Effect of Febuxostat on Joint Damage in Hyperuricemic Subjects With Early Gout

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01078389
• Collaborator: (none)
• Enrollment: 314
• Locations: 56
• Arms: 2
• Duration (Months): 42.1
• Patients Per Site: 5.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This purpose of this study is to assess the effect of febuxostat, once daily (QD), on joint damage in patients with elevated serum urate levels and gout.

Condition or Disease	Intervention/Treatment	Phase
Joint Damage	Drug: Febuxostat; Drug: Placebo for Febuxostat	Phase 2

Detailed Description

Gout is caused by high levels of uric acid in the body, and is associated with a broad range of comorbidities including heart disease, chronic kidney disease and additional risk factors like obesity and high blood pressure. Hyperuricemia, which is defined as an elevation in serum urate levels, develops into gout when urate crystals form from supersaturated body fluids and settle in joints and other organs. Urate-lowering therapy is used to treat hyperuricemia in patients with gout.

Current treatments focus on initiating urate-lowering therapy in hyperuricemic gout patients who have experienced multiple acute gout flares within the past year. However, joint damage caused by crystal deposition may occur much earlier than previously considered. Monosodium urate crystals have been found present in the joints of people with hyperuricemia who do not have any symptoms. The presence of monosodium urate crystals would indicate that after the crystals form, they stay within the joint if serum urate levels are not reduced. Lowering uric acid levels and maintaining them may reduce acute gout flare episodes and possibly halt or reduce joint damage in patients with gout.

This study will evaluate the effect of febuxostat on joint damage in hyperuricemic patients with early gout. All patients will receive gout flare prophylaxis for the first 6 months of the study. Gout flares may also be treated throughout the study.

A variety of imaging techniques are in use to evaluate gout. Plain radiographs (x-rays), Magnetic Resonance Imaging (MRI) and Dual Energy Computed Tomography (DECT) will be utilized in this study. The modified Sharp/Van Der Heijde scoring method (named after Drs. Sharp and Van Der Heijde) for assessment of x-rays has been validated in patients with chronic gout and will be used in this study for evaluating erosion and joint space narrowing. Participants are expected to have 15 visits which will include plain radiographic examinations at 5 visits, 3 Magnetic Resonance Imaging (MRI) examinations and 3 DECT procedures at selected sites.

Study Design

• Study Type: Interventional
• Actual Enrollment: 314 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 in Joint Damage in Hyperuricemic Subjects With Early Gout
• Study Start Date: Mar 1, 2010
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Febuxostat 40 mg or 80 mg Febuxostat 40 mg or 80 mg (based on serum urate levels at Day 14), capsules, orally, once daily for up to 24 Months.	Drug: Febuxostat; Febuxostat capsules; Other Names: Uloric TMX-67
Placebo Comparator: Placebo Febuxostat placebo-matching capsules, orally, once daily for up to 24 Months.	Drug: Placebo for Febuxostat; Febuxostat placebo-matching capsules

Outcome Measures

Primary Outcome Measures

1. Mean Change From Baseline to Month 24 in the Modified Sharp/Van Der Heijde Erosion Score of the Single Affected Joint [Baseline and Month 24]

   The single affected joint was defined as the joint with the history of the first acute gout flare. Radiographs (X-rays) of this single joint in the hands or feet were evaluated using the modified Sharp/van der Heijde method. Each erosion was assessed using a 4-point scale where 0=no erosions (best) to 3=large erosion passing the mid-line (worst). Individual erosion scores were summed to a maximum erosion score of 5 for joints in the hands and 10 for joints in the feet. Higher scores indicated more joint damage. A negative change from Baseline indicated improvement.

