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

A Phase 3, Randomized, Multicenter, Allopurinol and Placebo-Controlled Study Assessing the Safety and Efficacy of Oral Febuxostat in Subjects With Gout.

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

Study Overview

• Status: Completed
• Conditions: Gout
• Intervention / Treatment: Drug: Febuxostat; Drug: Febuxostat; Drug: Febuxostat; Drug: Allopurinol; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 1072
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo QD	Drug: Placebo; Placebo, orally, once daily for up to 28 weeks.
Experimental: Febuxostat 80 mg QD	Drug: Febuxostat; Febuxostat 80 mg, orally, once daily for up to 28 weeks.; Other Names: Uloric; TMX-67; Tei-6720; Drug: Febuxostat; Febuxostat 120 mg, orally, once daily for up to 28 weeks.; Other Names: Uloric; TMX-67; Tei-6720; Drug: Febuxostat; Febuxostat 240 mg, orally, once daily for up to 28 weeks.; Other Names: Uloric; TMX-67; Tei-6720
Experimental: Febuxostat 120 mg QD	Drug: Febuxostat; Febuxostat 80 mg, orally, once daily for up to 28 weeks.; Other Names: Uloric; TMX-67; Tei-6720; Drug: Febuxostat; Febuxostat 120 mg, orally, once daily for up to 28 weeks.; Other Names: Uloric; TMX-67; Tei-6720; Drug: Febuxostat; Febuxostat 240 mg, orally, once daily for up to 28 weeks.; Other Names: Uloric; TMX-67; Tei-6720
Experimental: Febuxostat 240 mg QD	Drug: Febuxostat; Febuxostat 80 mg, orally, once daily for up to 28 weeks.; Other Names: Uloric; TMX-67; Tei-6720; Drug: Febuxostat; Febuxostat 120 mg, orally, once daily for up to 28 weeks.; Other Names: Uloric; TMX-67; Tei-6720; Drug: Febuxostat; Febuxostat 240 mg, orally, once daily for up to 28 weeks.; Other Names: Uloric; TMX-67; Tei-6720
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram Per Deciliter (mg/dL).	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.	Last 3 visits (any last 3 visits up to week 28)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects Whose Serum Urate Levels Are <6.0 mg/dL at 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.	Week 28
Percentage of Subjects Whose Serum Urate Levels Are <6.0 mg/dL at Final Visit	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.	Final Visit (up to 28 weeks).
Percent Change From Baseline in Serum Urate Levels at 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.	Baseline and Week 28
Percent Change From Baseline in Serum Urate Levels at Final Visit	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.	Baseline and Final Visit (up to 28 weeks)
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.	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.	Baseline and Week 28
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.	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.	Baseline and Final Visit (up to 28 weeks)
Change in the Total Number of Tophi at Week 28 in the Subset of Subjects With Palpable Tophi at the Screening Visit.	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.	Baseline and Week 28
Change in the Total Number of Tophi at Final Visit in the Subset of Subjects With Palpable Tophi at the Screening Visit	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.	Final Visit (up to 28 weeks)
Percentage of Subjects Requiring Treatment for a Gout Flare Between Weeks 8 and 28 of the Double-Blind Treatment Period.	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.	Weeks 8 through 28

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

General Publications

• 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.

Helpful Links

• Uloric Package Insert

Study record dates

Study Major Dates

• Study Start: February 1, 2003
• Primary Completion (Actual): April 1, 2004
• Study Completion (Actual): April 1, 2004

Study Registration Dates

• First Submitted: September 9, 2005
• First Submitted That Met QC Criteria: September 9, 2005
• First Posted (Estimate): September 15, 2005

Study Record Updates

• Last Update Posted (Estimate): February 2, 2012
• Last Update Submitted That Met QC Criteria: January 31, 2012
• Last Verified: January 1, 2012

More Information

Terms related to this study

• Keywords: Uric Acid, gout, xanthine oxidase, febuxostat, tophi
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Metabolism, Inborn Errors; Crystal Arthropathies; Purine-Pyrimidine Metabolism, Inborn Errors; Gout; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Antioxidants; Free Radical Scavengers; Gout Suppressants; Allopurinol; Febuxostat
• Other Study ID Numbers: C02-009; U1111-1113-9740 (Registry Identifier: WHO)