[Show abstract][Hide abstract] ABSTRACT: AIM: Assess influences of demographics and co-morbidities of gout patients with or without diabetes on safety and efficacy of urate-lowering agents. MATERIALS AND METHODS: Post-hoc analysis of 312 diabetic and 1,957 non-diabetic gout patients (baseline serum urate levels [sUA] ≥8.0 mg/dL) enrolled in a 6-month randomized controlled trial comparing urate-lowering efficacy (ULE) and safety of daily xanthine oxidase inhibitors (XOIs) febuxostat (40 mg or 80 mg) and allopurinol (200 mg or 300 mg). We compared baseline demographic, gout, and co-morbid characteristics, ULE, and safety of XOI treatment in diabetic and non-diabetic gout patients. ULE was measured by the proportion of diabetic and non-diabetic patients in each treatment group achieving final visit sUA <6.0mg/dL. Safety was monitored throughout the trial. RESULTS: Diabetic gout patients were older, more frequently female, and had longer gout duration. Co-morbidities were more frequent among diabetic patients: cardiovascular disease; impaired renal function; hyperlipidemia; and obesity (BMI >30 kg/m(2) ) (p < 0.001 for all comparisons). Febuxostat 80 mg ULE exceeded that of febuxostat 40 mg or allopurinol (p <0.050) at all levels of renal function, achieving sUA goal range in the majority of diabetic and non-diabetic patients. Diabetics and non-diabetics reported self-limiting diarrhea and URIs as the most common AEs. CONCLUSIONS: Despite higher co-morbidity rates in diabetic patients, febuxostat and allopurinol were safe in both groups at the doses tested. Febuxostat 80 mg achieved sUA <6.0 mg/dL more often than febuxostat 40 mg or allopurinol at commonly prescribed doses.
Diabetes Obesity and Metabolism 05/2013; · 5.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Comprehensive safety evaluation of new drugs for noncardiac indications is needed in the area of cardiovascular (CV) outcomes, particularly in populations with high CV risk such as gout. Febuxostat is a potent nonpurine selective inhibitor of xanthine oxidase approved for the treatment of gout. Long-term CV safety of febuxostat is being established in a randomized, allopurinol-controlled clinical study in patients with gout who have increased CV risk using an analytical approach that provides 90% power to meet a noninferiority margin of 1.3 for the hazard ratio (HR) (febuxostat relative to allopurinol). The primary CV end point for this trial is a composite of CV death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina requiring urgent coronary revascularization. Approximately 7,500 men and women with gout and CV disease are being recruited and will be followed up for up to 5 years postrandomization. The statistical plan for the trial uses a design that evaluates the HR of febuxostat to allopurinol based on the primary CV composite end point when there are a maximum of 624 CV events. Interim analyses will be conducted when approximately 25%, 50%, and 75% of events have occurred. At each analysis, if the upper 1-sided confidence limit of the HR is <1.3, the study will be stopped, and the noninferiority of febuxostat relative to allopurinol with regard to CV risk will be declared. The CARES trial will define the CV safety profile of febuxostat and allopurinol in gout patients at high risk for CV events.
American heart journal 07/2012; 164(1):14-20. · 4.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The incidence of gout rises with increasing age. Management of elderly (≥65 years) gout patients can be challenging due to high rates of comorbidities, such as renal impairment and cardiovascular disease, and concomitant medication use. However, there is little data specifically addressing the efficacy and safety of available urate-lowering therapies (ULT) in the elderly. The objective of this post hoc analysis was to examine the efficacy and safety of ULT with febuxostat or allopurinol in a subset of elderly subjects enrolled in the CONFIRMS trial.
Hyperuricemic (serum urate [sUA] levels ≥ 8.0 mg/dL) gout subjects were enrolled in the 6-month, double-blind, randomized, comparative CONFIRMS trial and randomized, 1:1:1, to receive febuxostat, 40 mg or 80 mg, or allopurinol (200 mg or 300 mg based on renal function) once daily. Flare prophylaxis was provided throughout the study duration.Study endpoints were the percent of elderly subjects with sUA <6.0 mg/dL at the final visit, overall and by renal function status, percent change in sUA from baseline to final visit, flare rates, and rates of adverse events (AEs).
