Febuxostat - Clinical Efficacy

Clinical Efficacy

Many long and short-term clinical trials have proved the efficacy of Febuxostat in the treatment of gout and lowering uric acid levels. In these studies Febuxostat was found to be superior to Allopurinol in reducing the serum uric acid levels. Some notable landmark clinical trials are FACT, APEX, EXCEL, FOCUS and CONFIRMS.

Febuxostat versus Allopurinol Controlled Trial (FACT): 760 patients with gout and a sUA >8.0 mg/dl were randomly assigned to receive either febuxostat 80 or 120mg or allopurinol 300mg once daily for 52 weeks.The primary endpoint was the proportion of patients to achieve a sUA concentration below 6.0 mg/dl at the last three monthly measurements. The primary endpoint was achieved in 53% of patients receiving 80 mg febuxostat, 62% of patients receiving 120mg and 21% of those receiving allopurinol (p <0.001 for each febuxostat group compared with allopurinol).

Allopurinol Placebo controlled Efficacy study of febuXostat (APEX): The APEX trial was a head-to-head phase III controlled clinical trial for gout, with a total of 1072 patients with sUA levels higher than 8.0 mg/dl. Patients were randomized to a once daily fixed dose of placebo; febuxostat 80mg,120mg, or 240 mg; or allopurinol 300mg or 100mg, depending on their baseline serum creatinine (≤1.5 mg/dl or ≥1.6 to <2.0 mg/dl, respectively). The primary endpoint for the trial was the proportion of subjects with sUA levels below 6.0 mg/dl at each of the last three visits. After 1 year of treatment, 82% of the patients in all febuxostat groups achieved sUA levels below 6.0 mg/dl, compared with 39% of the patients in both allopurinol groups. In groups with moderate renal impairment the primary endpoint was achieved by 44% receiving febuxostat 80mg, 45% receiving 120mg, and 60% receiving 240mg, compared with 0% in the allopurinol and placebo groups.

Febuxostat Comparative EXtension Long-Term study (EXCEL): The EXCEL trial was the other long-term trial that assessed the clinical efficacy and safety of febuxostat against allopurinol. In this study, 1086 patients were enrolled to receive fixed daily doses of febuxostat 80mg or 120 mg, or allopurinol 300 mg. Dose adjustments were allowed during the first 6 months to maintain sUA levels between 3.0 and 6.0 mg/dl. The primary endpoint, as in most of the trials, was maintenance of sUA below 6.0 mg/dl and other measures assessed were flares requiring treatment, tophus size and safety profile. After the first month of treatment, nearly 80% of patients receiving either febuxostat dose achieved sUA less than 6 mg/dl, compared with only 46% of subjects on allopurinol. After ULT reassignment, more than 80% of all remaining subjects maintained target levels of sUA at each visit. Maintenance of sUA below 6.0 mg/dl resulted in baseline tophus resolution in 46%, 36%, and 29% of subjects on febuxostat 80mg, 120mg and allopurinol, respectively. In addition, gout flares were significantly reduced, obviating the need for gout flare therapy. Overall adverse events did not show significant differences among groups.

Febuxostat Open Label of Urate-Lowering Efficacy and Safety(FOCUS):The FOCUS trial was a 5-year extension study that assessed reduction and maintenance of sUA levels below 6.0 mg/dl as the primary efficacy endpoint. A total of 116 patients were initially enrolled to receive a dose of 80mg febuxostat with dose adjustment to either 40 or 120mg between weeks 4 and 24. At 5 years, 50% of patients were discontinued prematurely from the study with no apparent relation to adverse events; among the remaining 50% of patients, 93% maintained a sUA level below 6.0 mg/dl at 5 years. There was a clear association with no gout flares in these patients and most patients also had tophus resolution.