The purpose of this study is to determine the long-term safety of febuxostat, once daily (QD), compared to allopurinol in reducing serum urate levels in subjects with gout.
Uric acid is the end product of purine degradation in humans. Hyperuricemia, a urate concentration in serum exceeding the limit of urate solubility (approximately 7.0 mg/dL), is a common biochemical abnormality. Aberrations in any of the multiple mechanisms involved in the production and/or excretion of uric acid may increase serum urate concentrations, with persistent hyperuricemia as a marker for extracellular fluid monosodium urate supersaturation. As such, hyperuricemia is a necessary (but often insufficient) risk factor for monosodium urate crystal deposition in tissues and is the fundamental pathophysiological process underlying the clinical manifestations of gout, which is a chronic disease characterized by urate crystal formation and deposition in joints and bones. Gout may progress from episodic attacks of acute inflammatory arthritis to a disabling chronic disorder characterized by deforming arthropathy; destructive deposits of urate crystals (tophi) in bones, joints, and other organs; structural and functional renal impairment due to interstitial urate crystal deposition; and urinary tract stones composed entirely or partially of uric acid crystals. Management of gout requires chronic treatment aimed at lowering serum urate levels into a subsaturating range (usually \<6.0 mg/dL) in which crystal formation and deposition are prevented or reversed. Febuxostat (TMX-67) is a non-purine selective xanthine oxidase inhibitor being developed as an orally administered agent for the management of hyperuricemia in patients with gout. This study was originally designed and initiated having all subjects initially assigned to 80 mg febuxostat provided as an 80 mg tablet, to be administered orally. Subjects could be titrated to 120 mg, provided as one 40 and 80 mg tablet, between Months 2 and 6, if their serum uric acid rose \> 6.0 mg/dL; the dose could be down-titrated to 80 mg if the serum uric acid decreased to \< 3.0 mg/dL. The protocol was amended to add a comparator arm, and to have subjects randomized to 80 or 120 mg febuxostat or allopurinol (100 or 300 mg, dependent on renal function). The information below reflects the treatments following the implementation of the revised protocol.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1,086
Febuxostat 80 mg, tablets, orally, once daily.
Febuxostat 120 mg, tablets, orally, once daily.
Allopurinol 100 mg or 300 mg, tablets, orally, once daily.
Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 1.
Serum urate values were obtained at the Month 1 visit. The percentage of subjects whose serum urate was \<6.0 mg/dL at the Month 1 visit was summarized.
Time frame: Month 1
Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 12.
Serum urate values were obtained at the Month 12 visit. The percentage of subjects whose serum urate was \<6.0 mg/dL at the Month 12 visit was summarized.
Time frame: Month 12
Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 24.
Serum urate values were obtained at the Month 24 visit. The percentage of subjects whose serum urate was \<6.0 mg/dL at the Month 24 visit was summarized.
Time frame: Month 24
Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 36.
Serum urate values were obtained at the Month 36 visit. The percentage of subjects whose serum urate was \<6.0 mg/dL at the Month 36 visit was summarized.
Time frame: Month 36
Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Last Visit on Treatment.
The percentage of subjects whose serum urate was \<6.0 mg/dL at the last visit on treatment was summarized. The last visit on treatment was the last visit at which a serum urate value was collected prior to any changes in drug and/or dose from the initial treatment assignment.
Time frame: Last Visit on treatment (up to 40 months).
Percent Change in Serum Urate Levels From Baseline to the Last Visit on Treatment.
The percent change in serum urate from baseline to the last visit on treatment was summarized. The last visit on treatment was the last visit at which a serum urate value was collected prior to any changes in drug and/or dose from the initial treatment assignment.
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Time frame: Last Visit on treatment (up to 40 months).
Percent Change From Baseline in Primary Tophus Size at Month 12 for Subjects With Palpable Tophi Measured at Baseline.
The area of the primary tophus was calculated based on the length and width of the tophus measured at the Month 12 visit. The percent change from baseline in primary tophus size to the Month 12 visit was summarized.
Time frame: Month 12
Percent Change From Baseline in Primary Tophus Size at Month 24 for Subjects With Palpable Tophi Measured at Baseline.
The area of the primary tophus was calculated based on the length and width of the tophus measured at baseline and Month 24 visit. The percent change from baseline in primary tophus size to the Month 24 visit was summarized.
Time frame: Month 24
Percent Change From Baseline in Primary Tophus Size at Month 36 for Subjects With Palpable Tophi Measured at Baseline.
The area of the primary tophus was calculated based on the length and width of the tophus measured at baseline and Month 36 visit. The percent change from baseline in primary tophus size to the Month 36 visit was summarized.
Time frame: Month 36
Percent Change From Baseline in Primary Tophus Size at Final Visit for Subjects With Palpable Tophi Measured at Baseline.
The area of the primary tophus was calculated based on the length and width of the tophus measured at baseline and final visit. The percent change from baseline in primary tophus size to the final visit was summarized.
Time frame: Final Visit (up to 40 months).
Percent Change From Baseline in the Total Number of Tophi for Subjects With Palpable Tophi at Final Visit.
The number of tophi were counted at baseline and final visits. The percent change from baseline in the number of tophi to the final visit was summarized.
Time frame: Final Visit (up to 40 months).
Percentage of Subjects Requiring Treatment for Gout Flare up to Month 12.
The percentage of subjects requiring treatment for gout flare during the first twelve months of final stable treatment was summarized.
Time frame: Month 12
Percentage of Subjects Requiring Treatment for Gout Flare After Month 12.
The percentage of subjects requiring treatment for gout flare after the first 12 months of final stable treatment was summarized.
Time frame: After Month 12 to Final Visit