Secondary Outcome Measures

1. Mean Change From Baseline to Month 24 in the Modified Sharp/Van Der Heijde Total Scores From Full Hands and Feet Radiographs [Baseline and Month 24]

   Radiographs (X-rays) of 40 joints in the hands and 12 joints in the feet were evaluated using the modified Sharp/van der Heijde method. Each erosion was assessed using a 4-point scale where 0=no erosions (best) to 3=large erosion passing the mid-line (worst) for a total erosion score range of 0 to 320. Joint space narrowing (JSN) was assessed using a 5-point scale where 0=normal (best) to 4=absence of joint space, presumptive evidence of ankyloses, or complete luxation (worst) for a total JSN score range of 0 to 208. The Erosion Score and the JSN Score were combined for a total possible score of 0 to 528. Higher scores indicated more joint damage. A negative change from Baseline indicated improvement.

2. Mean Change From Baseline to Month 24 in the Modified Sharp/Van Der Heijde Erosion Scores From Full Hands and Feet Radiographs [Baseline and Month 24]

   Radiographs (X-rays) of 40 joints in the hands and 12 joints in the feet were evaluated using the modified Sharp/van der Heijde method. Each erosion was assessed using a 4-point scale where 0=no erosions (best) to 3=large erosion passing the mid-line (worst) for a total erosion score range of 0 to 320. Higher scores indicated more joint damage. A negative change from Baseline indicated improvement.

3. Mean Change From Baseline to Month 24 in the Rheumatoid Arthritis MRI Scoring System (RAMRIS) Score of the Single Affected Joint [Baseline and Month 24]

   The single affected joint was defined as the joint with the history of the first acute gout flare. Magnetic Resonance Imaging (MRI) was evaluated using the Rheumatoid Arthritis MRI Score (RAMRIS). Bone erosion in the proximal and distal location were each assessed in the affected joint using an 11-point scale where 0=no erosion (best) to 10=91-100% bone eroded (worst) for a bone erosion score range of 0 to 20. Bone marrow edema in the proximal and distal location were each assessed using a 4-point scale where 0=no edema (best) to 3=67-100% edema (worst) for a bone marrow edema (BME) score range of 0 to 6. Synovitis was assessed in the affected joint using a 4-point scale where 0=normal (best) to 3=severe (worst). Higher scores indicated more joint damage. A negative change from Baseline indicated improvement.

4. Mean Change From Baseline to Month 24 in the Modified Sharp/Van Der Heijde Total Score of the Single Affected Joint [Baseline and Month 24]

   The single affected joint was defined as the joint with the history of the first acute gout flare. Radiographs (X-rays) of the single affected joint in the hands or feet were evaluated using the modified Sharp/van der Heijde method. Each erosion was assessed using a 4-point scale where 0=no erosions (best) to 3=large erosion passing the mid-line (worst) and Joint space narrowing (JSN) was assessed using a 5-point scale where 0=normal (best) to 4=absence of joint space, presumptive evidence of ankyloses, or complete luxation (worst). The Erosion Score and the JSN Score were summed for the Total Score. Higher scores indicated more joint damage. A negative change from Baseline indicated improvement.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• The participant, or the participant's legally acceptable representative, signs a written informed consent form/Health Insurance Portability & Accountability Act (HIPAA) Authorization prior to the initiation of any study procedures.

• Must have a history or presence of gout defined as having one or more of the following conditions of the American Rheumatism Association (ARA) preliminary criteria for the diagnosis of gout

• A tophus proven to contain urate crystals by chemical or polarized light microscopic means and/or

• Characteristic urate crystals in the joint fluid and/or

• History of at least 6 of the following clinical, laboratory and x-ray phenomena*: *More than one flare criteria will be excluded for the purpose of this study if the participant has a history of only a single acute gout flare.

• More than one attack of acute arthritis*

• maximum inflammation developed within 1 day

• monoarticular arthritis

• redness observed over joints

• first metatarsophalangeal joint painful or swollen

• unilateral first metatarsophalangeal joint attack

• unilateral tarsal joint attack

• tophus (proven or suspected)

• hyperuricemia

• asymmetric swelling within a joint on x-ray

• sub-cortical cysts without erosions on x-ray

• joint fluid culture negative for organisms during attacks

• *More than one flare criteria will be excluded for the purpose of this study if the participant has a history of only a single acute gout flare.

