Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Comorbidities

Official Title: “A Multicenter, Randomized, Active-Control, Phase 3B Study to Evaluate the Cardiovascular Safety of Febuxostat and Allopurinol in Subjects With Gout and Cardiovascular Comorbidities”

The purpose of this study is to see if subjects with gout who receive febuxostat or allopurinol, once daily (QD), have a higher rate of serious heart and blood vessel complications.

Gout is caused by high levels of uric acid in the body, and is associated with a broad range of conditions including heart disease, chronic kidney disease and additional risk factors like obesity and high blood pressure. Hyperuricemia, which is defined as an elevation in serum urate levels, develops into gout when urate crystals form from supersaturated body fluids and settle in joints and other organs.

People with gout may also have a higher incidence of other conditions that may be associated with hyperuricemia, gout or both. This is supported by a growing body of research demonstrating that serum urate levels are an independent predictive factor for cardiovascular disease when the effects of other risk factors have been controlled.

This study will explore the cardiovascular safety of febuxostat to determine whether the use of febuxostat is associated with a moderate increase in the risk of serious adverse cardiovascular outcomes as compared to allopurinol.

Participation will last a maximum of 5 years and will include 15 to 20 visits to the study center.

Intervention(s) in this Clinical Trial

• Drug: Febuxostat
  • Febuxostat 40 mg or 80 mg (depending on serum uric acid levels), capsules, orally, once daily for up to 60 months.
• Drug: Allopurinol
  • Allopurinol 200 mg to 600 mg (depending on renal function), capsules, orally, once daily for up to 60 months.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Febuxostat 40 mg or 80 mg QD
  • (dependent on serum uric acid levels)
• Active Comparator: Allopurinol 200 mg to 600 mg QD
  • (dependent on renal function)

Primary Measures

• First occurrence of any event in the predefined Major Adverse Cardiovascular Events Composite.
  • Time Frame: At first occurrence (up to 60 Months)
    Safety Issue?: Yes

Secondary Measures

• First occurrence of any Antiplatelet Trialists' Collaborative Event.
  • Time Frame: At first occurrence (up to 60 Months)
    Safety Issue?: Yes
• First occurrence of Cardiovascular Death death.
  • Time Frame: At first occurrence (up to 60 Months)
    Safety Issue?: Yes
• First occurrence of Non-fatal Myocardial Infarction.
  • Time Frame: At first occurrence (up to 60 Months)
    Safety Issue?: Yes
• First occurrence of Non-fatal stroke.
  • Time Frame: At first occurrence (up to 60 Months)
    Safety Issue?: Yes
• First occurrence of Unstable Angina with Urgent Coronary Revascularization.
  • Time Frame: At first occurrence (up to 60 Months)
    Safety Issue?: Yes

Inclusion Criteria:

• Has a history of major cardiovascular or cerebrovascular disease including at least one of the following:
• Myocardial infarction
• Hospitalized unstable angina
• Cardiac or cerebrovascular revascularization procedure
• Stroke
• Hospitalized for transient ischemic attack
• Peripheral vascular disease
• History of diabetes mellitus with evidence of micro- or macrovascular disease
• Has a history or presence of gout defined as having one or more of the American

Rheumatism Association criteria for the diagnosis of gout:

• A tophus proven to contain urate crystals by chemical or polarized light microscopic means, and/or
• Characteristic urate crystals in the joint fluid, and/or
• History of at least 6 of the following clinical, laboratory, and x-ray phenomena:
• More than 1 attack of acute arthritis
• Maximum inflammation developed within 1 day
• Monoarticular arthritis
• Redness observed over joints
• First metatarsophalangeal joint painful or swollen
• Unilateral first metatarsophalangeal joint attack
• Unilateral tarsal joint attack
• Tophus (proven or suspected)
• Hyperuricemia
• Asymmetric swelling within a joint on x-ray
• Subcortical cysts without erosions on x-ray
• Joint fluid culture negative for organisms during attack
• Must have either:
• a serum urate level greater than or equal to 7.0 mg/dL at the Day -7 Visit OR
• a serum urate level greater than or equal to 6.0 mg/dL at the Day -7 Visit AND inadequately controlled gout

Exclusion Criteria:

• Has secondary hyperuricemia
• Has a history of xanthinuria
• Has received urate-lowering or excluded medication during the screening period
• Has a known hypersensitivity to febuxostat or allopurinol or any components of their formulation
• Has active peptic ulcer disease
• Has a history of cancer within 5 years prior to the first dose of study medication
• Had a myocardial infarction or stroke within 60 days prior to the Screening Visit
• Has alanine aminotransferase and/or aspartate aminotransferase values greater than 2 times the upper limit of normal during the Screening period
• Has a history of drug abuse or a history of alcohol abuse within 5 years prior to the Screening Visit or the subject consumes more than14 alcoholic beverages per week
• Has received any investigational medicinal product within the 30 days prior to the Screening Visit and throughout the study
• Has an estimated creatinine clearance less than 30 mL/min
• Is required to take excluded medications
• Has a known history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 50 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

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

Overall Clinical Trial Officials and Contacts

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

Overall Contact: Takeda Study Registration Call Center 800-778-2860 medicalinformation@tpna.com

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01101035

Study ID Number: TMX-67_301

ClinicalTrials.gov Identifier: NCT01101035

Health Authority: United States: Food and Drug Administration

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