Of 2,269 subjects enrolled, 374 were elderly. Febuxostat 80 mg was significantly more efficacious (82.0%) than febuxostat 40 mg (61.7%; p < 0.001) or allopurinol (47.3%; p < 0.001) for achieving the primary efficacy endpoint. Febuxostat 40 mg was also superior to allopurinol in this population (p = 0.029). In subjects with mild-to-moderate renal impairment, significantly greater ULT efficacy was observed with febuxostat 40 mg (61.6%; p = 0.028) and febuxostat 80 mg (82.5%; p < 0.001) compared to allopurinol 200/300 mg (46.9%). Compared to allopurinol 200/300 mg, the mean percent change in sUA from baseline was significantly greater for both febuxostat 80 mg (p < 0.001) and febuxostat 40 mg (p = 0.011) groups. Flare rates declined steadily in all treatment groups. Rates of AEs were low and comparable across treatments.
These data suggest that either dose of febuxostat is superior to commonly prescribed fixed doses of allopurinol (200/300 mg) in subjects ≥65 years of age with high rates of renal dysfunction. In addition, in this high-risk population, ULT with either drug was well tolerated.
[Show abstract][Hide abstract] ABSTRACT: Despite an increasing incidence of gout in older age patients with multiple metabolic and cardiovascular comorbidities, there are limited data addressing whether currently available urate-lowering therapy is comparably effective and safe in older (≥65 years of age) versus younger (<65 years of age) patients. In this secondary analysis of data from the CONFIRMS trial, we found that among 374 older subjects, urate-lowering therapy with approved doses of febuxostat or commonly prescribed doses of allopurinol was at least comparable to that in 1894 younger subjects and was well tolerated despite high rates of renal impairment and cardiovascular comorbidities in the older subjects.
[Show abstract][Hide abstract] ABSTRACT: Hyperuricemia of gout can arise due to either overproduction or underexcretion of uric acid. Not all available urate-lowering therapies are equally effective and safe for use in patients with renal disease. The objective of this post-hoc analysis was to determine the effectiveness of the xanthine oxidase inhibitor febuxostat in reducing serum urate (sUA) levels in gouty patients who were either overproducers or underexcretors.
Gouty subjects 18 to 85 years of age with sUA ≥ 8.0 mg/dl at baseline were enrolled in a Phase 2, 28-day, multicenter, randomized, double-blind, placebo-controlled trial and randomized to receive febuxostat 40 mg, 80 mg, or 120 mg daily, or placebo. The primary efficacy endpoint was the proportion of subjects with sUA < 6.0 mg/dl at Day 28. Secondary efficacy endpoints included percentage reductions in sUA and urinary uric acid (uUA) from baseline to Day 28.
Of the 153 subjects, 118 (77%) were underexcretors (uUA ≤ 800 mg/24 h) and 32 (21%) were overproducers (uUA > 800 mg/24 h); baseline uUA data were missing for 3 subjects. Treatment with febuxostat led to the majority of subjects achieving sUA < 6.0 mg/dl at Day 28. Treatment with any dose of febuxostat led to significantly greater percentage reductions in uUA than that observed in the placebo group, for both underexcretors and overproducers.
Febuxostat is a highly efficacious urate-lowering therapy in patients with gout regardless of overproduction or underexcretion status.
The Journal of Rheumatology 05/2011; 38(7):1385-9. · 3.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The association between hyperuricemia, gout, and impaired renal function has long been recognized. Recent data provide evidence for the causal relationship between elevated serum urate (sUA) and renal changes, leading to declines in glomerular filtration rates. In healthy adults, glomerular filtration rate wanes with age. Urate-lowering therapy (ULT) with allopurinol has been shown to stabilize or reverse this.
Here we examine the long-term effects of ULT with febuxostat on estimated glomerular filtration rate (eGFR).
This is a post hoc analysis of the Febuxostat Open-label Clinical trial of Urate-lowering efficacy and Safety study, during which 116 hyperuricemic gout subjects received daily doses of febuxostat (40, 80, or 120 mg) for up to 5 years. sUA concentrations and eGFR were assessed regularly. Results were stratified by mean change in sUA from baseline. Mathematical modeling was used to predict the effect of sUA reduction on eGFR.
Maintenance or improvement in eGFR was inversely correlated with the quantitative reduction in sUA from baseline. For every 1 mg/dL decrease in sUA, the model projected an expected improvement in eGFR of 1 mL/min from the untreated value.
