Febuxostat Versus Allopurinol Control Trial in Subjects With Gout - Study Results

Study Type:	Interventional
Study Design:	Randomized, Double Blind (Subject, Investigator, Outcomes Assessor), Active Control, Parallel Assignment
Condition:	Gout
Interventions:	Drug: Febuxostat Drug: Allopurinol

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Subjects were enrolled at 112 investigative sites, 106 in the United States and 6 in Canada, from 11 July 2002 to 20 February 2004.

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Subjects currently receiving urate-lowering therapy discontinued those urate-lowering therapies and initiated prophylactic medications before enrollment in once daily (QD) treatment groups.

	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Allopurinol 300 mg QD
STARTED	256	251	253
COMPLETED	168	153	187
NOT COMPLETED	88	98	66
Lost to Follow-up	25	18	21
Adverse Event	16	23	8
Gout Flare	10	28	9
Personal Reason(s)	19	13	13
Other	11	14	14
Protocol Violation	7	2	1

Baseline Characteristics

Reporting Groups

	Description
Febuxostat 80 mg QD	Febuxostat 80 mg, orally, once daily for up to 52 weeks.
Febuxostat 120 mg QD	Febuxostat 120 mg, orally, once daily for up to 52 weeks.
Allopurinol 300 mg QD	Allopurinol 300 mg, orally, once daily for up to 52 weeks.

Baseline Measures

	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Allopurinol 300 mg QD	Total
Number of Participants [units: participants]	256	251	253	760
Age, Customized [units: subjects]
<45 years	75	71	84	230
45 years to <65 years	140	133	125	398
≥65 years	41	47	44	132
Age [units: years] Mean ± Standard Deviation	51.8 ± 11.69	52.0 ± 12.12	51.6 ± 12.63	51.8 ± 12.13
Gender [units: subjects]
Female	13	8	10	31
Male	243	243	243	729
Body Mass Index [units: subjects]
<18.5 kilogram per meter² (kg/m²)	0	0	0	0
18.5 kg/m² to <25 kg/m²	15	12	7	34
25 kg/m² to <30 kg/m²	75	87	89	251
≥30 kg/m²	166	152	154	472
missing	0	0	3	3
Calculated Creatinine Clearance^[1] [units: subjects]
<50 milliliters per minute (mL/min)	13	8	13	34
50 mL/min to <80 mL/min	77	90	68	235
80 mL/min to <120 mL/min	138	130	140	408
≥120 mL/min	28	23	29	80
missing	0	0	3	3
Presence of Primary Palpable Tophus [units: subjects]
Yes	52	53	46	151
No, but other tophi present	1	2	3	6
No and no other tophi present	203	196	204	603
Race/Ethnicity [units: subjects]
White	193	199	195	587
Black or African American	24	20	18	62
Hispanic	22	17	19	58
Asian	10	9	6	25
Other	7	6	15	28

[1]	Calculated creatinine clearance based on the Cockcroft-Gault equation using ideal body weight.

Outcome Measures

Show All Outcome Measures

1. Primary:

Percentage of Subjects With the Last 3 Serum Urate Levels <6.0 Milligrams Per Deciliter (mg/dL) [ Last 3 Visits (up to 52 weeks) ]

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Measure Type	Primary
Measure Title	Percentage of Subjects With the Last 3 Serum Urate Levels <6.0 Milligrams Per Deciliter (mg/dL)
Measure Description	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.
Time Frame	Last 3 Visits (up to 52 weeks)
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Analysis was performed on the intent-to-treat (ITT) subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had a baseline serum urate ≥8.0 mg/dL.

Reporting Groups

	Description
Febuxostat 80 mg QD	Febuxostat 80 mg, orally, once daily for up to 52 weeks.
Febuxostat 120 mg QD	Febuxostat 120 mg, orally, once daily for up to 52 weeks.
Allopurinol 300 mg QD	Allopurinol 300 mg, orally, once daily for up to 52 weeks.

Measured Values

	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Allopurinol 300 mg QD
Number of Participants Analyzed [units: participants]	255	250	251
Percentage of Subjects With the Last 3 Serum Urate Levels <6.0 Milligrams Per Deciliter (mg/dL) [units: Percentage of subjects]	53	62	21

Statistical Analysis 1 for Percentage of Subjects With the Last 3 Serum Urate Levels <6.0 Milligrams Per Deciliter (mg/dL)

Groups ^[1]	Febuxostat 80 mg QD vs. Allopurinol 300 mg QD
Non-Inferiority/Equivalence Test ^[2]	Yes
Difference in percentage ^[3]	32
97.5% Confidence Interval	( 23.1 to 41.3 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	Non-inferiority of febuxostat 80 mg to allopurinol was declared if the value of the lower bound of the 97.5% confidence interval is > -10%.
[3]	Other relevant estimation information:
	No text entered.

Statistical Analysis 2 for Percentage of Subjects With the Last 3 Serum Urate Levels <6.0 Milligrams Per Deciliter (mg/dL)

Groups ^[1]	Febuxostat 120 mg QD vs. Allopurinol 300 mg QD
Non-Inferiority/Equivalence Test ^[2]	Yes
Difference in percentage ^[3]	41
97.5% Confidence Interval	( 31.5 to 49.5 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Details of power calculation, definition of non-inferiority margin, and other key parameters:
	Non-inferiority of febuxostat 120 mg to allopurinol was declared if the value of the lower bound of the 97.5% confidence interval is > -10%.
[3]	Other relevant estimation information:
	No text entered.

