Effect of Febuxostat on Renal Function in Patients With Gout and Moderate to Severe Renal Impairment

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01082640
• Collaborator: (none)
• Enrollment: 96
• Locations: 58
• Arms: 3
• Duration (Months): 25
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the effect of febuxostat, once daily (QD) or twice daily (BID), on renal function in gout patients with elevated serum urate levels and who have moderate to severe renal impairment.

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

Detailed Description

Gout is caused by high levels of uric acid in the body, and is associated with a broad range of conditions including heart disease, chronic kidney disease and high blood pressure. Hyperuricemia, which is defined as an elevation in serum urate levels, develops into gout when urate crystals form in the body and settle in joints and other organs.

Approximately 40-60% of patients with hyperuricemia and gout have some degree of renal impairment. Hyperuricemia has long been associated with renal disease, and chronic hyperuricemia as seen in gout can lead to deposition of urate crystals resulting in diminished renal function.

This study will evaluate the effect of febuxostat on the renal function of patients with hyperuricemia and gout and moderate to severe renal impairment.

All participants must have an average sitting blood pressure measurement less than 160 mmHg systolic and less than 95 mmHg diastolic. All participants must meet the American Rheumatism Association (ARA) diagnostic criteria for gout (subjects with tophi were excluded). Participants are expected to return to the site for approximately 10 visits.

Study Design

• Study Type: Interventional
• Actual Enrollment: 96 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-Blind, Phase 2 Study to Evaluate the Effect of Febuxostat Versus Placebo on Renal Function in Gout Subjects With Hyperuricemia and Moderate to Severe Renal Impairment
• Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: May 1, 2012
• Actual Study Completion Date: May 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo-matching capsules, orally, twice daily for up to 12 months.	Drug: Placebo; Febuxostat placebo-matching capsules
Experimental: Febuxostat 30 mg BID Febuxostat 30 mg, capsules, orally, twice daily (BID) for up to 12 months.	Drug: Febuxostat; Febuxostat capsules; Other Names: Uloric TMX-67
Experimental: Febuxostat 40/80 mg QD Participants initially received febuxostat 40 mg, capsules, once daily (QD) and one placebo-matching capsule QD and remained on this dose for up to 12 months if their serum urate (sUA) was <6.0 mg/dL at the Day 14 visit. Participants whose sUA was ≥6.0 mg/dL at the Day 14 visit received febuxostat 80 mg, capsule, QD, and one placebo-matching capsule QD at the Month 1 visit, and for the remainder of the study.	Drug: Febuxostat; Febuxostat capsules; Other Names: Uloric TMX-67 ; Drug: Placebo; Febuxostat placebo-matching capsules

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Month 12 in Serum Creatinine [Baseline and Month 12]

   Renal function was assessed by measuring the change from Baseline in serum creatinine. Analyses were conducted by the Central Laboratory.

Secondary Outcome Measures

1. Change From Baseline to Month 12 in Estimated Glomerular Filtration Rate (eGFR) [Baseline and Month 12]

   Change from baseline to Month 12 in estimated Glomerular Filtration Rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula (as calculated by the central laboratory).

2. Percentage of Participants With Serum Urate (sUA) Less Than 6 mg/dL at Month 12 [Month 12]

   Serum urate concentrations were determined using the enzymatic method as performed by the Central Laboratory.

3. Mean Clearance (CL/F) of Febuxostat at Steady State [The 2 pre-dose PK samples collected were collected at any 2 of the following visits: Months 3, 6, 9, and/or 12, at -0.25 to 0 hours. The 4 postdose PK samples were collected at Months 3, 6, and/or 9, at 0.25; 0.75 to 2.0; 2.5 to 4.0; and 5 to 12 hours.]

   Mean CL/F at steady state were estimated using a population pharmacokinetic (PK) approach, based on 2 PK samples collected prior to dosing, and 4 PK samples collected postdose.

