cases where the serum UA target cannot be achieved with allopurinol alone at an appropriate dosage, treatment guidelines recommend substitution therapy (e.g., with febuxostat or a uricosuric agent) or combination therapy that includes allopurinol with a uricosuric agent. The current U.S.-based study is one of two replicate randomized controlled trials where this recommendation is formally investigated for the first time.
Objective: Lesinurad is a selective uric acid reabsorption inhibitor used for the treatment of gout in combination with a xanthine oxidase inhibitor. The Combining Lesinurad with Allopurinol Standard of Care in Inadequate Responders (CLEAR 1) study, a 12-month, multi-center, randomized, double-blind, placebo-controlled phase III trial, was conducted to investigate daily lesinurad (200 mg or 400 mg orally) added to allopurinol vs. placebo plus allopurinol in patients with serum urate (UA) levels above a target of <6.0 mg/dL.
Lesinurad (RDEA594) is a novel selective uric acid reabsorption inhibitor for the treatment of gout in combination with a xanthine oxidase inhibitor. Lesinurad inhibits the uric acid transporter URAT1, which is responsible for reabsorption of urate from the renal tubular lumen. By inhibiting URAT1, lesinurad increases the excretion of uric acid in the kidney and lowers serum UA levels. Lesinurad in combination with allopurinol, therefore, provides a dual mechanism of action for managing the hyperuricemia of gout: increased urinary excretion of uric acid and reduced urate production.
Lesinurad in combination with allopurinol has demonstrated greater reductions in serum UA than allopurinol alone in phase I and II studies.
Methods: Patients receiving ≥300 mg of allopurinol (≥200 mg in those with moderate renal impairment) who had serum UA levels ≥6.5 mg/dL at screening and ≥2 gout flares during the previous year were studied. The primary end point was the proportion of patients achieving a serum UA level of <6.0 mg/dL at month 6. Key secondary end points were the mean gout flare rate requiring treatment (months 7–12) and the proportions of patients with complete resolution of ≥1 target tophus (month 12). Safety assessments included adverse events and laboratory data.