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

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00174967
• Collaborator: (none)
• Enrollment: 153
• Arms: 4
• Duration (Months): 5.9

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the efficacy of febuxostat, once daily (QD), in reducing serum urate levels in subjects with gout.

Condition or Disease	Intervention/Treatment	Phase
Gout	Drug: Placebo; Drug: Febuxostat; Drug: Febuxostat; Drug: Febuxostat	Phase 2

Detailed Description

Gout is a chronic urate crystal deposition disorder, which if left untreated may result in progressive disease characterized by joint and bone destruction from tophaceous deposits and renal impairment due to gouty nephropathy. Hyperuricemia, defined as a serum urate concentration of >7.0 milligrams per deciliter (mg/dL), is the underlying metabolic aberration leading to urate crystal deposition in gout. Gout has several clinical presentations, including: recurrent acute attacks of inflammatory arthritis; deposition of monosodium urate monohydrate crystals in joints, bones and even parenchymal organs (tophaceous gout); renal impairment; and uric acid nephrolithiasis. As serum urate levels increase beyond >7.0 mg/dL, the risks for gouty arthritis or for renal calculi increase.

Currently allopurinol is the only xanthine oxidase inhibitor available. Allopurinol is the agent of choice for reduction of serum urate levels in patients with: uric acid overproduction; unresponsive or intolerant to uricosuric agents; impaired renal function; uric acid urolithiasis; or tophi.

Febuxostat (TMX-67) is a non-purine selective xanthine oxidase inhibitor being developed as an orally administered agent for management of hyperuricemia in patients with gout.

Study Design

• Study Type: Interventional
• Actual Enrollment: 153 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Diagnostic
• Official Title: Phase II, Dose-Response, Safety and Efficacy Study of Oral TMX-67 in Subjects With Gout.
• Study Start Date: Jan 1, 2001
• Actual Primary Completion Date: Jul 1, 2001
• Actual Study Completion Date: Jul 1, 2001

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo QD	Drug: Placebo; Febuxostat placebo-matching tablets, orally, once daily for up to 4 weeks.
Experimental: Febuxostat 40 mg QD	Drug: Febuxostat; Febuxostat 40 mg, tablets, orally, once daily for up to 4 weeks.; Other Names: TMX-67 Tei-6720 Uloric
Experimental: Febuxostat 80 mg QD	Drug: Febuxostat; Febuxostat 80 mg, tablets, orally, once daily for up to 4 weeks.; Other Names: TMX-67 Tei-6720 Uloric
Experimental: Febuxostat 120 mg QD	Drug: Febuxostat; Febuxostat 120 mg, tablets, orally, once daily for up to 4 weeks.; Other Names: TMX-67 Tei-6720 Uloric

Outcome Measures

Primary Outcome Measures

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

   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.

Secondary Outcome Measures

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

   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.

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

   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.

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

   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.

4. Percent Change in Serum Urate Levels From Baseline to the Day 7 Visit. [Baseline and Day 7.]

   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.

5. Percent Change in Serum Urate Levels From Baseline to the Day 14 Visit. [Baseline and Day 14.]

   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.

6. Percent Change in Serum Urate Levels From Baseline to the Day 21 Visit [Baseline and Day 21.]

   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.

7. Percent Change in Serum Urate Levels From Baseline to the Day 28 Visit. [Baseline and Day 28.]

   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.

8. Maximum Percent Change in Serum Urate Level From Baseline During the Entire Treatment Period. [Baseline and Any visit (Day 7, 14, 21,or 28)]

   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.

9. Percent Change in 24-hour Urine Uric Acid Level From Baseline to Day 28. [Baseline and Day 28.]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Hyperuricemia (serum uric acid ≥8.0 mg/dL).

• Must meet American College of Rheumatology criteria for gout.

• Must have adequate renal function (serum creatinine <1.5 mg/dL).

• Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.

Exclusion Criteria:

• History of xanthinuria

• Alcohol consumption >14/week

• Has a history of significant concomitant illness.

• Has active liver disease.