• Is male and at least 18 years of age OR;

• Female ≥45 years of age and at least 2 years post-menopausal AND has a Follicle Stimulating Hormone (FSH) level ≥40 IU/L OR

• Female receiving hormone replacement therapy (HRT) must be ≥55 years of age (FSH level not required).

• Has hyperuricemia defined as serum Uric Acid (sUA) level ≥7.0 mg/dL at Screening.

• Has a history of ≤2 (1 or 2) flares. In participants with a history of 2 flares, must have had only one flare in any 12 month period. The primary affected joint will be based on the location of the first gout flare which must be located within right or left metatarsophalangeal (MTP), interphalangeal (IP), ankle, metacarpophalangeal (MCP), Proximal Inter-Phalangeal (PIP), or distal inter-phalangeal (DIP) joints prior to Screening.

• Is capable of understanding and complying with protocol requirements, including scheduled clinic procedures.

Exclusion Criteria:

• Previously on urate-lowering therapy (allopurinol, febuxostat or probenecid).

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

• Has a history of xanthinuria.

• Has a known hypersensitivity to any component of the febuxostat formulation.

• Has rheumatoid arthritis.

• Has active peptic ulcer disease.

• Has a history of cancer, except basal cell carcinoma of the skin, which has not been in remission for at least 5 years prior to the first dose of study medication.

• Has experienced either a myocardial infarction (MI) or stroke within 90 days prior to the Screening visit.

• Has alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) values greater than 2.0 the upper limit of normal during the Screening period.

• Has a significant medical condition and/or conditions that would interfere with the treatment, safety or compliance with the protocol at the discretion of the Investigator.

• Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse with 5 years prior to the Screening visit. Participant consumes >14 alcoholic beverages/week.

• Has received any investigational medicinal product within 30 days prior to the Screening visit. In addition, the participant has been previously randomized into this study and received at least one dose of double blind study drug treatment.

• Has an estimated Glomerular filtration rate (eGFR) <60 mL/min calculated using the Modification of Diet in Renal Disease (MDRD) formula by the Central Laboratory.

• Has a serum creatinine at Screening greater than 2.0 mg/dL.

• Has a known history of infection with hepatitis B, hepatitis C or human immunodeficiency virus.

• Is a study site employee, or is an immediate family member (ie, spouse, parent, child, and sibling) of a study site employee involved in conduct of this study.

• Is unable to understand verbal or written English or any other language for which a certified translation of the approved informed consent form is available.

• Is required to take excluded medications.

• Magnetic Resolution Imaging:

• Has a known hypersensitivity to gadolinium

• Has history of severe asthma

• Has an electronically, magnetically or mechanically activated implanted device

• Has any object that could present a potential hazard or interfere with MRI interpretation secondary to the artifact (i.e. metallic foreign bodies)

• Has a significant medical condition considered by the Investigator (or radiologist) to interfere with the participant's ability to receive gadolinium (eg Sickle cell anemia).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Mesa	Arizona	United States
2		Tucson	Arizona	United States
3		Burbank	California	United States
4		Carmichael	California	United States
5		Costa Mesa	California	United States
6		Irvine	California	United States
7		Orange	California	United States
8		Rancho Cucamonga	California	United States
9		San Diego	California	United States
10		San Luis Obispo	California	United States
11		Trumbull	Connecticut	United States
12		Boynton Beach	Florida	United States
13		Daytona Beach	Florida	United States
14		Fort Lauderdale	Florida	United States
15		Hialeah	Florida	United States
16		Miami	Florida	United States
17		Sanford	Florida	United States
18		Tampa	Florida	United States
19		Winter Park	Florida	United States
20		Honolulu	Hawaii	United States
21		Arlington Heights	Illinois	United States
22		Avon	Indiana	United States
23		Greenfield	Indiana	United States
24		Wichita	Kansas	United States
25		Rockport	Maine	United States
26		Chaska	Minnesota	United States
27		Belzoni	Mississippi	United States
28		Olive Branch	Mississippi	United States
29		Billings	Montana	United States
30		Missoula	Montana	United States
31		Bellevue	Nebraska	United States
32		Henderson	Nevada	United States
33		Las Vegas	Nevada	United States
34		Albuquerque	New Mexico	United States
35		Charlotte	North Carolina	United States
36		Lenoir	North Carolina	United States
37		Shelby	North Carolina	United States
38		Dayton	Ohio	United States
39		Franklin	Ohio	United States
40		Willoughby Hills	Ohio	United States
41		Oklahoma City	Oklahoma	United States
42		Eugene	Oregon	United States
43		Duncansville	Pennsylvania	United States
44		East Providence	Rhode Island	United States
45		Columbia	South Carolina	United States
46		Rapid City	South Dakota	United States
47		Kingsport	Tennessee	United States
48		Austin	Texas	United States
49		Houston	Texas	United States
50		San Antonio	Texas	United States
51		Southlake	Texas	United States
52		Sugar Land	Texas	United States
53		Arlington	Virginia	United States
54		Burke	Virginia	United States
55		Manassas	Virginia	United States
56		Kenosha	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: NCT01078389
• Other Study ID Numbers: TMX-67_204; U1111-1113-8098
• First Posted: Mar 2, 2010
• Last Update Posted: Sep 10, 2014
• Last Verified: Sep 1, 2014

