Abstract 757: Urate-Lowering Therapy (Febuxostat [FEB] or Allopurinol [ALLO]) in Subjects with Gout: Interim Results from the Febuxostat Comparative Extension Long-Term Study (EXCEL)
Assil Saleh, M.D.
Authors:
M. A. Becker, H. R. Schumacher, Jr, P. A. MacDonald, E. J. Lloyd, C. Lademacher,
N. Joseph-Ridge
Background:
Febuxostat is a non-purine selective inhibitor of xanthine oxidase. Results from the FACT study, a phase 3, randomized, double-blind, 52-week, multi-center trial, recently showed that febuxostat dosed at 80mg and 120mg daily is more effective than allopurinol 300 mg daily in decreasing serum uric acid levels in patients with gout and serum uric acid levels ≥ 8mg/dl. M.A. Becker et al, N Engl J Med. 2005 Dec 8;353(23):2450-61. There was no difference between treatment groups in gout flares or tophus area. The authors’ objective in this study was to assess the efficacy of febuxostat compared to allopurinol in lowering serum urate levels to less than 6.0g/dl at and beyond 24 months of follow up.
Methods:
The EXCEL study was an open-label extension study where 735 subjects from two phase 3 clinical trials of febuxostat and allopurinol (FACT and APEX trials), were randomized to daily febuxostat (80 mg or 120 mg) or daily allopurinol 300 mg (100 mg for subjects with renal failure).
During the first 6 months of this trial, cross-over into different treatment arms was permitted to maintain serum uric acid levels between 3.0 and 6.0 mg/dl, handle adverse events (AEs) or at the investigator’s discretion, with no required washout period. Subjects whose serum urate concentrations remained ≥6.0 mg/dL at six months were terminated from the study and considered treatment failures.
Results:
184 (25%) subjects discontinued treatment by the end of the study. The proportion of participants who remained in their initial treatment groups were: 78% of those on febuxostat 80mg, 71% of those on febuxostat 120mg, and 41% of those on allopurinol. Treatment failure occurred in 18% of subjects treated with febuxostat 80mg, 8% treated with febuxostat 120mg, and 57% treated with allopurinol. In the subset of these allopurinol patients who subsequently were treated with febuxostat 80mg, 54% remained treatment failures. After increasing the febuxostat dose to 120 mg daily in this subgroup of dual-drug failures, 59% achieved a serum urate concentration below 6.0 mg/dl. Therefore, 67% of subjects initially treated with allopurinol were successfully treated with febuxostat.
Adverse event rates were similar for both drugs tested in this trial. The most common observed adverse events (≥ 5 events per 100 patient-years) included upper respiratory tract infections, musculoskeletal and connective tissue signs and symptoms, joint related signs and symptoms, headaches, and diarrhea. The serious adverse event rate was similar for both agents (10 events per 100 patient-years for febuxostat) and (11 events per 100 patient years for allopurinol). The most frequent of these serious adverse events were cardiac disorders (3 events per 100 patient-years for both agents). These particular subjects all had a prior history of cardiovascular disease or cardiac risk factors.
Conclusions:
Greater than 50% of the subjects in this study who were randomized to allopurinol therapy at standard doses were treatment failures (defined as inability to achieve or maintain serum uric acid levels <6.0 mg/dl). The majority of these patients (67%) were successfully treated with febuxostat.
Editorial:
This large, unblinded extension trial provides compelling data for the efficacy of febuxostat in reducing serum urate in gout patients. It proved to be particularly useful therapy in patients who failed traditional allopurinol treatment. The larger question that remains, however, is whether simple pharmacologic reduction and maintenance of reduction of serum urate will directly correlate with clinical improvement in gout. This study is an important first step, particularly because it establishes that febuxostat confers no significantly increased risk of adverse effects over allopurinol.
