Dose-Response, Safety and Efficacy of Febuxostat in Subjects With Gout - Study Results

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

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Subjects were enrolled at 24 investigative sites from 31 January 2001 to 9 July 2001

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

	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
STARTED	37	40	38	38
COMPLETED	36	37	36	36
NOT COMPLETED	1	3	2	2
Adverse Event	1	2	2	1
Gout Flare	0	0	0	1
Not Specified	0	1	0	0

	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD	Total
Number of Participants [units: participants]	37	40	38	38	153
Age, Customized [units: subjects]
<45 years	8	10	7	12	37
45 years to <65 years	21	19	23	17	80
≥65 years	8	11	8	9	36
Age [units: years] Mean ± Standard Deviation	52.2 ± 14.04	55.2 ± 13.09	56.2 ± 10.83	52.4 ± 12.63	54.0 ± 12.69
Gender [units: subjects]
Female	4	2	5	6	17
Male	33	38	33	32	136
Race/Ethnicity, Customized [units: subjects]
White	32	35	34	32	133
Black or African American	3	3	2	3	11
Hispanic	1	1	1	1	4
Asian	0	1	1	0	2
Other	1	0	0	2	3
Body Mass Index [units: subjects]
≤25 kilogram per meter² (kg/m²)	2	3	3	0	8
>25 kg/m² to 30 kg/m²	12	12	14	13	51
>30 kg/m² to 35 kg/m²	16	12	12	16	56
>35 kg/m² to 40 kg/m²	4	7	5	6	22
>40 kg/m²	3	6	3	3	15
missing	0	0	1	0	1

Measure Type	Primary
Measure Title	Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 Milligram Per Deciliter (mg/dL) at the Day 28 Visit.
Measure Description	Serum urate values were obtained at the Day 28 visit. The percentage of subjects whose serum urate decreased to <6.0 mg/dL at the Day 28 visit was summarized.
Time Frame	Day 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 performed on intent-to-treat (ITT) subjects, defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥8.0 mg/dL. The last observation carried forward (LOCF) method was used to impute missing data. The baseline value was carried forward if no postbaseline visits were available.

Reporting Groups

	Description
Febuxostat 40 mg QD	Febuxostat 40 mg, orally, once daily.
Febuxostat 80 mg QD	Febuxostat 80 mg, orally, once daily.
Febuxostat 120 mg QD	Febuxostat 120 mg, orally, once daily.
Placebo QD	Placebo, orally, once daily

Measured Values

	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Number of Participants Analyzed [units: participants]	34	37	34	35
Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 Milligram Per Deciliter (mg/dL) at the Day 28 Visit. [units: percentage of subjects]	56	76	94	0

Statistical Analysis 1 for Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 Milligram Per Deciliter (mg/dL) at the Day 28 Visit.

Groups ^[1]	Febuxostat 40 mg QD vs. Placebo 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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using Fisher’s exact test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 2 for Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 Milligram Per Deciliter (mg/dL) at the Day 28 Visit.

Groups ^[1]	Febuxostat 80 mg QD vs. Placebo 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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using Fisher’s exact test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 3 for Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 Milligram Per Deciliter (mg/dL) at the Day 28 Visit.

Groups ^[1]	Febuxostat 120 mg QD vs. Placebo 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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using Fisher’s exact test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Measure Type	Secondary
Measure Title	Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 7 Visit.
Measure Description	Serum urate values were obtained at the Day 7 visit. The percentage of subjects whose serum urate decreased to <6.0 mg/dL at the Day 7 visit was summarized.
Time Frame	Day 7.
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.
The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. The LOCF method was used to impute missing data. The baseline value was carried forward if no post-baseline visits were available.

Reporting Groups

	Description
Febuxostat 40 mg QD	Febuxostat 40 mg, orally, once daily.
Febuxostat 80 mg QD	Febuxostat 80 mg, orally, once daily.
Febuxostat 120 mg QD	Febuxostat 120 mg, orally, once daily.
Placebo QD	Placebo, orally, once daily

Measured Values

	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Number of Participants Analyzed [units: participants]	34	37	34	35
Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 7 Visit. [units: percentage of subjects]	50	59	91	3

Statistical Analysis 1 for Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 7 Visit.

