Gout, a progressive, debilitating form of inflammatory arthritis, is caused by factors that elevate serum uric acid (sUA) levels, leading to hyperuricemia. Persistent elevated sUA can result in monosodium urate crystal deposition in joints and soft tissues, causing acute and chronic inflammation. The goals of gout treatment are to reduce sUA levels to inhibit the formation of new crystals, and to promote the dissolution of existing crystals. Guidelines recommend a target sUA level of <6.0 mg/dL in patients with the disease.
Allopurinol, a purine analog, is frequently used as initial urate-lowering therapy in patients with gout. However, a significant percentage of patients (>50%) do not achieve the recommended sUA level target with this approach to treatment. Results from a recent clinical trial by Thomas Bardin, MD, Head of the Department of Rheumatology, Hôpital Lariboisière, Paris, France, and colleagues have shown that the addition of lesinurad, a selective uric acid reabsorption inhibitor, can improve outcomes in patients who have not achieved sustained reductions in sUA with allopurinol alone (Bardin T, et al. Ann Rheum Dis. 2017;76:811-820).
The international, randomized, double-blind, placebo-controlled, phase 3 CLEAR 2 trial, which took place between December 2011 and July 2014, was conducted at sites in 12 countries in North America, Europe, South Africa, Australia, and New Zealand, and included 610 patients. Eligible patients included men or women aged 18 to 85 years who had been diagnosed with gout (determined by 1977 American Rheumatism Association preliminary classification criteria), a body mass index <45 kg/m2, inadequate urate-lowering response to allopurinol monotherapy, and who had experienced ≥2 gout flares in the previous year. The majority of patients were men (96.2%) with a mean age of 51.2 years, a time since gout diagnosis of 11.5 years, and a baseline sUA level of 6.9 mg/dL.
Patients were randomized in a 1:1:1 ratio to receive 200 mg (n = 204) or 400 mg (n = 200) of lesinurad daily in combination with allopurinol (at their prestudy dose), or allopurinol plus placebo (n = 206). The majority (84.1%) of patients received allopurinol at a dose of 300 mg daily, with 6.6% receiving <300 mg daily and 9.3% receiving >300 mg daily.
To reduce gout flares, colchicine or a nonsteroidal anti-inflammatory drug was given 14 days before baseline through month 5, unless patients could not tolerate these prophylactic drugs. As per American College of Rheumatology recommendations, patients enrolled in the study were instructed to try to drink 2 liters of fluid daily to maintain hydration.
The primary efficacy end point of the study was the percentage of patients who had sUA levels <6.0 mg/dL by month 6. Important secondary end points included the mean rate of clinically relevant gout flares that necessitated treatment (an increase in current or new medication) between the end of month 6 and the end of month 12, and the percentage of patients who had target tophi affecting hands and wrists and/or feet and ankles at baseline and achieved complete resolution of ≥1 target tophi by month 12.
By month 6, both arms that received lesinurad (200 mg or 400 mg) had significantly increased proportions of patients who achieved sUA levels <6.0 mg/dL compared with the allopurinol monotherapy arm (55.4% vs 66.5% vs 23.3%, respectively; P <.0001).
“Onset of sUA reduction in the lesinurad groups was rapid, with significant differences from the allopurinol-alone group by first assessment at month 1,” said Dr Bardin and colleagues. In addition, this significant increase was sustained over 12 months.
There were no significant differences observed between treatment arms regarding gout flares that necessitated treatment or complete target tophus resolution.
The proportion of patients who experienced treatment-related adverse events in the allopurinol monotherapy, lesinurad 200-mg, and lesinurad 400-mg arms were 70.9%, 74.5%, and 80.5%, respectively, and the incidence of serious treatment-related adverse events in these arms was 3.9%, 4.4%, and 9.5%, respectively. The most common grade 3/4 toxicities were increased blood creatine kinase and myocardinal infarction. Renal treatment-related adverse events occurred in 4.9%, 5.9%, and 15.0% of patients, respectively.
“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,” Dr Bardin and colleagues concluded.