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

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 65 investigative sites in the United States from 10 March 2010 to 3 September 2013.
Pre-assignment Detail	Participants with a diagnosis of gout were enrolled equally in 1 of 2 treatment groups, once a day placebo or febuxostat 40 mg or 80 mg based on serum urate levels.

Arm/Group Title	Febuxostat 40 mg or 80 mg	Placebo
Arm/Group Description	Febuxostat 40 mg or 80 mg (based on serum urate levels at Day 14), capsules, orally, once daily for up to 24 Months.	Febuxostat placebo-matching capsules, orally, once daily for up to 24 Months.
Period Title: Overall Study
STARTED	157	157
COMPLETED	93	90
NOT COMPLETED	64	67

Baseline Characteristics

Arm/Group Title	Febuxostat 40 mg or 80 mg	Placebo	Total
Arm/Group Description	Febuxostat 40 mg or 80 mg (based on serum urate levels at Day 14), capsules, orally, once daily for up to 24 Months.	Febuxostat placebo-matching capsules, orally, once daily for up to 24 Months.	Total of all reporting groups
Overall Participants	157	157	314
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.4 (12.36)	50.1 (11.72)	50.8 (12.04)
Age, Customized (participants) [Number]
<45 years	49 31.2%	42 26.8%	91 29%
45 to <65 years	85 54.1%	99 63.1%	184 58.6%
≥65 years	23 14.6%	16 10.2%	39 12.4%
Sex: Female, Male (Count of Participants)
Female	14 8.9%	12 7.6%	26 8.3%
Male	143 91.1%	145 92.4%	288 91.7%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	1 0.6%	0 0%	1 0.3%
Asian	8 5.1%	10 6.4%	18 5.7%
Black or African American	25 15.9%	24 15.3%	49 15.6%
Native Hawaiian or Other Pacific Islander	1 0.6%	0 0%	1 0.3%
White	119 75.8%	121 77.1%	240 76.4%
Other	3 1.9%	2 1.3%	5 1.6%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	26 16.6%	36 22.9%	62 19.7%
Not Hispanic or Latino	131 83.4%	121 77.1%	252 80.3%
Region of Enrollment (participants) [Number]
United States	157 100%	157 100%	314 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	176.3 (9.22)	176.5 (8.36)	176.4 (8.79)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	102.8 (20.88)	100.7 (21.20)	101.7 (21.04)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	33.1 (6.40)	32.3 (6.23)	32.7 (6.32)
BMI Categories (participants) [Number]
<25 kg/m^2	11 7%	11 7%	22 7%
25 to <30 kg/m^2	37 23.6%	46 29.3%	83 26.4%
≥30 kg/m^2	109 69.4%	100 63.7%	209 66.6%
Smoking History (participants) [Number]
Never Smoked	84 53.5%	94 59.9%	178 56.7%
Current Smoker	32 20.4%	25 15.9%	57 18.2%
Ex-Smoker	41 26.1%	38 24.2%	79 25.2%
Alcohol History (participants) [Number]
Never Drank	37 23.6%	35 22.3%	72 22.9%
Current Drinker	103 65.6%	106 67.5%	209 66.6%
Ex-Drinker	17 10.8%	16 10.2%	33 10.5%
Renal History (Modification of Diet in Renal Disease [MDRD]) (participants) [Number]
Moderately Impaired MDRD	3 1.9%	2 1.3%	5 1.6%
Mildly Impaired MDRD	105 66.9%	115 73.2%	220 70.1%
Normal MDRD	49 31.2%	40 25.5%	89 28.3%