4. Mean Area Under the Concentration-Time Curve During the Dosing Interval (AUC[0-τ]) of Febuxostat at Steady State [The 2 pre-dose PK samples collected were collected at any 2 of the following visits: Months 3, 6, 9, and/or 12, at -0.25 to 0 hours. The 4 postdose PK samples were collected at Months 3, 6, and/or 9, at 0.25; 0.75 to 2.0; 2.5 to 4.0; and 5 to 12 hours.]

   Mean AUC during the dosing interval at steady state was estimated using a population pharmacokinetic (PK) approach, based on 2 PK samples collected prior to dosing, and 4 PK samples collected postdose.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Must have a serum urate greater than 7 mg/dL and a serum creatinine greater than or equal to 1.5 mg at Day -21

• Must have a history or presence of gout defined as having one or more of the American Rheumatism Association criteria for the diagnosis of gout (the criteria related to tophi have been excluded for the purpose of the study)

• Must have an estimated Glomerular Filtration Rate (eGFR) of 15 or greater, or less than or equal to 50 mL/min, AND a serum creatinine greater than 1.5 mg/dL at Screening Visit Day -21

Exclusion Criteria:

• Has secondary hyperuricemia (eg, due to myeloproliferative disorder, or organ transplant)

• Has tophaceous gout

• Has a history of xanthinuria

• Has received aspirin greater than 325 mg/day within 35 days prior to Day 1/Randomization Visit

• Has known hypersensitivity or allergy to allopurinol or any component in its formulation

• Has known hypersensitivity to febuxostat or colchicine or any components in their formulation

• Has myocardial infarction or stroke within the 90 days prior to the Screening Visit

• Has alanine aminotransferase and/or aspartate aminotransferase values greater than 2.0 times the upper limit of normal

• Has end stage renal disease or is likely to be a candidate for dialysis over the 1 year study period

• Has a serum creatinine less than or equal to 1.5 mg/dL, or an estimated Glomerular Filtration Rate at Day -21 Screening Visit less than 15 mL/min or greater than 50 mL/min as calculated by the central laboratory

• Is required to take excluded medications

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Peoria	Arizona	United States
3		Sierra Vista	Arizona	United States
4		Tucson	Arizona	United States
5		Little Rock	Arkansas	United States
6		Huntington Park	California	United States
7		Irvine	California	United States
8		Lakewood	California	United States
9		Long Beach	California	United States
10		Sacramento	California	United States
11		San Diego	California	United States
12		San Jose	California	United States
13		Tustin	California	United States
14		Arvada	Colorado	United States
15		Westminster	Colorado	United States
16		Wheat Ridge	Colorado	United States
17		Middlebury	Connecticut	United States
18		Brandon	Florida	United States
19		Daytona Beach	Florida	United States
20		Jacksonville	Florida	United States
21		Miami	Florida	United States
22		Pinellas Park	Florida	United States
23		Port Charlotte	Florida	United States
24		Port Orange	Florida	United States
25		Augusta	Georgia	United States
26		Conyers	Georgia	United States
27		Dunwoody	Georgia	United States
28		Honolulu	Hawaii	United States
29		Boise	Idaho	United States
30		Evergreen Park	Illinois	United States
31		Springfield	Illinois	United States
32		Valparaiso	Indiana	United States
33		Wichita	Kansas	United States
34		Elizabethtown	Kentucky	United States
35		Paducah	Kentucky	United States
36		Baltimore	Maryland	United States
37		Detroit	Michigan	United States
38		Kalamazoo	Michigan	United States
39		Brooklyn Center	Minnesota	United States
40		Neptune City	New Jersey	United States
41		Morganton	North Carolina	United States
42		Wilmington	North Carolina	United States
43		Fargo	North Dakota	United States
44		Oklahoma City	Oklahoma	United States
45		Portland	Oregon	United States
46		Bethlehem	Pennsylvania	United States
47		Anderson	South Carolina	United States
48		Greer	South Carolina	United States
49		Chattanooga	Tennessee	United States
50		Houston	Texas	United States
51		Odessa	Texas	United States
52		San Antonio	Texas	United States
53		Danville	Virginia	United States
54		Fairfax	Virginia	United States
55		Richmond	Virginia	United States
56		Williamsburg	Virginia	United States
57		Clarksburg	West Virginia	United States
58		Wauwatosa	Wisconsin	United States