Groups ^[1]	Febuxostat 40 mg QD vs. Placebo 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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using Fisher’s exact test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 2 for Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 7 Visit.

Groups ^[1]	Febuxostat 80 mg QD vs. Placebo 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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using Fisher’s exact test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 3 for Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 7 Visit.

Groups ^[1]	Febuxostat 120 mg QD vs. Placebo 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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using Fisher’s exact test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Measure Type	Secondary
Measure Title	Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 14 Visit.
Measure Description	Serum urate values were obtained at the Day 14 visit. The percentage of subjects whose serum urate decreased to <6.0 mg/dL at the Day 14 visit was summarized.
Time Frame	Day 14.
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.
The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. The LOCF method was used to impute missing data. The baseline value was carried forward if no post-baseline visits were available.

Reporting Groups

	Description
Febuxostat 40 mg QD	Febuxostat 40 mg, orally, once daily.
Febuxostat 80 mg QD	Febuxostat 80 mg, orally, once daily.
Febuxostat 120 mg QD	Febuxostat 120 mg, orally, once daily.
Placebo QD	Placebo, orally, once daily

Measured Values

	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Number of Participants Analyzed [units: participants]	34	37	34	35
Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 14 Visit. [units: percentage of subjects]	56	68	94	0

Statistical Analysis 1 for Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 14 Visit.

Groups ^[1]	Febuxostat 40 mg QD vs. Placebo 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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using Fisher’s exact test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 2 for Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 14 Visit.

Groups ^[1]	Febuxostat 80 mg QD vs. Placebo 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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using Fisher’s exact test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 3 for Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 14 Visit.

Groups ^[1]	Febuxostat 120 mg QD vs. Placebo 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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using Fisher’s exact test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Measure Type	Secondary
Measure Title	Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 21 Visit.
Measure Description	Serum urate values were obtained at the Day 21 visit. The percentage of subjects whose serum urate decreased to <6.0 mg/dL at the Day 21 visit was summarized.
Time Frame	Day 21.
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.
The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. The LOCF method was used to impute missing data. The baseline value was carried forward if no post-baseline visits were available.

Reporting Groups

	Description
Febuxostat 40 mg QD	Febuxostat 40 mg, orally, once daily.
Febuxostat 80 mg QD	Febuxostat 80 mg, orally, once daily.
Febuxostat 120 mg QD	Febuxostat 120 mg, orally, once daily.
Placebo QD	Placebo, orally, once daily

Measured Values

	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Number of Participants Analyzed [units: participants]	34	37	34	35
Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 21 Visit. [units: percentage of subjects]	59	76	97	0

Statistical Analysis 1 for Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 21 Visit.

Groups ^[1]	Febuxostat 40 mg QD vs. Placebo 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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using Fisher’s exact test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 2 for Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 21 Visit.

Groups ^[1]	Febuxostat 80 mg QD vs. Placebo 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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using Fisher’s exact test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 3 for Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 21 Visit.

Groups ^[1]	Febuxostat 120 mg QD vs. Placebo 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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using Fisher’s exact test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Measure Type	Secondary
Measure Title	Percent Change in Serum Urate Levels From Baseline to the Day 7 Visit.
Measure Description	Serum urate values were obtained at the Day 7 visit. The percent change in serum urate from baseline to the Day 7 visit was summarized.
Time Frame	Baseline and Day 7.
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.
The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. The LOCF method was used to impute missing data. The baseline value was carried forward if no post-baseline visits were available.

Reporting Groups

	Description
Febuxostat 40 mg QD	Febuxostat 40 mg, orally, once daily.
Febuxostat 80 mg QD	Febuxostat 80 mg, orally, once daily.
Febuxostat 120 mg QD	Febuxostat 120 mg, orally, once daily.
Placebo QD	Placebo, orally, once daily

Measured Values

	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Number of Participants Analyzed [units: participants]	34	37	34	35
Percent Change in Serum Urate Levels From Baseline to the Day 7 Visit. [units: percent change from baseline] Mean ± Standard Deviation	-35.0 ± 9.67	-39.2 ± 15.9	-53.44 ± 12.3	0.71 ± 12.6

Statistical Analysis 1 for Percent Change in Serum Urate Levels From Baseline to the Day 7 Visit.

Groups ^[1]	Febuxostat 40 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 2 for Percent Change in Serum Urate Levels From Baseline to the Day 7 Visit.