Outcome Measures

1. Primary Outcome

Title	Mean Change From Baseline to Month 24 in the Modified Sharp/Van Der Heijde Erosion Score of the Single Affected Joint
Description	The single affected joint was defined as the joint with the history of the first acute gout flare. Radiographs (X-rays) of this single joint in the hands or feet were evaluated using the modified Sharp/van der Heijde method. Each erosion was assessed using a 4-point scale where 0=no erosions (best) to 3=large erosion passing the mid-line (worst). Individual erosion scores were summed to a maximum erosion score of 5 for joints in the hands and 10 for joints in the feet. Higher scores indicated more joint damage. A negative change from Baseline indicated improvement.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all randomized participants who received at least one dose of study medication. Participants were analyzed according to the treatment group to which they actually received. Participants with data available for analysis and missing values at Month 24 imputed using linear extrapolation are included in the analysis.

Arm/Group Title	Febuxostat 40 mg or 80 mg	Placebo
Arm/Group Description	Febuxostat 40 mg or 80 mg (based on serum urate levels at Day 14), capsules, orally, once daily for up to 24 Months.	Febuxostat placebo-matching capsules, orally, once daily for up to 24 Months.
Measure Participants	86	82
Baseline	0.16 (0.444)	0.11 (0.438)
Change from Baseline at Month 24	0.01 (0.330)	0.01 (0.248)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg or 80 mg, Placebo
	Comments	Change from Baseline at Month 24
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.472
	Comments
	Method	Ranked Analysis of Covariance (ANCOVA)
	Comments	Baseline modified Sharp/van der Heijde Erosion Score as a covariate.

2. Secondary Outcome

Title	Mean Change From Baseline to Month 24 in the Modified Sharp/Van Der Heijde Total Scores From Full Hands and Feet Radiographs
Description	Radiographs (X-rays) of 40 joints in the hands and 12 joints in the feet were evaluated using the modified Sharp/van der Heijde method. Each erosion was assessed using a 4-point scale where 0=no erosions (best) to 3=large erosion passing the mid-line (worst) for a total erosion score range of 0 to 320. Joint space narrowing (JSN) was assessed using a 5-point scale where 0=normal (best) to 4=absence of joint space, presumptive evidence of ankyloses, or complete luxation (worst) for a total JSN score range of 0 to 208. The Erosion Score and the JSN Score were combined for a total possible score of 0 to 528. Higher scores indicated more joint damage. A negative change from Baseline indicated improvement.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all randomized participants who received at least one dose of study medication. Participants were analyzed according to the treatment group to which they actually received. Participants with data available at Baseline and Month 24 are included in the analysis.

Arm/Group Title	Febuxostat 40 mg or 80 mg	Placebo
Arm/Group Description	Febuxostat 40 mg or 80 mg (based on serum urate levels at Day 14), capsules, orally, once daily for up to 24 Months.	Febuxostat placebo-matching capsules, orally, once daily for up to 24 Months.
Measure Participants	91	86
Baseline	4.98 (9.707)	4.56 (8.631)
Change from Baseline at Month 24 (n=78,74)	0.31 (2.447)	0.29 (1.746)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg or 80 mg, Placebo
	Comments	Change from Baseline at Month 24
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.548
	Comments
	Method	Ranked ANCOVA
	Comments	Baseline modified Sharp/van der Heijde Total Score from full hands and feet as a covariate.