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Uloric Package Insert

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT01082640
• Other Study ID Numbers: TMX-67_203; U1111-1113-8008
• First Posted: Mar 8, 2010
• Last Update Posted: Sep 25, 2013
• Last Verified: Sep 1, 2013

• Keywords provided by Takeda: Gout; physiology; Hyperuricemia; Uric Acid; Drug Therapy
• Additional relevant MeSH terms: Renal Insufficiency; Febuxostat

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 46 investigative sites in the United States from 09 April 2010 to 31 May 2012.
Pre-assignment Detail	Participants meeting the American Rheumatism Association (ARA) diagnostic criteria for gout (subjects with tophi were excluded). were randomized to 1 of 3 arms in a 1:1:1 ratio to receive either febuxostat 40 mg/80 mg once daily (QD) or febuxostat 30 mg twice daily (BID) or placebo for up to 12 months.

Arm/Group Title	Placebo	Febuxostat 30 mg BID	Febuxostat 40/80 mg QD
Arm/Group Description	Placebo-matching capsules, orally, twice daily for up to 12 months.	Febuxostat 30 mg, capsules, orally, twice daily (BID) for up to 12 months.	Participants initially received 40 mg febuxostat once daily (QD) and remained on 40 mg QD for up to 12 months if their serum urate (sUA) was <6.0 mg/dL at the Day 14 visit. Participants whose sUA was ≥6.0 mg/dL at the Day 14 visit received febuxostat 80 mg QD at the Month 1 visit, and for the remainder of the study.
Period Title: Overall Study
STARTED	32	32	32
COMPLETED	15	17	24
NOT COMPLETED	17	15	8