Groups ^[1]	Febuxostat 80 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 3 for Percent Change in Serum Urate Levels From Baseline to the Day 7 Visit.

Groups ^[1]	Febuxostat 120 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Measure Type	Secondary
Measure Title	Percent Change in Serum Urate Levels From Baseline to the Day 14 Visit.
Measure Description	Serum urate values were obtained at the Day 14 visit. The percent change in serum urate from baseline to the Day 14 visit was summarized.
Time Frame	Baseline and Day 14.
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.
The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. The LOCF method was used to impute missing data. The baseline value was carried forward if no post-baseline visits were available.

Reporting Groups

	Description
Febuxostat 40 mg QD	Febuxostat 40 mg, orally, once daily.
Febuxostat 80 mg QD	Febuxostat 80 mg, orally, once daily.
Febuxostat 120 mg QD	Febuxostat 120 mg, orally, once daily.
Placebo QD	Placebo, orally, once daily

Measured Values

	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Number of Participants Analyzed [units: participants]	34	37	34	35
Percent Change in Serum Urate Levels From Baseline to the Day 14 Visit. [units: percent change from baseline] Mean ± Standard Deviation	-37.1 ± 11.70	-41.8 ± 14.63	-56.9 ± 8.36	1.62 ± 10.21

Statistical Analysis 1 for Percent Change in Serum Urate Levels From Baseline to the Day 14 Visit.

Groups ^[1]	Febuxostat 40 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 2 for Percent Change in Serum Urate Levels From Baseline to the Day 14 Visit.

Groups ^[1]	Febuxostat 80 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 3 for Percent Change in Serum Urate Levels From Baseline to the Day 14 Visit.

Groups ^[1]	Febuxostat 120 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Measure Type	Secondary
Measure Title	Percent Change in Serum Urate Levels From Baseline to the Day 21 Visit
Measure Description	Serum urate values were obtained at the Day 21 visit. The percent change in serum urate from baseline to the Day 21 visit was summarized.
Time Frame	Baseline and Day 21.
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.
The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. The last observation carried forward (LOCF) method was used to impute missing data. The baseline value was carried forward if no post-baseline visits were available.

Reporting Groups

	Description
Febuxostat 40 mg QD	Febuxostat 40 mg, orally, once daily.
Febuxostat 80 mg QD	Febuxostat 80 mg, orally, once daily.
Febuxostat 120 mg QD	Febuxostat 120 mg, orally, once daily.
Placebo QD	Placebo, orally, once daily

Measured Values

	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Number of Participants Analyzed [units: participants]	34	37	34	35
Percent Change in Serum Urate Levels From Baseline to the Day 21 Visit [units: percent change from baseline] Mean ± Standard Deviation	-37.3 ± 11.30	-43.9 ± 16.3	-59.4 ± 7.58	-0.57 ± 10.63

Statistical Analysis 1 for Percent Change in Serum Urate Levels From Baseline to the Day 21 Visit

Groups ^[1]	Febuxostat 40 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 2 for Percent Change in Serum Urate Levels From Baseline to the Day 21 Visit

Groups ^[1]	Febuxostat 80 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 3 for Percent Change in Serum Urate Levels From Baseline to the Day 21 Visit

Groups ^[1]	Febuxostat 120 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Measure Type	Secondary
Measure Title	Percent Change in Serum Urate Levels From Baseline to the Day 28 Visit.
Measure Description	Serum urate values were obtained at the Day 28 visit. The percent change in serum urate from baseline to the Day 28 visit was summarized.
Time Frame	Baseline and Day 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.
The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. The LOCF method was used to impute missing data. The baseline value was carried forward if no post-baseline visits were available.

Reporting Groups

	Description
Febuxostat 40 mg QD	Febuxostat 40 mg, orally, once daily.
Febuxostat 80 mg QD	Febuxostat 80 mg, orally, once daily.
Febuxostat 120 mg QD	Febuxostat 120 mg, orally, once daily.
Placebo QD	Placebo, orally, once daily

Measured Values

	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Number of Participants Analyzed [units: participants]	34	37	34	35
Percent Change in Serum Urate Levels From Baseline to the Day 28 Visit. [units: percent change from baseline] Mean ± Standard Deviation	-36.6 ± 12.07	-44.3 ± 17.53	-59.1 ± 9.92	-2.2 ± 12.5

Statistical Analysis 1 for Percent Change in Serum Urate Levels From Baseline to the Day 28 Visit.

