Phase 3, Febuxostat, Allopurinol and Placebo-Controlled Study in Gout Subjects. - 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 Drug: Placebo

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Subjects were enrolled at 167 investigative sites in the United States from 21 February 2003 to 07 April 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	Febuxostat 240 mg QD	Allopurinol QD	Placebo QD
STARTED	267	269	134	268	134
COMPLETED	174	200	86	211	101
NOT COMPLETED	93	69	48	57	33
Lost to Follow-up	19	17	9	17	10
Adverse Event	18	16	11	18	5
Personal Reason(s)	16	16	9	9	9
Other	15	8	6	5	3
Gout Flare	13	6	8	1	0
Protocol Violation	6	3	3	6	3
Therapeutic Failure	6	3	2	1	3

	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Febuxostat 240 mg QD	Allopurinol QD	Placebo QD	Total
Number of Participants [units: participants]	267	269	134	268	134	1072
Age, Customized [units: subjects]
<45 years	82	79	33	82	36	312
45 years to <65 years	146	154	71	147	79	597
≥65 years	39	36	30	39	19	163
Age [units: years] Mean ± Standard Deviation	50.6 ± 12.24	51.2 ± 11.57	54.3 ± 12.83	51.8 ± 12.25	51.5 ± 12.18	51.6 ± 12.17
Gender [units: subjects]
Female	16	13	8	19	11	67
Male	251	256	126	249	123	1005
Race/Ethnicity, Customized [units: subjects]
White	200	214	107	206	108	835
Black or African American	38	27	13	33	9	120
Hispanic	13	16	8	17	10	64
Asian	8	8	1	6	3	26
Other	8	4	5	6	4	27
Body Mass Index [units: subjects]
<18.5 kilogram per meter² (kg/m²)	0	0	0	0	0	0
18.5 kg/m² to <25 kg/m²	10	11	9	15	16	61
25 kg/m² to <30 kg/m²	85	81	42	91	48	347
≥30 kg/m²	172	176	83	161	70	662
missing	0	1	0	1	0	2
Presence of a Primary PalpableTophus [units: subjects]
Yes	48	53	25	64	29	219
No, but other tophi present	0	3	1	1	1	6
No, and no other tophi present	219	213	108	203	104	847
Serum Creatinine [units: subjects]
≤1.5 milligram per deciliter (mg/dL)	258	258	129	258	129	1032
>1.5 mg/dL	9	11	5	10	5	40

Outcome Measures

1. Primary:

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

Hide Outcome Measure 1

Measure Type	Primary
Measure Title	Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram 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 (any last 3 visits up to week 28)
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 all randomized subjects who took at least 1 dose of study drug and had a baseline serum urate ≥8.0 mg/dL. If subject prematurely discontinued from study before at least 3 serum urate levels were obtained, subject was considered a nonresponder; if at least 3 serum urate were obtained postbaseline, those 3 visits were used.

Reporting Groups

	Description
Febuxostat 80 mg QD	Febuxostat 80 mg, orally, once daily for up to 28 weeks.
Febuxostat 120 mg QD	Febuxostat 120 mg, orally, once daily for up to 28 weeks.
Febuxostat 240 mg QD	Febuxostat 240 mg, orally, once daily for up to 28 weeks.
Allopurinol QD	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 QD	Placebo, orally, once daily for up to 28 weeks.

Measured Values

	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Febuxostat 240 mg QD	Allopurinol QD	Placebo QD
Number of Participants Analyzed [units: participants]	262	269	134	268	134
Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram Per Deciliter (mg/dL). [units: Percentage of subjects]	48	65	69	22	0

Statistical Analysis 1 for Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram Per Deciliter (mg/dL).

Groups ^[1]	Febuxostat 80 mg QD vs. Placebo QD
Method ^[2]	Cochran-Mantel-Haenszel
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:
	The Cochran-Mantel-Haenszel test was stratified by baseline renal function (serum creatinine ≤1.5 mg/dL versus [v.] >1.5 mg/dL).
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The overall 0.05 level of significance for the multiple comparisons of each febuxostat dose to placebo was controlled using Hochberg's method. The p-value was statistically significant.

Statistical Analysis 2 for Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram Per Deciliter (mg/dL).

Groups ^[1]	Febuxostat 120 mg QD vs. Placebo QD
Method ^[2]	Cochran-Mantel-Haenszel
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:
	The Cochran-Mantel-Haenszel test was stratified by baseline renal function (serum creatinine ≤1.5 mg/dL v. >1.5 mg/dL).
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The overall 0.05 level of significance for the multiple comparisons of each febuxostat dose to placebo was controlled using Hochberg's method. The p-value was statistically significant.

Statistical Analysis 3 for Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram Per Deciliter (mg/dL).

Groups ^[1]	Febuxostat 240 mg QD vs. Placebo QD
Method ^[2]	Cochran-Mantel-Haenszel
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:
	The Cochran-Mantel-Haenszel test was stratified by baseline renal function (serum creatinine ≤1.5 mg/dL v. >1.5 mg/dL).
[3]	Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
	The overall 0.05 level of significance for the multiple comparisons of each febuxostat dose to placebo was controlled using Hochberg's method. The p-value was statistically significant.