3. Secondary Outcome

Title	Mean Change From Baseline to Month 24 in the Modified Sharp/Van Der Heijde Erosion Scores From Full Hands and Feet Radiographs
Description	Radiographs (X-rays) of 40 joints in the hands and 12 joints in the feet were evaluated using the modified Sharp/van der Heijde method. Each erosion was assessed using a 4-point scale where 0=no erosions (best) to 3=large erosion passing the mid-line (worst) for a total erosion score range of 0 to 320. Higher scores indicated more joint damage. A negative change from Baseline indicated improvement.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all randomized participants who received at least one dose of study medication. Participants were analyzed according to the treatment group to which they actually received. Participants with data available at Baseline and Month 24 are included in the analysis.

Arm/Group Title	Febuxostat 40 mg or 80 mg	Placebo
Arm/Group Description	Febuxostat 40 mg or 80 mg (based on serum urate levels at Day 14), capsules, orally, once daily for up to 24 Months.	Febuxostat placebo-matching capsules, orally, once daily for up to 24 Months.
Measure Participants	91	86
Baseline	0.36 (1.160)	0.17 (0.473)
Change from Baseline at Month 24 (n=78,74)	0.17 (1.709)	0.11 (0.969)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg or 80 mg, Placebo
	Comments	Change from Baseline at Month 24
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.389
	Comments
	Method	Ranked ANCOVA
	Comments	Baseline modified Sharp/van der Heijde Erosion Score from full hands and feet as a covariate.

4. Secondary Outcome

Title	Mean Change From Baseline to Month 24 in the Rheumatoid Arthritis MRI Scoring System (RAMRIS) Score of the Single Affected Joint
Description	The single affected joint was defined as the joint with the history of the first acute gout flare. Magnetic Resonance Imaging (MRI) was evaluated using the Rheumatoid Arthritis MRI Score (RAMRIS). Bone erosion in the proximal and distal location were each assessed in the affected joint using an 11-point scale where 0=no erosion (best) to 10=91-100% bone eroded (worst) for a bone erosion score range of 0 to 20. Bone marrow edema in the proximal and distal location were each assessed using a 4-point scale where 0=no edema (best) to 3=67-100% edema (worst) for a bone marrow edema (BME) score range of 0 to 6. Synovitis was assessed in the affected joint using a 4-point scale where 0=normal (best) to 3=severe (worst). Higher scores indicated more joint damage. A negative change from Baseline indicated improvement.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all randomized participants who received at least one dose of study medication. Participants were analyzed according to the treatment group to which they actually received. Participants with data available at Baseline and Month 24 are included in the analysis.

Arm/Group Title	Febuxostat 40 mg or 80 mg	Placebo
Arm/Group Description	Febuxostat 40 mg or 80 mg (based on serum urate levels at Day 14), capsules, orally, once daily for up to 24 Months.	Febuxostat placebo-matching capsules, orally, once daily for up to 24 Months.
Measure Participants	157	157
Synovitis:Baseline (BL)(n=82,76)	1.29 (0.782)	1.09 (0.687)
Synovitis:Change from Baseline (n=75,67)	-0.43 (0.713)	-0.07 (0.531)
Erosion (Distal+Proximal):Baseline (n=84,77)	1.63 (0.935)	1.48 (0.916)
Erosion (Distal+Proximal):Change from BL(n=79,69)	-0.01 (0.702)	0.04 (0.475)
Edema (Distal+Proximal):Baseline (BL) (n=81,75)	0.73 (1.022)	0.51 (0.919)
Edema (Distal+Proximal):Change from BL(n=77,66)	-0.36 (0.916)	-0.10 (0.962)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg or 80 mg, Placebo
	Comments	Synovitis: Change from Baseline at Month 24
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Ranked ANCOVA
	Comments	Baseline RAMRIS Synovitis Score as a covariate.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg or 80 mg, Placebo
	Comments	Erosion(Distal+Proximal): Change from Baseline at Month 24
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.634
	Comments
	Method	Ranked ANCOVA
	Comments	Baseline RAMRIS Erosion(Distal+Proximal) Score as a covariate.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg or 80 mg, Placebo
	Comments	Edema(Distal+Proximal): Change from Baseline at Month 24
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.307
	Comments
	Method	Ranked ANCOVA
	Comments	Baseline RAMRIS Edema(Distal+Proximal) Score as a covariate.

