Phase 3, Febuxostat, Allopurinol and Placebo-Controlled Study in Gout Subjects. (APEX)

Study Description

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Brief Summary:

The purpose of this study is to compare febuxostat, allopurinol and placebo, once daily (QD), in subjects with gout.

Condition or disease	Intervention/treatment	Phase
Gout	Drug: Febuxostat; Drug: Allopurinol; Drug: Placebo	Phase 3

Detailed Description:

A Phase 3 Study comparing 80 mg, 120 mg or 240 mg of febuxostat, allopurinol (300 mg for those with normal renal function and 100 mg for those with impaired renal function) and placebo administered once daily in subjects with gout.

Subjects will receive treatment for 28 weeks.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	1072 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	A Phase 3, Randomized, Multicenter, Allopurinol and Placebo-Controlled Study Assessing the Safety and Efficacy of Oral Febuxostat in Subjects With Gout.
Study Start Date :	February 2003
Actual Primary Completion Date :	April 2004
Actual Study Completion Date :	April 2004

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Febuxostat 80 mg QD	Drug: Febuxostat; Febuxostat 80 mg, orally, once daily for up to 28 weeks.; Other Names: TMX-67; Tei-6720; Uloric
Experimental: Febuxostat 120 mg QD	Drug: Febuxostat; Febuxostat 120 mg, orally, once daily for up to 28 weeks.; Other Names: TMX-67; Tei-6720; Uloric
Experimental: Febuxostat 240 mg QD	Drug: Febuxostat; Febuxostat 240 mg, orally, once daily for up to 28 weeks.; Other Names: TMX-67; Tei-6720; Uloric
Active Comparator: Allopurinol QD	Drug: Allopurinol; Allopurinol, orally, once daily for up to 28 weeks. Dose of allopurinol received was based on renal status. Subjects with serum creatinine ≤1.5 mg/dL received 300 mg once daily; subjects with serum creatinine >1.5 mg/dL and ≤2.0 mg/dL received 100 mg once daily.
Placebo Comparator: Placebo QD	Drug: Placebo; Placebo, orally, once daily for up to 28 weeks.

Outcome Measures

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Primary Outcome Measures :

1. Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram Per Deciliter (mg/dL). [ Time Frame: Last 3 visits (any last 3 visits up to week 28) ]
   Each subject's serum urate at the last 3 visits determined the subject's response for the primary efficacy variable. A subject who prematurely discontinued without least 3 postbaseline serum urate levels was considered a nonresponder; if at least 3 serum urate were obtained postbaseline, those 3 visits were used. The last 3 visits used may have differed for each subject.

Secondary Outcome Measures :