Statistical Analysis 3 for Percentage of Subjects With the Last 3 Serum Urate Levels <6.0 Milligrams Per Deciliter (mg/dL)

Groups ^[1]	Febuxostat 80 mg QD vs. Allopurinol 300 mg QD
Method ^[2]	Fisher Exact
P Value ^[3]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Comparisons of each febuxostat dose to allopurinol were adjusted to control the overall 0.05 level of significance for superiority by using Hochberg's method for multiple comparisons.

Statistical Analysis 4 for Percentage of Subjects With the Last 3 Serum Urate Levels <6.0 Milligrams Per Deciliter (mg/dL)

Groups ^[1]	Febuxostat 120 mg QD vs. Allopurinol 300 mg QD
Method ^[2]	Fisher Exact
P Value ^[3]	<0.001

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Comparisons of each febuxostat dose to allopurinol were adjusted to control the overall 0.05 level of significance for superiority by using Hochberg's method for multiple comparisons.

Statistical Analysis 5 for Percentage of Subjects With the Last 3 Serum Urate Levels <6.0 Milligrams Per Deciliter (mg/dL)

Groups ^[1]	Febuxostat 80 mg QD vs. Febuxostat 120 mg QD
Method ^[2]	Fisher Exact
P Value ^[3]	0.072

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	No text entered.
[2]	Other relevant information, such as adjustments or degrees of freedom:
	No text entered.
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	Statistical significance was determined at 0.05 level without adjustment for multiple comparisons.

2. Secondary:

Percentage of Subjects With Serum Urate <6.0 mg/dL at Week 28 Visit [ Week 28 ]

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3. Secondary:

Percentage of Subjects With Serum Urate <6.0 mg/dL at Week 52 Visit [ Week 52 ]

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4. Secondary:

Percentage of Subjects With Serum Urate <6.0 mg/dL at Final Visit [ Final Visit (up to 52 weeks) ]

Show Outcome Measure 4

5. Secondary:

Percent Change From Baseline in Serum Urate Levels at Week 28. [ Baseline and Week 28 ]

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6. Secondary:

Percent Change From Baseline in Serum Urate Levels at Week 52. [ Baseline and Week 52 ]

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7. Secondary:

Percent Change From Baseline in Serum Urate Levels at Final Visit [ Baseline and Final Visit (up to 52 weeks) ]

Show Outcome Measure 7

8. Secondary:

Percent Change From Baseline in Tophus Size at Week 28, as Determined by Physical Measurement, in Subjects With a Palpable Primary Tophus at Screening. [ Baseline and Week 28 ]

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9. Secondary:

Percent Change From Baseline in Tophus Size at Week 52, as Determined by Physical Measurement, in Subjects With a Palpable Primary Tophus at Screening. [ Baseline and Week 52 ]

Show Outcome Measure 9

10. Secondary:

Percent Change From Baseline in Tophus Size at Final Visit, as Determined by Physical Measurement, in Subjects With a Palpable Primary Tophus at Screening. [ Baseline and Final Visit (up to 52 weeks) ]

Show Outcome Measure 10

11. Secondary:

Change From Baseline in Total Number of Tophi at Week 28 in Subjects With Palpable Tophi at Screening. [ Baseline and Week 28 ]

Show Outcome Measure 11

12. Secondary:

Change From Baseline in Total Number of Tophi at Week 52 in Subjects With Palpable Tophi at Screening. [ Baseline and Week 52 ]

Show Outcome Measure 12

13. Secondary:

Change From Baseline in Total Number of Tophi at Final Visit in Subjects With Palpable Tophi at Screening. [ Baseline and Final Visit (up to 52 weeks) ]

Show Outcome Measure 13

14. Secondary:

Percentage of Subjects Requiring Treatment for Gout Flares Between Weeks 8 and 52. [ Weeks 8 through 52 ]

Show Outcome Measure 14

Serious Adverse Events

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Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The agreement is:

	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed. Restriction Description: No publication related to study results will be published prior to publication of a multi-center report submitted for publication within 18 months after conclusion or termination of a study. Results publications will be submitted to sponsor for review 60 days in advance of publication. Sponsor can require removal of confidential information unrelated to study results. Sponsor can embargo a proposed publication for another 60 days to preserve intellectual property.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Sr. VP, Clinical Science
Organization: Takeda Global Research & Development Center, Inc.
phone: 800-778-2860
e-mail: clinicaltrialregistry@tpna.com

Publications of Results:

Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA, Streit J, Joseph-Ridge N. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005 Dec 8;353(23):2450-61.

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.

Responsible Party:	Takeda Global Research & Development Center, Inc. ( Sr. VP, Clinical Science )
Study ID Numbers:	C02-010
Study First Received:	January 29, 2005
Results First Received:	March 12, 2009
Last Updated:	August 17, 2009
ClinicalTrials.gov Identifier:	NCT00102440 History of Changes
Health Authority:	United States: Food and Drug Administration