Baseline Characteristics

Arm/Group Title	Placebo	Febuxostat 30 mg BID	Febuxostat 40/80 mg QD	Total
Arm/Group Description	Placebo-matching capsules, orally, twice daily for up to 12 months.	Febuxostat 30 mg, capsules, orally, twice daily (BID) for up to 12 months.	Participants initially received 40 mg febuxostat once daily (QD) and remained on 40 mg QD for up to 12 months if their serum urate (sUA) was <6.0 mg/dL at the Day 14 visit. Participants whose sUA was ≥6.0 mg/dL at the Day 14 visit received febuxostat 80 mg QD at the Month 1 visit, and for the remainder of the study.	Total of all reporting groups
Overall Participants	32	32	32	96
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.3 (12.05)	67.3 (11.11)	63.6 (8.15)	65.7 (10.57)
Sex: Female, Male (Count of Participants)
Female	6 18.8%	7 21.9%	6 18.8%	19 19.8%
Male	26 81.3%	25 78.1%	26 81.3%	77 80.2%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	3 9.4%	2 6.3%	3 9.4%	8 8.3%
Not Hispanic or Latino	29 90.6%	30 93.8%	29 90.6%	88 91.7%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	0 0%	1 3.1%	0 0%	1 1%
Asian	0 0%	2 6.3%	3 9.4%	5 5.2%
Native Hawaiian or Other Pacific Islander	2 6.3%	0 0%	1 3.1%	3 3.1%
Black or African American	4 12.5%	5 15.6%	7 21.9%	16 16.7%
White	25 78.1%	24 75%	21 65.6%	70 72.9%
Other	1 3.1%	0 0%	0 0%	1 1%
Region of Enrollment (participants) [Number]
United States	32 100%	32 100%	32 100%	96 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	172.6 (11.55)	173.8 (9.60)	172.8 (9.48)	173.1 (10.16)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	100.7 (27.54)	98.8 (19.84)	102.6 (25.85)	100.7 (24.42)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	33.3 (6.36)	32.8 (6.45)	34.2 (7.30)	33.4 (6.67)
Prior Use of ARB or ACEi (participants) [Number]
Angiotensin receptor blocker (ARB)	8 25%	8 25%	8 25%	24 25%
Angiotensin converting enzyme inhibitors (ACEi)	13 40.6%	13 40.6%	13 40.6%	39 40.6%
None	11 34.4%	11 34.4%	11 34.4%	33 34.4%
Renal History Based on Creatinine Clearance (participants) [Number]
Severely impaired	17 53.1%	9 28.1%	10 31.3%	36 37.5%
Moderately impaired	15 46.9%	23 71.9%	22 68.8%	60 62.5%
Serum creatinine level (participants) [Number]
Less than 2.0 mg/dL	10 31.3%	13 40.6%	14 43.8%	37 38.5%
2.0 to <2.5 mg/dL	7 21.9%	13 40.6%	9 28.1%	29 30.2%
Greater than 2.5 mg/dL	15 46.9%	6 18.8%	9 28.1%	30 31.3%
Serum Urate (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	10.8 (1.96)	10.4 (1.43)	10.4 (1.70)	10.5 (1.70)
Serum Urate Categories (participants) [Number]
<9.0 mg/dL	7 21.9%	5 15.6%	4 12.5%	16 16.7%
9.0 to <10.0 mg/dL	6 18.8%	6 18.8%	10 31.3%	22 22.9%
≥10 mg/dL	19 59.4%	21 65.6%	18 56.3%	58 60.4%
Gout flares in the past year (participnts) [Number]
1-3 flares	21	16	19	56
4-6 flares	4	8	3	15
More than 6	2	3	5	10
Time since last gout flare (participants) [Number]
Less than 1 month ago	5 15.6%	5 15.6%	5 15.6%	15 15.6%
1 to less than 4 months ago	2 6.3%	7 21.9%	5 15.6%	14 14.6%
4 to less than 6 months ago	4 12.5%	4 12.5%	2 6.3%	10 10.4%
6 to less than 12 months ago	14 43.8%	8 25%	11 34.4%	33 34.4%
more than 1 year ago	7 21.9%	8 25%	9 28.1%	24 25%
Previous urate-lowering therapy (participants) [Number]
Febuxostat	0 0%	5 15.6%	2 6.3%	7 7.3%
Allopurinol	19 59.4%	22 68.8%	21 65.6%	62 64.6%
Probenecid	0 0%	0 0%	1 3.1%	1 1%
None	11 34.4%	6 18.8%	9 28.1%	26 27.1%
Other	3 9.4%	2 6.3%	2 6.3%	7 7.3%
Number of Lifetime Kidney Stone Episodes (episodes) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [episodes]	4.8 (3.90)	3.0 (1.67)	1.8 (1.78)	2.8 (2.56)
Kidney Stone Passage (participants) [Number]
Number [participants]	2 6.3%	1 3.1%	3 9.4%	6 6.3%
Composition of most recent passed stone (participants) [Number]
Calcium Oxalate	1 3.1%	0 0%	1 3.1%	2 2.1%
Uric acid	1 3.1%	0 0%	1 3.1%	2 2.1%
Calcium citrate	0 0%	0 0%	1 3.1%	1 1%
Mixed	0 0%	1 3.1%	0 0%	1 1%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Month 12 in Serum Creatinine
Description	Renal function was assessed by measuring the change from Baseline in serum creatinine. Analyses were conducted by the Central Laboratory.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Full analysis set, including all patients who were randomized and received at least 1 dose of double-blind study medication. Only patients with both a baseline value and at least 1 value during the double-blind treatment period are included in the analysis. Missing data were imputed as carrying forward the last observed post-baseline value.