Individuals with the greatest reductions in sUA may experience reduced rates of renal deterioration or even stabilization of renal function. Further studies examining the impact of long-term ULT on renal function in hyperuricemic gout patients are needed to both confirm our results and verify if improvements in renal function are feasible in such patients.
Journal of clinical rheumatology: practical reports on rheumatic & musculoskeletal diseases 01/2011; 17(1):7-13. · 1.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Use of urate-lowering therapy (ULT), such as febuxostat or allopurinol, is recommended for the long-term management of hyperuricemia in patients with gout to reduce the incidence of acute flares. Because of the paradoxical relationship between early use of ULT and the increased incidence of gout flares, prophylaxis with either low-dose colchicine or NSAIDs has been recommended, although there have been concerns about the long-term prophylactic use of these agents.
The present analysis examined flare rates during the 3 Phase III trials of febuxostat based on mean postbaseline serum urate (sUA) concentrations and duration of prophylaxis. Adverse events (AEs) were assessed by prophylaxis with colchicine or naproxen.
This investigator-initiated, post hoc reanalysis of data on gout flares from the 3 randomized, placebo-controlled, Phase III trials evaluated the proportion of patients requiring treatment for gout flares at 4-week intervals based on mean postbaseline sUA concentrations <6.0 and ≥ 6.0 mg/dL. The 3 trials enrolled males or females aged 18-85 years who had a diagnosis of gout and a baseline sUA concentration ≥ 8.0 mg/dL. Patients received ULT (febuxostat or allopurinol) or placebo for 6 months or 1 year and flare prophylaxis with colchicine 0.6 mg/d or naproxen 250 mg BID for 8 weeks or 6 months. The prophylactic regimen was chosen at the discretion of the investigator, based on renal function and known intolerance to either drug. Patients with an estimated creatinine clearance <50 mL/min were not to receive naproxen. AEs were summarized based on prophylaxis with colchicine or naproxen.
The 3 trials enrolled a total of 4101 patients with gout. The majority were white (80.1%), male (94.5%), and obese (body mass index ≥ 30 kg/m(2)) (62.8%). The mean duration of gout ranged from 10.9-11.9 years, and the mean baseline sUA concentration ranged from 9.6-9.9 mg/dL. Flare rates increased sharply (up to 40%) at the end of 8 weeks of prophylaxis and then declined gradually, whereas flare rates were consistently low (range, 3%-5%) at the end of 6 months of prophylaxis. Mean postbaseline sUA concentrations were correlated with flare rates; by the end of each study, patients with a mean postbaseline sUA concentration <6.0 mg/dL had fewer flares than did those with a mean postbaseline sUA concentration ≥ 6.0 mg/dL. There were differences in rates of AEs between prophylaxis groups, but the rates did not increase with increased duration of prophylaxis.
This analysis of gout flare data from the 3 Phase III trials of febuxostat found that flare prophylaxis for up to 6 months during the initiation of ULT appeared to provide greater benefit than flare prophylaxis for 8 weeks, with no increase in AEs.
[Show abstract][Hide abstract] ABSTRACT: Purpose: Compare efficacy, gout flare rates, and safety of 6-month febuxostat or allopurinol treatment between subjects whose gout and hyperuricemia was successfully treated in prior trials with febuxostat or allopurinol for 3-5 years vs subjects not previously so treated.
Methods: In the 6-month CONFIRMS trial, 2269 subjects with gout and hyperuricemia received daily febuxostat 40 or 80 mg or allopurinol (300 or 200 mg based on creatinine clearance). There were 276 subjects from the previous FOCUS (5 yrs) or EXCEL (3 yrs) trials maintaining serum urate level (sUA) <6 mg/dL for up to 5 yrs on febuxostat 40, 80, or 120 mg or allopurinol 300 mg. Randomization was stratified by renal function and prior long-term urate-lowering therapy (ULT) study participation. Subjects with previous ULT washed out for ≥30 days and had baseline sUA ≥8 mg/dL before entering CONFIRMS. Subjects received colchicine or naproxen for gout flare prophylaxis.