• Has a body mass index greater than 50 kilogram per meter² (kg/m²)

• Any other significant medical condition that would interfere with the treatment, safety or compliance with the protocol, as defined by the investigator.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Takeda

Investigators

• Study Chair: Medical Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Uloric Package Insert

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00174967
• Other Study ID Numbers: TMX-00-004; U1111-1114-1992
• First Posted: Sep 15, 2005
• Last Update Posted: Jul 29, 2011
• Last Verified: Jul 1, 2011

• Keywords provided by , ,: Uric Acid; xanthine oxidase; tophi; Drug Therapy
• Additional relevant MeSH terms: Gout; Febuxostat

Study Results

Participant Flow

Recruitment Details	Subjects were enrolled at 24 investigative sites from 31 January 2001 to 9 July 2001
Pre-assignment Detail	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.

Arm/Group Title	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Arm/Group Description	Febuxostat 40 mg, orally, once daily.	Febuxostat 80 mg, orally, once daily.	Febuxostat 120 mg, orally, once daily.	Placebo, orally, once daily
Period Title: Overall Study
STARTED	37	40	38	38
COMPLETED	36	37	36	36
NOT COMPLETED	1	3	2	2

Baseline Characteristics

Arm/Group Title	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD	Total
Arm/Group Description	Febuxostat 40 mg, orally, once daily.	Febuxostat 80 mg, orally, once daily.	Febuxostat 120 mg, orally, once daily.	Placebo, orally, once daily	Total of all reporting groups
Overall Participants	37	40	38	38	153
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.2 (14.04)	55.2 (13.09)	56.2 (10.83)	52.4 (12.63)	54.0 (12.69)
Age, Customized (participants) [Number]
<45 years	8 21.6%	10 25%	7 18.4%	12 31.6%	37 24.2%
45 years to <65 years	21 56.8%	19 47.5%	23 60.5%	17 44.7%	80 52.3%
≥65 years	8 21.6%	11 27.5%	8 21.1%	9 23.7%	36 23.5%
Sex: Female, Male (Count of Participants)
Female	4 10.8%	2 5%	5 13.2%	6 15.8%	17 11.1%
Male	33 89.2%	38 95%	33 86.8%	32 84.2%	136 88.9%
Race/Ethnicity, Customized (participants) [Number]
White	32 86.5%	35 87.5%	34 89.5%	32 84.2%	133 86.9%
Black or African American	3 8.1%	3 7.5%	2 5.3%	3 7.9%	11 7.2%
Hispanic	1 2.7%	1 2.5%	1 2.6%	1 2.6%	4 2.6%
Asian	0 0%	1 2.5%	1 2.6%	0 0%	2 1.3%
Other	1 2.7%	0 0%	0 0%	2 5.3%	3 2%
Body Mass Index (participants) [Number]
≤25 kilogram per meter² (kg/m²)	2 5.4%	3 7.5%	3 7.9%	0 0%	8 5.2%
>25 kg/m² to 30 kg/m²	12 32.4%	12 30%	14 36.8%	13 34.2%	51 33.3%
>30 kg/m² to 35 kg/m²	16 43.2%	12 30%	12 31.6%	16 42.1%	56 36.6%
>35 kg/m² to 40 kg/m²	4 10.8%	7 17.5%	5 13.2%	6 15.8%	22 14.4%
>40 kg/m²	3 8.1%	6 15%	3 7.9%	3 7.9%	15 9.8%
missing	0 0%	0 0%	1 2.6%	0 0%	1 0.7%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Arm/Group Description	Febuxostat 40 mg, orally, once daily.	Febuxostat 80 mg, orally, once daily.	Febuxostat 120 mg, orally, once daily.	Placebo, orally, once daily
Measure Participants	34	37	34	35
Number [percentage of subjects]	56	76	94	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 80 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 120 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	Fisher Exact
	Comments