1. Percentage of Subjects Whose Serum Urate Levels Are <6.0 mg/dL at Week 28 [ Time Frame: Week 28 ]
   Serum urate values were obtained at the Week 28 visit. The percentage of subjects whose serum urate was <6.0 mg/dL at the Week 28 visit was summarized.
2. Percentage of Subjects Whose Serum Urate Levels Are <6.0 mg/dL at Final Visit [ Time Frame: Final Visit (up to 28 weeks). ]
   The percentage of subjects whose serum urate was <6.0 mg/dL at the final visit was summarized. The final visit was the last visit at which a serum urate value was collected and may have differed by subject.
3. Percent Change From Baseline in Serum Urate Levels at Week 28. [ Time Frame: Baseline and Week 28 ]
   Serum urate values were obtained at the Week 28 visit. The percent change in serum urate was calculated as [(Week 28 - baseline levels)/baseline]*100 and summarized.
4. Percent Change From Baseline in Serum Urate Levels at Final Visit [ Time Frame: Baseline and Final Visit (up to 28 weeks) ]
   The percent change in serum urate from baseline to the Final visit was summarized. The percent change in serum urate was calculated as [(Final visit - baseline levels)/baseline]*100. The final visit was the last visit at which a serum urate value was collected. The timing of the final visit may have differed for each subject.
5. Percent Change in Primary Tophus Size at Week 28, as Determined by Physical Measurement in the Subset of Subjects With Palpable Tophi at the Screening Visit. [ Time Frame: Baseline and Week 28 ]
   The percent change from baseline in primary tophus size as determined by physical measurement was calculated as [(Week 28 - baseline sizes)/baseline]*100 for the subset of subjects with a primary palpable tophus at the Screening Visit. If the primary tophus was no longer palpable at the Week 28 visit, the size was assumed to be zero.
6. Percent Change in Primary Tophus Size at Final Visit, as Determined by Physical Measurement in the Subset of Subjects With Palpable Tophi at the Screening Visit. [ Time Frame: Baseline and Final Visit (up to 28 weeks) ]
   Percent change in primary tophus size was calculated as [(Final Visit - baseline sizes)/baseline]*100 for the subset of subjects with a primary palpable tophus at Screening. If tophus was not palpable at Final visit, the size was assumed to be 0. The timing of the final visit may have differed for each subject.
7. Change in the Total Number of Tophi at Week 28 in the Subset of Subjects With Palpable Tophi at the Screening Visit. [ Time Frame: Baseline and Week 28 ]
   Change from baseline at Week 28 in the total number of tophi per subject was calculated for the subset of subjects with palpable tophi at the Screening Visit. If the tophi were not palpable at the Week 28 visit, the total count was assumed to be 0.
8. Change in the Total Number of Tophi at Final Visit in the Subset of Subjects With Palpable Tophi at the Screening Visit [ Time Frame: Final Visit (up to 28 weeks) ]
   Change in number of tophi/subject was calculated for the subset of subjects with palpable tophi at the Screening. If the tophi were not palpable at the Final Visit, total count was assumed to be 0. The timing of the final visit may have differed for each subject.
9. Percentage of Subjects Requiring Treatment for a Gout Flare Between Weeks 8 and 28 of the Double-Blind Treatment Period. [ Time Frame: Weeks 8 through 28 ]
   Percentage of subjects requiring treatment for a gout flare between Weeks 8 and 28 of the double-blind treatment period was summarized. A subject who reported more than 1 gout flare during this period was counted only once.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 85 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Hyperuricemia (serum urate ≥8.0 mg/dL and gout by American Rheumatism Association Criteria
• Renal function defined as a serum creatinine level of < 2.0 mg/dL and creatinine clearance of > 20 milliliters per minute (mL/min) by Cockroft and Gault formula.

Exclusion Criteria:

• History of xanthinuria
• Intolerance to allopurinol
• Presence of renal calculi,
• Alcohol intake of ≥ 14 drinks/week
• Clinically significant medical condition

Contacts and Locations

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Sponsors and Collaborators

Takeda

Investigators

Study Director:	Medical Director	Takeda

More Information

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Additional Information:

Uloric Package Insert 

FDA Safety Alerts and Recalls 

Publications of Results:

Schumacher HR Jr, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, Lademacher C, Joseph-Ridge N. Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: a 28-week, phase III, randomized, double-blind, parallel-group trial. Arthritis Rheum. 2008 Nov 15;59(11):1540-8. doi: 10.1002/art.24209.

Becker MA, MacDonald PA, Hunt BJ, Lademacher C, Joseph-Ridge N. Determinants of the clinical outcomes of gout during the first year of urate-lowering therapy. Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):585-91. doi: 10.1080/15257770802136032.

Wortmann RL, Macdonald PA, Hunt B, Jackson RL. Effect of prophylaxis on gout flares after the initiation of urate-lowering therapy: analysis of data from three phase III trials. Clin Ther. 2010 Dec;32(14):2386-97. doi: 10.1016/j.clinthera.2011.01.008.

Chohan S, Becker MA, MacDonald PA, Chefo S, Jackson RL. Women with gout: efficacy and safety of urate-lowering with febuxostat and allopurinol. Arthritis Care Res (Hoboken). 2012 Feb;64(2):256-61. doi: 10.1002/acr.20680.

Responsible Party:	Takeda
ClinicalTrials.gov Identifier:	NCT00174915 History of Changes
Other Study ID Numbers:	C02-009; U1111-1113-9740 ( Registry Identifier: WHO )
First Posted:	September 15, 2005
Results First Posted:	July 16, 2009
Last Update Posted:	February 2, 2012
Last Verified:	January 2012

Keywords provided by Takeda:

Uric Acid, gout, xanthine oxidase, febuxostat, tophi

Additional relevant MeSH terms:

Gout; Arthritis; Joint Diseases; Musculoskeletal Diseases; Crystal Arthropathies; Rheumatic Diseases; Purine-Pyrimidine Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Allopurinol	Febuxostat; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gout Suppressants; Antirheumatic Agents; Free Radical Scavengers; Antioxidants; Protective Agents; Physiological Effects of Drugs