Results: Demographics in this prior treatment subset were similar to those of the entire group. Proportions of subjects with prior participation who achieved sUA <6 mg/dL at final visit in the febuxostat 40 or 80 mg and allopurinol groups were 57%, 77%, and 52%, respectively, vs 43%, 66%, and 41%, respectively, among subjects without prior participation (p≤0.05). Overall, subjects with prior participation in each group had lower flare rates (p≤0.001) vs those without prior participation. The most frequent AEs were URIs, abnormal LFTs, musculoskeletal pain, and diarrhea, and rates of AEs were similar among subjects with and without prior participation.
Conclusions: The subset with 3-5 yrs of ULT achieved sUA <6 mg/dL more often and had substantially fewer reported gout flares vs subjects without ULT. This demonstrates the clinical benefit of maintaining sUA <6 mg/dL in reducing subsequent gout flare incidence and supports the likelihood of long-term urate pool depletion during successful ULT.
2009 American College of Clinical Pharmacy Annual Meeting; 10/2009
[Show abstract][Hide abstract] ABSTRACT: To compare the urate-lowering efficacy and safety of febuxostat, allopurinol, and placebo in a large group of subjects with hyperuricemia and gout, including persons with impaired renal function.
Subjects (n = 1,072) with hyperuricemia (serum urate level > or = 8.0 mg/dl) and gout with normal or impaired (serum creatinine level >1.5 to < or = 2.0 mg/dl) renal function were randomized to receive once-daily febuxostat (80 mg, 120 mg, or 240 mg), allopurinol (300 or 100 mg, based on renal function), or placebo for 28 weeks.
Significantly (P < or = 0.05) higher percentages of subjects treated with febuxostat 80 mg (48%), 120 mg (65%), and 240 mg (69%) attained the primary end point of last 3 monthly serum urate levels <6.0 mg/dl compared with allopurinol (22%) and placebo (0%). A significantly (P < 0.05) higher percentage of subjects with impaired renal function treated with febuxostat 80 mg (4 [44%] of 9), 120 mg (5 [45%] of 11), and 240 mg (3 [60%] of 5) achieved the primary end point compared with those treated with 100 mg of allopurinol (0 [0%] of 10). Proportions of subjects experiencing any adverse event or serious adverse event were similar across groups, although diarrhea and dizziness were more frequent in the febuxostat 240 mg group. The primary reasons for withdrawal were similar across groups except for gout flares, which were more frequent with febuxostat than with allopurinol.
At all doses studied, febuxostat more effectively lowered and maintained serum urate levels <6.0 mg/dl than did allopurinol (300 or 100 mg) or placebo in subjects with hyperuricemia and gout, including those with mild to moderately impaired renal function.
[Show abstract][Hide abstract] ABSTRACT: Clinical benefit early in urate-lowering treatment of gout is difficult to document. We examined data from 1,832 gouty subjects treated with either urate-lowering agents or placebo to identify determinants of gout flare incidence and tophus size during year 1 of treatment. Reductions from pretreatment serum urate levels influenced flare frequency and tophus size, but the effect of urate level on flare incidence was biphasic. Lower urate levels were associated with higher flare incidence early in treatment but lower incidence by one year. The complex relationship between urate-lowering and clinical outcome early in treatment has implications for both clinical and investigative approaches to urate-lowering management.
[Show abstract][Hide abstract] ABSTRACT: In order to evaluate the safety, pharmacological properties, and urate-lowering efficacy of febuxostat, a non-purine, selective inhibitor of xanthine oxidase, a Phase 1, 2-week, multiple-dose, placebo-controlled, dose-escalation study was conducted in 154 healthy adults of both sexes. Daily febuxostat doses in the range 10 mg to 120 mg resulted in proportional mean serum urate reductions ranging from 25% to 70% and in proportional increases in maximum febuxostat plasma concentrations and area under plasma concentration versus time curves. Accompanying the hypouricemic effect were increases in serum xanthine concentrations, decreases in urinary uric acid excretion, and increases in urinary xanthine and hypoxanthine excretion, confirming inhibition of xanthine oxidase activity by febuxostat. Hepatic conjugation and oxidative metabolism were the major pathways of elimination of febuxostat from the body, and renal elimination did not appear to play a significant role. Although not uncommon, adverse events were mild and self-limited, and no deaths or serious adverse events were observed. Febuxostat is a safe and potent hypouricemic agent in healthy humans.