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Arm/Group Description	Febuxostat 40 mg, orally, once daily.	Febuxostat 80 mg, orally, once daily.	Febuxostat 120 mg, orally, once daily.	Placebo, orally, once daily
Measure Participants	34	37	34	35
Number [percentage of subjects]	50	59	91	3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 80 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 120 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	Fisher Exact
	Comments

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Arm/Group Description	Febuxostat 40 mg, orally, once daily.	Febuxostat 80 mg, orally, once daily.	Febuxostat 120 mg, orally, once daily.	Placebo, orally, once daily
Measure Participants	34	37	34	35
Number [percentage of subjects]	56	68	94	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 80 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 120 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	Fisher Exact
	Comments

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Arm/Group Description	Febuxostat 40 mg, orally, once daily.	Febuxostat 80 mg, orally, once daily.	Febuxostat 120 mg, orally, once daily.	Placebo, orally, once daily
Measure Participants	34	37	34	35
Number [percentage of subjects]	59	76	97	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 80 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 120 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	Fisher Exact
	Comments

5. Secondary Outcome

Title	Percent Change in Serum Urate Levels From Baseline to the Day 7 Visit.
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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Arm/Group Description	Febuxostat 40 mg, orally, once daily.	Febuxostat 80 mg, orally, once daily.	Febuxostat 120 mg, orally, once daily.	Placebo, orally, once daily
Measure Participants	34	37	34	35
Mean (Standard Deviation) [percent change from baseline]	-35.0 (9.67)	-39.2 (15.9)	-53.44 (12.3)	0.71 (12.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 80 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 120 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

6. Secondary Outcome

Title	Percent Change in Serum Urate Levels From Baseline to the Day 14 Visit.
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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Arm/Group Description	Febuxostat 40 mg, orally, once daily.	Febuxostat 80 mg, orally, once daily.	Febuxostat 120 mg, orally, once daily.	Placebo, orally, once daily
Measure Participants	34	37	34	35
Mean (Standard Deviation) [percent change from baseline]	-37.1 (11.70)	-41.8 (14.63)	-56.9 (8.36)	1.62 (10.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 80 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 120 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

7. Secondary Outcome

Title	Percent Change in Serum Urate Levels From Baseline to the Day 21 Visit
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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Arm/Group Description	Febuxostat 40 mg, orally, once daily.	Febuxostat 80 mg, orally, once daily.	Febuxostat 120 mg, orally, once daily.	Placebo, orally, once daily
Measure Participants	34	37	34	35
Mean (Standard Deviation) [percent change from baseline]	-37.3 (11.30)	-43.9 (16.3)	-59.4 (7.58)	-0.57 (10.63)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 80 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 120 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

8. Secondary Outcome

Title	Percent Change in Serum Urate Levels From Baseline to the Day 28 Visit.
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.

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Arm/Group Description	Febuxostat 40 mg, orally, once daily.	Febuxostat 80 mg, orally, once daily.	Febuxostat 120 mg, orally, once daily.	Placebo, orally, once daily
Measure Participants	34	37	34	35
Mean (Standard Deviation) [percent change from baseline]	-36.6 (12.07)	-44.3 (17.53)	-59.1 (9.92)	-2.2 (12.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 80 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 120 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

9. Secondary Outcome

Title	Maximum Percent Change in Serum Urate Level From Baseline During the Entire Treatment Period.
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)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Arm/Group Description	Febuxostat 40 mg, orally, once daily.	Febuxostat 80 mg, orally, once daily.	Febuxostat 120 mg, orally, once daily.	Placebo, orally, once daily
Measure Participants	34	37	34	35
Mean (Standard Deviation) [percent change from baseline]	42.5 (10.04)	49.2 (13.24)	62.8 (7.05)	10.0 (11.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 80 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 120 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

10. Secondary Outcome

Title	Percent Change in 24-hour Urine Uric Acid Level From Baseline to Day 28.
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.