Arm/Group Title	Placebo	Febuxostat 30 mg BID	Febuxostat 40/80 mg QD
Arm/Group Description	Placebo-matching capsules, orally, twice daily for up to 12 months.	Febuxostat 30 mg, capsules, orally, twice daily (BID) for up to 12 months.	Participants initially received 40 mg febuxostat once daily (QD) and remained on 40 mg QD for up to 12 months if their serum urate (sUA) was <6.0 mg/dL at the Day 14 visit. Participants whose sUA was ≥6.0 mg/dL at the Day 14 visit received febuxostat 80 mg QD at the Month 1 visit, and for the remainder of the study.
Measure Participants	32	32	31
Baseline	2.52 (0.126)	2.10 (0.126)	2.22 (0.128)
Change from Baseline at Month 12	0.19 (0.094)	0.09 (0.093)	0.23 (0.094)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat 30 mg BID
	Comments	All statistical tests were two sided and conducted at the 0.05 significance level.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.459
	Comments	No adjustment for multiplicity was made.
	Method	ANCOVA
	Comments	The model included treatment as a factor, and the baseline value and prior use of an ARB or an ACEi or none as covariates.
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.37 to 0.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.134
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat 40/80 mg QD
	Comments	All statistical tests were two sided and conducted at the 0.05 significance level.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.789
	Comments	No adjustment for multiplicity was made.
	Method	ANCOVA
	Comments	The model included treatment as a factor, and the baseline value and prior use of an ARB or an ACEi or none as covariates.
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.133
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline to Month 12 in Estimated Glomerular Filtration Rate (eGFR)
Description	Change from baseline to Month 12 in estimated Glomerular Filtration Rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula (as calculated by the central laboratory).
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Full analysis set with available data at Baseline. and at least 1 post-baseline value. Missing data was imputed as carrying forward the last post-baseline value.

Arm/Group Title	Placebo	Febuxostat 30 mg BID	Febuxostat 40/80 mg QD
Arm/Group Description	Placebo-matching capsules, orally, twice daily for up to 12 months.	Febuxostat 30 mg, capsules, orally, twice daily (BID) for up to 12 months.	Participants initially received 40 mg febuxostat once daily (QD) and remained on 40 mg QD for up to 12 months if their serum urate (sUA) was <6.0 mg/dL at the Day 14 visit. Participants whose sUA was ≥6.0 mg/dL at the Day 14 visit received febuxostat 80 mg QD at the Month 1 visit, and for the remainder of the study.
Measure Participants	32	32	31
Baseline	29.31 (1.461)	34.14 (1.461)	34.08 (1.484)
Change from Baseline at Month 12	-2.05 (1.198)	0.33 (1.172)	-0.86 (0.190)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat 30 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.162
	Comments	No adjustment for multiplicity was made.
	Method	ANCOVA
	Comments	The model included treatment as a factor, and the baseline value and prior use of an ARB or an ACEi or none as covariates.
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	2.38
	Confidence Interval	(2-Sided) 95%; -0.97 to 5.73
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.687
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat 40/80 mg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.485
	Comments	No adjustment for multiplicity was made.
	Method	ANCOVA
	Comments	The model included treatment as a factor, and the baseline value and prior use of an ARB or an ACEi or none as covariates.
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95%; -2.18 to 4.57
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.698
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants With Serum Urate (sUA) Less Than 6 mg/dL at Month 12
Description	Serum urate concentrations were determined using the enzymatic method as performed by the Central Laboratory.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

Full analysis set, including all patients who were randomized and received at least 1 dose of double-blind study medication. A patient was included in the analysis only when there was at least 1 value during the double-blind treatment period. Missing data were imputed as carrying forward the last observed post-baseline value.

