Allopurinol Versus Febuxostat in Subjects Completing the Phase 3 Trials C02-009 or C02-010

Official Title: “A Phase 3, Open-Label, Randomized, Allopurinol-Controlled Study to Assess the Long-Term Safety of Oral Febuxostat in Subjects With Gout”

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.

Intervention(s) in this Clinical Trial

• Drug: Febuxostat
  • Febuxostat 80 mg, tablets, orally, once daily.
• Drug: Febuxostat
  • Febuxostat 120 mg, tablets, orally, once daily.
• Drug: Allopurinol
  • Allopurinol 100 mg or 300 mg, tablets, orally, once daily.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Febuxostat 80 mg QD
• Experimental: Febuxostat 120 mg QD
• Active Comparator: Allopurinol QD

Primary Measures

• Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 1.
  • Time Frame: Month 1
    Safety Issue?: No
• Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 12.
  • Time Frame: Month 12
    Safety Issue?: No
• Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 24.
  • Time Frame: Month 24
    Safety Issue?: No
• Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 36.
  • Time Frame: Month 36
    Safety Issue?: No
• Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Last Visit on Treatment.
  • Time Frame: Last Visit on treatment (up to 40 months).
    Safety Issue?: No

Secondary Measures

• Percent Change in Serum Urate Levels From Baseline to the Last Visit on Treatment.
  • Time Frame: Last Visit on treatment (up to 40 months).
    Safety Issue?: No
• Percent Change From Baseline in Primary Tophus Size at Month 12 for Subjects With Palpable Tophi Measured at Baseline.
  • Time Frame: Month 12
    Safety Issue?: No
• Percent Change From Baseline in Primary Tophus Size at Month 24 for Subjects With Palpable Tophi Measured at Baseline.
  • Time Frame: Month 24
    Safety Issue?: No
• Percent Change From Baseline in Primary Tophus Size at Month 36 for Subjects With Palpable Tophi Measured at Baseline.
  • Time Frame: Month 36
    Safety Issue?: No
• Percent Change From Baseline in Primary Tophus Size at Final Visit for Subjects With Palpable Tophi Measured at Baseline.
  • Time Frame: Final Visit (up to 40 months).
    Safety Issue?: No
• Percent Change From Baseline in the Total Number of Tophi for Subjects With Palpable Tophi at Final Visit.
  • Time Frame: Final Visit (up to 40 months).
    Safety Issue?: No
• Percentage of Subjects Requiring Treatment for Gout Flare up to Month 12.
  • Time Frame: Month 12
    Safety Issue?: No
• Percentage of Subjects Requiring Treatment for Gout Flare After Month 12.
  • Time Frame: After Month 12 to Final Visit
    Safety Issue?: No

Inclusion Criteria:

• Is receiving thiazide diuretic therapy (only to subjects randomized to or receiving febuxostat).
• Has a serum urate level less than 8.0 mg/dL and is not taking uric acid-lowering therapy (other than allopurinol or febuxostat).
• Has participated in a clinical study in which febuxostat was administered.
• Is completing Phase 3 Studies C02-009 or C02-010.
• Must not have experienced any serious study drug-related adverse events in the previous study.
• Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study

Exclusion Criteria:

• Has had any other significant medical condition as defined by the investigator that would interfere with the treatment, safety, or compliance with the protocol.
• Is intolerant of allopurinol.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 85 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Takeda Global Research & Development Center, Inc. Industry

Overall Clinical Trial Officials and Contacts

Medical Director Study Chair Takeda Global Research & Development Center, Inc.  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00175019

Study ID Number: C02-021

ClinicalTrials.gov Identifier: NCT00175019

Health Authority: United States: Food and Drug Administration

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