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Febuxostat 40 mg QD	Febuxostat 80 mg QD	Febuxostat 120 mg QD	Placebo QD
Arm/Group Description	Febuxostat 40 mg, orally, once daily.	Febuxostat 80 mg, orally, once daily.	Febuxostat 120 mg, orally, once daily.	Placebo, orally, once daily
Measure Participants	33	35	34	34
Mean (Standard Deviation) [percent change from baseline]	-43.6 (28.9)	-46.5 (27.0)	-45.7 (30.1)	5.9 (37.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 80 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 120 mg QD, Placebo QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	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.
	Method	t-test, 2 sided
	Comments

Adverse Events

Arm/Group Title	Febuxostat 40 mg QD		Febuxostat 80 mg QD		Febuxostat 120 mg QD		Placebo QD
Arm/Group Description	Febuxostat 40 mg, orally, once daily.		Febuxostat 80 mg, orally, once daily.		Febuxostat 120 mg, orally, once daily.		Placebo, orally, once daily
All Cause Mortality
	Febuxostat 40 mg QD		Febuxostat 80 mg QD		Febuxostat 120 mg QD		Placebo QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Febuxostat 40 mg QD		Febuxostat 80 mg QD		Febuxostat 120 mg QD		Placebo QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		1/40 (2.5%)		2/38 (5.3%)		0/38 (0%)
General disorders
Back Pain	0/37 (0%)		0/40 (0%)		1/38 (2.6%)		0/38 (0%)
Nervous system disorders
Delirium	0/37 (0%)		1/40 (2.5%)		0/38 (0%)		0/38 (0%)
Guillian Barre Syndrome	0/37 (0%)		1/40 (2.5%)		0/38 (0%)		0/38 (0%)
Psychiatric disorders
Suicide Attempt	0/37 (0%)		0/40 (0%)		1/38 (2.6%)		0/38 (0%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	0/37 (0%)		1/40 (2.5%)		0/38 (0%)		0/38 (0%)
Other (Not Including Serious) Adverse Events
	Febuxostat 40 mg QD		Febuxostat 80 mg QD		Febuxostat 120 mg QD		Placebo QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/37 (48.6%)		19/40 (47.5%)		16/38 (42.1%)		17/38 (44.7%)
Gastrointestinal disorders
Diarrhoea	1/37 (2.7%)		8/40 (20%)		4/38 (10.5%)		4/38 (10.5%)
Dyspepsia	1/37 (2.7%)		2/40 (5%)		0/38 (0%)		0/38 (0%)
Increased Appetite	2/37 (5.4%)		0/40 (0%)		0/38 (0%)		0/38 (0%)
General disorders
Abdominal Pain	1/37 (2.7%)		1/40 (2.5%)		2/38 (5.3%)		3/38 (7.9%)
Back Pain	3/37 (8.1%)		2/40 (5%)		2/38 (5.3%)		1/38 (2.6%)
Flu Syndrome	1/37 (2.7%)		0/40 (0%)		1/38 (2.6%)		2/38 (5.3%)
Pain	6/37 (16.2%)		3/40 (7.5%)		2/38 (5.3%)		4/38 (10.5%)
Infections and infestations
Infection	1/37 (2.7%)		0/40 (0%)		1/38 (2.6%)		2/38 (5.3%)
Injury, poisoning and procedural complications
Accidental Injury	0/37 (0%)		2/40 (5%)		1/38 (2.6%)		0/38 (0%)
Investigations
Liver Function Tests Abnormal	2/37 (5.4%)		1/40 (2.5%)		1/38 (2.6%)		1/38 (2.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/37 (5.4%)		1/40 (2.5%)		2/38 (5.3%)		0/38 (0%)
Myalgia	1/37 (2.7%)		1/40 (2.5%)		2/38 (5.3%)		2/38 (5.3%)
Nervous system disorders
Headache	3/37 (8.1%)		2/40 (5%)		2/38 (5.3%)		1/38 (2.6%)
Respiratory, thoracic and mediastinal disorders
Pharyngitis	0/37 (0%)		1/40 (2.5%)		0/38 (0%)		2/38 (5.3%)
Skin and subcutaneous tissue disorders
Rash	0/37 (0%)		1/40 (2.5%)		3/38 (7.9%)		0/38 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.