Arm/Group Title	Placebo	Febuxostat 30 mg BID	Febuxostat 40/80 mg QD
Arm/Group Description	Placebo-matching capsules, orally, twice daily for up to 12 months.	Febuxostat 30 mg, capsules, orally, twice daily (BID) for up to 12 months.	Participants initially received 40 mg febuxostat once daily (QD) and remained on 40 mg QD for up to 12 months if their serum urate (sUA) was <6.0 mg/dL at the Day 14 visit. Participants whose sUA was ≥6.0 mg/dL at the Day 14 visit received febuxostat 80 mg QD at the Month 1 visit, and for the remainder of the study.
Measure Participants	32	32	31
Number [percentage of participants]	0 0%	68.8 215%	45.2 141.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat 30 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Prior use of an ARB, ACEi, or none was a stratification variable.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat 40/80 mg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Prior use of an ARB, ACEi, or none was a stratification variable.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 30 mg BID, Febuxostat 40/80 mg QD
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.062
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Prior use of an ARB, ACEi, or none was a stratification variable.

4. Secondary Outcome

Title	Mean Clearance (CL/F) of Febuxostat at Steady State
Description	Mean CL/F at steady state were estimated using a population pharmacokinetic (PK) approach, based on 2 PK samples collected prior to dosing, and 4 PK samples collected postdose.
Time Frame	The 2 pre-dose PK samples collected were collected at any 2 of the following visits: Months 3, 6, 9, and/or 12, at -0.25 to 0 hours. The 4 postdose PK samples were collected at Months 3, 6, and/or 9, at 0.25; 0.75 to 2.0; 2.5 to 4.0; and 5 to 12 hours.

Outcome Measure Data

Analysis Population Description

Participants who received febuxostat and had available data for PK analysis.

Arm/Group Title	Febuxostat 30 mg BID	Febuxostat 40 mg QD	Febuxostat 80 mg QD
Arm/Group Description	Febuxostat 30 mg, capsules, orally, twice daily (BID) for up to 12 months.	Participants initially received 40 mg febuxostat once daily (QD) and remained on 40 mg QD for up to 12 months if their serum urate (sUA) was <6.0 mg/dL at the Day 14 visit.	Participants with serum urate levels ≥6.0 mg/dL at the Day 14 visit received febuxostat 80 mg QD from the Month 1 visit through Month 12.
Measure Participants	25	9	20
Mean (Standard Deviation) [liters/hour]	8.16 (2.31)	8.71 (2.21)	10.9 (4.70)

5. Secondary Outcome

Title	Mean Area Under the Concentration-Time Curve During the Dosing Interval (AUC[0-τ]) of Febuxostat at Steady State
Description	Mean AUC during the dosing interval at steady state was estimated using a population pharmacokinetic (PK) approach, based on 2 PK samples collected prior to dosing, and 4 PK samples collected postdose.
Time Frame	The 2 pre-dose PK samples collected were collected at any 2 of the following visits: Months 3, 6, 9, and/or 12, at -0.25 to 0 hours. The 4 postdose PK samples were collected at Months 3, 6, and/or 9, at 0.25; 0.75 to 2.0; 2.5 to 4.0; and 5 to 12 hours.

Outcome Measure Data

Analysis Population Description

Participants who received febuxostat and had available data for PK analysis.

Arm/Group Title	Febuxostat 30 mg BID	Febuxostat 40 mg QD	Febuxostat 80 mg QD
Arm/Group Description	Febuxostat 30 mg, capsules, orally, twice daily (BID) for up to 12 months.	Participants initially received 40 mg febuxostat once daily (QD) and remained on 40 mg QD for up to 12 months if their serum urate (sUA) was <6.0 mg/dL at the Day 14 visit.	Participants with serum urate levels ≥6.0 mg/dL at the Day 14 visit received febuxostat 80 mg QD from the Month 1 visit through Month 12.
Measure Participants	25	9	20
Mean (Standard Deviation) [hr*µg/mL]	3.98 (1.21)	4.91 (1.29)	8.21 (2.30)