Groups ^[1]	Febuxostat 40 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 2 for Percent Change in Serum Urate Levels From Baseline to the Day 28 Visit.

Groups ^[1]	Febuxostat 80 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 3 for Percent Change in Serum Urate Levels From Baseline to the Day 28 Visit.

Groups ^[1]	Febuxostat 120 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Measure Type	Secondary
Measure Title	Maximum Percent Change in Serum Urate Level From Baseline During the Entire Treatment Period.
Measure Description	Serum urate values were obtained at the Day 7, 14, 21,and 28 visits. The maximum percent change in serum urate levels obtained at any visit was summarized.
Time Frame	Baseline and Any visit (Day 7, 14, 21,or 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.
The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL.

Reporting Groups

	Description
Febuxostat 40 mg QD	Febuxostat 40 mg, orally, once daily.
Febuxostat 80 mg QD	Febuxostat 80 mg, orally, once daily.
Febuxostat 120 mg QD	Febuxostat 120 mg, orally, once daily.
Placebo QD	Placebo, orally, once daily

Measured Values

	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Number of Participants Analyzed [units: participants]	34	37	34	35
Maximum Percent Change in Serum Urate Level From Baseline During the Entire Treatment Period. [units: percent change from baseline] Mean ± Standard Deviation	42.5 ± 10.04	49.2 ± 13.24	62.8 ± 7.05	10.0 ± 11.12

Statistical Analysis 1 for Maximum Percent Change in Serum Urate Level From Baseline During the Entire Treatment Period.

Groups ^[1]	Febuxostat 40 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 2 for Maximum Percent Change in Serum Urate Level From Baseline During the Entire Treatment Period.

Groups ^[1]	Febuxostat 80 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 3 for Maximum Percent Change in Serum Urate Level From Baseline During the Entire Treatment Period.

Groups ^[1]	Febuxostat 120 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Measure Type	Secondary
Measure Title	Percent Change in 24-hour Urine Uric Acid Level From Baseline to Day 28.
Measure Description	24-hour urine uric acid levels were obtained at the Day 28 visit. The percent change in 24-hour urine uric acid level from baseline to the Day 28 visit was summarized.
Time Frame	Baseline and Day 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.
The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. Missing data was not imputed

Reporting Groups

	Description
Febuxostat 40 mg QD	Febuxostat 40 mg, orally, once daily.
Febuxostat 80 mg QD	Febuxostat 80 mg, orally, once daily.
Febuxostat 120 mg QD	Febuxostat 120 mg, orally, once daily.
Placebo QD	Placebo, orally, once daily

Measured Values

	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Number of Participants Analyzed [units: participants]	33	35	34	34
Percent Change in 24-hour Urine Uric Acid Level From Baseline to Day 28. [units: percent change from baseline] Mean ± Standard Deviation	-43.6 ± 28.9	-46.5 ± 27.0	-45.7 ± 30.1	5.9 ± 37.1

Statistical Analysis 1 for Percent Change in 24-hour Urine Uric Acid Level From Baseline to Day 28.

Groups ^[1]	Febuxostat 40 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 2 for Percent Change in 24-hour Urine Uric Acid Level From Baseline to Day 28.

Groups ^[1]	Febuxostat 80 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Statistical Analysis 3 for Percent Change in 24-hour Urine Uric Acid Level From Baseline to Day 28.

Groups ^[1]	Febuxostat 120 mg QD vs. Placebo QD
Method ^[2]	t-test, 2 sided
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:
	Pairwise comparisons between placebo and each of the febuxostat treatment groups were performed using a t-test. Adjustment for multiple comparisons was made using Hochberg’s procedure.

Responsible Party:	Takeda Global Research & Development Center, Inc. ( Sr. VP, Clinical Science )
Study ID Numbers:	TMX-00-004
Study First Received:	September 9, 2005
Results First Received:	March 12, 2009
Last Updated:	August 13, 2009
ClinicalTrials.gov Identifier:	NCT00174967 History of Changes
Health Authority:	United States: Food and Drug Administration