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.
Results: The study patients (n=603) were predominantly male and had a mean ±SD age of 51.9 ±11.3 years, a gout duration of 11.8 ±9.4 years, a baseline serum UA level of 6.94 ±1.27 mg/dL, and were receiving an allopurinol dosage of 306.6 ±59.58 mg/day. Lesinurad at doses of 200 mg or 400 mg added to allopurinol therapy significantly increased the proportions of patients who achieved serum UA target levels by month 6 compared with those receiving allopurinol alone (54.2%, 59.2% and 27.9%, respectively, P<0.0001). Lesinurad was not significantly superior to allopurinol alone in terms of the secondary end points: rates of gout flares and complete resolution of tophi. Lesinurad was generally well tolerated; the safety profile of the 200 mg dose was comparable to that of allopurinol alone, except for higher incidences of predominantly reversible elevations of serum creatinine levels.
Conclusion: Lesinurad added to allopurinol represents a new treatment option for patients needing additional urate-lowering therapy.
Excerpted and adapted from:
Saag KG, Fitz-Patrick D, Kopicko P, et al. Lesinurad combined with allopurinol: A randomized, double-blind, placebo-controlled study in gout patients with an inadequate response to standard-of-care allopurinol (a US-Based Study). Arthritis Rheumatol. 2017 Jan;69(1):203–212. doi: 10.1002/art.39840.