Adverse Events

Time Frame	From first double-blind dose date and up to 30 days after the last dose.
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Placebo		Febuxostat 30 mg BID		Febuxostat 40/80 mg QD
Arm/Group Description	Placebo-matching capsules, orally, twice daily for up to 12 months.		Febuxostat 30 mg, capsules, orally, twice daily (BID) for up to 12 months.		Participants initially received 40 mg febuxostat once daily (QD) and remained on 40 mg QD for up to 12 months if their serum urate (sUA) was <6.0 mg/dL at the Day 14 visit. Participants whose sUA was ≥6.0 mg/dL at the Day 14 visit received febuxostat 80 mg QD at the Month 1 visit, and for the remainder of the study.
All Cause Mortality
	Placebo		Febuxostat 30 mg BID		Febuxostat 40/80 mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Febuxostat 30 mg BID		Febuxostat 40/80 mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/32 (21.9%)		5/32 (15.6%)		8/32 (25%)
Cardiac disorders
Cardiac Failure Congestive	0/32 (0%)		1/32 (3.1%)		1/32 (3.1%)
Cardiogenic Shock	0/32 (0%)		0/32 (0%)		1/32 (3.1%)
Acute Myocardial Infarction	2/32 (6.3%)		0/32 (0%)		1/32 (3.1%)
Atrial Fibrillation	0/32 (0%)		0/32 (0%)		2/32 (6.3%)
Cardiac Arrest	1/32 (3.1%)		0/32 (0%)		0/32 (0%)
Ventricular Fibrillation	0/32 (0%)		0/32 (0%)		1/32 (3.1%)
Gastrointestinal disorders
Diarrhoea	0/32 (0%)		0/32 (0%)		1/32 (3.1%)
Gastrooesophageal Reflux Disease	0/32 (0%)		1/32 (3.1%)		0/32 (0%)
General disorders
Adverse Drug Reaction	0/32 (0%)		0/32 (0%)		1/32 (3.1%)
Hepatobiliary disorders
Cholecystitis	0/32 (0%)		0/32 (0%)		1/32 (3.1%)
Cholelithiasis	0/32 (0%)		0/32 (0%)		1/32 (3.1%)
Infections and infestations
Urinary Tract Infection	1/32 (3.1%)		0/32 (0%)		0/32 (0%)
Injury, poisoning and procedural complications
Fall	0/32 (0%)		0/32 (0%)		1/32 (3.1%)
Metabolism and nutrition disorders
Type 2 Diabetes Mellitus	0/32 (0%)		1/32 (3.1%)		0/32 (0%)
Hyperkalaemia	0/32 (0%)		0/32 (0%)		1/32 (3.1%)
Dehydration	1/32 (3.1%)		0/32 (0%)		0/32 (0%)
Fluid Overload	1/32 (3.1%)		0/32 (0%)		0/32 (0%)
Musculoskeletal and connective tissue disorders
Flank Pain	1/32 (3.1%)		0/32 (0%)		0/32 (0%)
Musculoskeletal Pain	1/32 (3.1%)		0/32 (0%)		0/32 (0%)
Pain In Extremity	0/32 (0%)		1/32 (3.1%)		0/32 (0%)
Nervous system disorders
Cerebrovascular Accident	1/32 (3.1%)		0/32 (0%)		0/32 (0%)
Renal and urinary disorders
Renal Failure	1/32 (3.1%)		0/32 (0%)		0/32 (0%)
Renal Failure Acute	2/32 (6.3%)		1/32 (3.1%)		1/32 (3.1%)
Renal Failure Chronic	0/32 (0%)		0/32 (0%)		1/32 (3.1%)