Statistical Analysis 4 for Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram Per Deciliter (mg/dL).

Groups ^[1]	Febuxostat 80 mg QD vs. Allopurinol QD
Non-Inferiority/Equivalence Test ^[2]	Yes
Difference in percentage ^[3]	25.7
97.5% Confidence Interval	( 16.7 to 34.7 )

[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 5 for Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram Per Deciliter (mg/dL).

Groups ^[1]	Febuxostat 120 mg QD vs. Allopurinol QD
Non-Inferiority/Equivalence Test ^[2]	Yes
Difference in percentage ^[3]	42.7
97.5% Confidence Interval	( 34.0 to 51.3 )

[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 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 6 for Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram Per Deciliter (mg/dL).

Groups ^[1]	Febuxostat 80 mg QD vs. Allopurinol QD
Method ^[2]	Cochran-Mantel-Haenszel
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:
	The Cochran-Mantel-Haenszel test was stratified by baseline renal function (serum creatinine ≤1.5 mg/dL v. >1.5 mg/dL).
[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. The p-value was statistically significant.

Statistical Analysis 7 for Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram Per Deciliter (mg/dL).

Groups ^[1]	Febuxostat 120 mg QD vs. Allopurinol QD
Method ^[2]	Cochran-Mantel-Haenszel
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:
	The Cochran-Mantel-Haenszel test was stratified by baseline renal function (serum creatinine ≤1.5 mg/dL v. >1.5 mg/dL).
[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. The p-value was statistically significant.

Statistical Analysis 8 for Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram Per Deciliter (mg/dL).

Groups ^[1]	Febuxostat 80 mg QD vs. Febuxostat 120 mg QD
Method ^[2]	Cochran-Mantel-Haenszel
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:
	The Cochran-Mantel-Haenszel test was stratified by baseline renal function (serum creatinine ≤1.5 mg/dL v. >1.5 mg/dL).
[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.

Statistical Analysis 9 for Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram Per Deciliter (mg/dL).

Groups ^[1]	Febuxostat 240 mg QD vs. Allopurinol QD
Method ^[2]	Cochran-Mantel-Haenszel
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:
	The Cochran-Mantel-Haenszel test was stratified by baseline renal function (serum creatinine ≤1.5 mg/dL v. >1.5 mg/dL).
[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.

Statistical Analysis 10 for Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram Per Deciliter (mg/dL).

Groups ^[1]	Febuxostat 80 mg QD vs. Febuxostat 240 mg QD
Method ^[2]	Cochran-Mantel-Haenszel
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:
	The Cochran-Mantel-Haenszel test was stratified by baseline renal function (serum creatinine ≤1.5 mg/dL v. >1.5 mg/dL).
[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.

Statistical Analysis 11 for Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram Per Deciliter (mg/dL).

Groups ^[1]	Febuxostat 120 mg QD vs. Febuxostat 240 mg QD
Method ^[2]	Cochran-Mantel-Haenszel
P Value ^[3]	0.479

[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:
	The Cochran-Mantel-Haenszel test was stratified by baseline renal function (serum creatinine ≤1.5 mg/dL v. >1.5 mg/dL).
[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.

Statistical Analysis 12 for Percentage of Subjects Whose Last Three Serum Urate Levels Are <6.0 Milligram Per Deciliter (mg/dL).

Groups ^[1]	Allopurinol QD vs. Placebo QD
Method ^[2]	Cochran-Mantel-Haenszel
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:
	The Cochran-Mantel-Haenszel test was stratified by baseline renal function (serum creatinine ≤1.5 mg/dL v. >1.5 mg/dL).
[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 Whose Serum Urate Levels Are <6.0 mg/dL at Week 28 [ Week 28 ]

Show Outcome Measure 2

3. Secondary:

Percentage of Subjects Whose Serum Urate Levels Are <6.0 mg/dL at Final Visit [ Final Visit (up to 28 weeks). ]

Show Outcome Measure 3

4. Secondary:

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

Show Outcome Measure 4

5. Secondary:

Percent Change From Baseline in Serum Urate Levels at Final Visit [ Baseline and Final Visit (up to 28 weeks) ]

Show Outcome Measure 5

6. Secondary:

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. [ Baseline and Week 28 ]

Show Outcome Measure 6

7. Secondary:

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. [ Baseline and Final Visit (up to 28 weeks) ]

Show Outcome Measure 7

8. Secondary:

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

Show Outcome Measure 8

9. Secondary:

Change in the Total Number of Tophi at Final Visit in the Subset of Subjects With Palpable Tophi at the Screening Visit [ Final Visit (up to 28 weeks) ]

Show Outcome Measure 9

10. Secondary:

Percentage of Subjects Requiring Treatment for a Gout Flare Between Weeks 8 and 28 of the Double-Blind Treatment Period. [ Weeks 8 through 28 ]

Show Outcome Measure 10

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:

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.

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. ( Senior Vice President, Clinical Science )
Study ID Numbers:	C02-009
Study First Received:	September 9, 2005
Results First Received:	March 12, 2009
Last Updated:	August 13, 2009
ClinicalTrials.gov Identifier:	NCT00174915 History of Changes
Health Authority:	United States: Food and Drug Administration