Febuxostat has been extensively studied with more than 4000 patients investigated in one phase II clinical trial and three phase III randomized controlled trials, some of them followed for over 5 years ().
Summary of phase II and III* and open-label$ extension studies of febuxostat.
The first phase II randomized double-blind dose-response study was performed in 153 patients with chronic gout in which febuxostat 40, 80 and 120 mg/day were compared with placebo over a period of 28 days, using colchicine as prophylaxis in all groups [Becker et al. 2005a
The primary endpoint was the proportion of patients achieving a sUA level of <6.0 mg/dl on day 28. Greater proportions of febuxostat-treated patients achieved the primary endpoint with statistical significance (p < 0.001 for each comparison), in 0% of patients on placebo and in 56% of patients taking 40 mg, 76% taking 80 mg, and 94% taking 120 mg. Secondary endpoints included the mean sUA reduction from baseline to day 28, which was 2% in the placebo group, 37% in those on 40 mg, 44% in the 80 mg group, and 59% in the 120 mg group. Gout flares occurred with similar frequency in the placebo and 40 mg groups (37% and 35%, respectively) and at higher frequency in the higher doses of febuxostat: 43% at 80 mg and 55% in the 120 mg group. The safety profiles for febuxostat and placebo were similar, as treatment-related adverse events did not show differences among placebo and the three groups of febuxostat.
The phase II trial was followed by the FOCUS clinical trial (Febuxostat Open Label of Urate-Lowering Efficacy and Safety) as an extension study. A total of 116 patients were enrolled and some of them were followed for more than 5 years [Schumacher et al. 2009
]. The results of the FOCUS trial are discussed later in this review.
The phase III randomized allopurinol comparison clinical trials were FACT (Febuxostat versus
Allopurinol Controlled Trial) a 52-week doubleblind study of 760 patients, APEX (Allopurinol Placebo-Controlled Efficacy Study of Febuxostat) a 28-week, double-blind, placebo-controlled study of 1072 patients, and CONFIRMS a phase III double-blind randomized controlled trial that further examined the comparative urate-lowering efficacy and safety of febuxostat and allopurinol in a larger number of patients (2269) followed for 6 months [Becker et al. 2010
; Schumacher et al. 2008
; Becker et al. 2005b
The EXCEL clinical trial (Febuxostat Comparative Extension Long-Term Study) was a long-term nonblinded extension study in patients completing FACT and APEX, involving 1086 patients [Becker et al. 2009
In the FACT trial, 760 patients with gout and a sUA >8.0 mg/dl were randomly assigned to receive either febuxostat 80 or 120 mg or allopurinol 300 mg once daily for 52 weeks. Prophylaxis with naproxen or colchicine for acute flares was provided during the first 8 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. Secondary endpoints included reduction in the incidence of acute flares and tophus area [Becker et al. 2005b
The primary endpoint was achieved in 53% of patients receiving 80 mg febuxostat, 62% of patients receiving 120 mg and 21% of those receiving allopurinol (p
< 0.001 for each febuxostat group compared with allopurinol). There were no significant differences noted in secondary endpoints between groups. A significant number of patients in both febuxostat groups were discontinued from the study compared with the allopurinol group, and four deaths occurred in both febuxostat groups, compared with none in the allopurinol group, but the deaths were not considered to be drug related [Lustberg, 2006
; Becker et al. 2005b
]. The higher rate of discontinuation in the febuxostat groups was due to the higher incidence of loss to follow-up, adverse events, and gout flares. Abnormal liver function test results led to the withdrawal of five patients receiving 80 mg febuxostat, seven receiving 120 mg febuxostat, and one receiving allopurinol [Becker et al. 2005b
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 80 mg, 120 mg, or 240 mg; or allopurinol 300 mg or 100 mg, 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 [Schumacher et al. 2008
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 80 mg, 45% receiving 120 mg, and 60% receiving 240 mg, compared with 0% in the allopurinol and placebo groups [Schumacher et al. 2008
In the CONFIRMS trial the main objective was to compare the urate-lowering efficacy of febuxostat at doses of 40 and 80 mg compared with allopurinol 300/200 mg in patients with mild-to-moderate renal impairment, and also to obtain prospective and uniform information regarding the safety of febuxostat, especially regarding cardiovascular safety. A total of 2269 patients were randomized to febuxostat 40 mg or 80 mg and allopurinol 300 mg or 200 mg in moderate renal impairment to compare urate-lowering efficacy and safety in subjects with gout and sUA greater than 8.0 mg/dl in a 6-month trial [Becker et al. 2010
The primary endpoint was the proportion of all patients and those with mild/moderate renal impairment achieving sUA less than 6.0 mg/dl. Safety assessments included a blinded adjudication of each cardiovascular adverse event and death using the Anti-Platelet Trialists' Collaboration (APTC) endpoints. The primary endpoint was achieved in 45%, 67% and 42% of patients on febuxostat 40 mg, 80 mg and allopurinol, respectively. No statistical difference was seen between febuxostat 40 mg and allopurinol and it was considered as noninferior to allopurinol; however, febuxostat 80 mg was superior to both groups (p
< 0.001). In the groups with moderate renal impairment, febuxostat 80 mg was superior (p
< 0.001) to both 40 mg and allopurinol (endpoint achieved in 72%, 50%, and 42%, respectively) and febuxostat 40 mg was marginally superior to allopurinol (p
< 0.021) [Becker et al. 2010
Adverse events were not significantly different among groups: APTC rates were 0.0% (95% CI 0.0–0.486) for febuxostat 40 mg and 0.4% (95% CI 0.082–1.155) (three patients) for both febuxostat and allopurinol. One death occurred in each of the febuxostat groups, compared with three deaths in the allopurinol groups [Becker et al. 2010
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 80 mg febuxostat with dose adjustment to either 40 or 120 mg 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 [Schumacher et al. 2009
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 80 mg 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 80 mg, 120 mg 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 [Becker et al. 2009