Renal Impairment	1/32 (3.1%)		0/32 (0%)		0/32 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/32 (0%)		1/32 (3.1%)		0/32 (0%)
Chronic Obstructive Pulmonary Disease	1/32 (3.1%)		0/32 (0%)		0/32 (0%)
Respiratory Failure	0/32 (0%)		1/32 (3.1%)		1/32 (3.1%)
Vascular disorders
Deep Vein Thrombosis	0/32 (0%)		0/32 (0%)		1/32 (3.1%)
Iliac Artery Occlusion	0/32 (0%)		1/32 (3.1%)		0/32 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Febuxostat 30 mg BID		Febuxostat 40/80 mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/32 (62.5%)		21/32 (65.6%)		23/32 (71.9%)
Gastrointestinal disorders
Diarrhoea	4/32 (12.5%)		2/32 (6.3%)		4/32 (12.5%)
Nausea	3/32 (9.4%)		2/32 (6.3%)		0/32 (0%)
Vomiting	3/32 (9.4%)		2/32 (6.3%)		0/32 (0%)
Gastritis	1/32 (3.1%)		0/32 (0%)		2/32 (6.3%)
General disorders
Oedema peripheral	2/32 (6.3%)		1/32 (3.1%)		2/32 (6.3%)
Immune system disorders
Drug hypersensitivity	0/32 (0%)		2/32 (6.3%)		0/32 (0%)
Infections and infestations
Bronchitis	2/32 (6.3%)		3/32 (9.4%)		0/32 (0%)
Nasopharyngitis	0/32 (0%)		2/32 (6.3%)		1/32 (3.1%)
Urinary tract infection	2/32 (6.3%)		2/32 (6.3%)		1/32 (3.1%)
Injury, poisoning and procedural complications
Fall	2/32 (6.3%)		0/32 (0%)		0/32 (0%)
Investigations
Blood creatinine increased	1/32 (3.1%)		5/32 (15.6%)		2/32 (6.3%)
Hepatic enzyme increased	0/32 (0%)		2/32 (6.3%)		0/32 (0%)
C-Reactive protein increased	0/32 (0%)		0/32 (0%)		2/32 (6.3%)
Blood creatine phosphokinase increased	1/32 (3.1%)		1/32 (3.1%)		2/32 (6.3%)
Metabolism and nutrition disorders
Hyperkalaemia	2/32 (6.3%)		1/32 (3.1%)		4/32 (12.5%)
Hypokalaemia	2/32 (6.3%)		0/32 (0%)		0/32 (0%)
Hypoglycaemia	2/32 (6.3%)		0/32 (0%)		0/32 (0%)
Musculoskeletal and connective tissue disorders
Back pain	1/32 (3.1%)		2/32 (6.3%)		2/32 (6.3%)
Pain in extremity	2/32 (6.3%)		3/32 (9.4%)		3/32 (9.4%)
Arthralgia	3/32 (9.4%)		3/32 (9.4%)		3/32 (9.4%)
Arthritis	0/32 (0%)		0/32 (0%)		2/32 (6.3%)
Muscle spasms	2/32 (6.3%)		2/32 (6.3%)		1/32 (3.1%)
Osteoarthritis	0/32 (0%)		2/32 (6.3%)		0/32 (0%)
Tendonitis	0/32 (0%)		2/32 (6.3%)		1/32 (3.1%)
Nervous system disorders
Headache	1/32 (3.1%)		2/32 (6.3%)		0/32 (0%)
Dizziness	1/32 (3.1%)		2/32 (6.3%)		1/32 (3.1%)
Psychiatric disorders
Depression	0/32 (0%)		2/32 (6.3%)		0/32 (0%)
Renal and urinary disorders
Renal impairment	2/32 (6.3%)		0/32 (0%)		1/32 (3.1%)
Skin and subcutaneous tissue disorders
Rash	0/32 (0%)		2/32 (6.3%)		1/32 (3.1%)
Vascular disorders
Hypotension	0/32 (0%)		0/32 (0%)		3/32 (9.4%)
Hypertension	2/32 (6.3%)		1/32 (3.1%)		0/32 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.