5. Secondary Outcome

Title	Mean Change From Baseline to Month 24 in the Modified Sharp/Van Der Heijde Total Score of the Single Affected Joint
Description	The single affected joint was defined as the joint with the history of the first acute gout flare. Radiographs (X-rays) of the single affected joint in the hands or feet were evaluated using the modified Sharp/van der Heijde method. Each erosion was assessed using a 4-point scale where 0=no erosions (best) to 3=large erosion passing the mid-line (worst) and Joint space narrowing (JSN) was assessed using a 5-point scale where 0=normal (best) to 4=absence of joint space, presumptive evidence of ankyloses, or complete luxation (worst). The Erosion Score and the JSN Score were summed for the Total Score. Higher scores indicated more joint damage. A negative change from Baseline indicated improvement.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set included all randomized participants who received at least one dose of study medication. Participants were analyzed according to the treatment group to which they actually received. Participants with data available at Baseline and Month 24 are included in the analysis.

Arm/Group Title	Febuxostat 40 mg or 80 mg	Placebo
Arm/Group Description	Febuxostat 40 mg or 80 mg (based on serum urate levels at Day 14), capsules, orally, once daily for up to 24 Months.	Febuxostat placebo-matching capsules, orally, once daily for up to 24 Months.
Measure Participants	86	82
Baseline	0.85 (1.057)	0.77 (1.022)
Change from Baseline at Month 24(n=81,76)	0.00 (0.602)	0.05 (0.361)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Febuxostat 40 mg or 80 mg, Placebo
	Comments	Change from Baseline at Month 24
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.122
	Comments
	Method	Ranked ANCOVA
	Comments	Baseline modified Sharp/van der Heijde Total Score as a covariate.

Adverse Events

Time Frame	Treatment-emergent adverse events are adverse events, regardless of relationship to study drug, that started on or after the first dose of study drug and no more than 30 days after last dose of study drug (Up to 25 months)
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	Febuxostat 40 mg or 80 mg		Placebo
Arm/Group Description	Febuxostat 40 mg or 80 mg (based on serum urate levels at Day 14), capsules, orally, once daily for up to 24 Months.		Febuxostat placebo-matching capsules, orally, once daily for up to 24 Months.
All Cause Mortality
	Febuxostat 40 mg or 80 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Febuxostat 40 mg or 80 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/157 (8.3%)		11/157 (7%)
Cardiac disorders
Cardiac failure congestive	1/157 (0.6%)		1/157 (0.6%)
Acute myocardial infarction	1/157 (0.6%)		0/157 (0%)
Angina pectoris	1/157 (0.6%)		0/157 (0%)
Mitral valve incompetence	0/157 (0%)		1/157 (0.6%)
Left ventricular dysfunction	0/157 (0%)		1/157 (0.6%)
Atrial fibrillation	0/157 (0%)		1/157 (0.6%)
Ventricular fibrillation	0/157 (0%)		1/157 (0.6%)
Eye disorders
Vitreous haemorrhage	0/157 (0%)		1/157 (0.6%)
Diabetic retinopathy	0/157 (0%)		1/157 (0.6%)
Gastrointestinal disorders
Colitis	1/157 (0.6%)		0/157 (0%)
General disorders
Impaired healing	0/157 (0%)		1/157 (0.6%)
Oedema peripheral	1/157 (0.6%)		0/157 (0%)
Chest pain	0/157 (0%)		1/157 (0.6%)
Hepatobiliary disorders
Cholecystitis acute	1/157 (0.6%)		0/157 (0%)
Cholelithiasis	1/157 (0.6%)		0/157 (0%)
Bile duct obstruction	1/157 (0.6%)		0/157 (0%)
Infections and infestations
Appendicitis	1/157 (0.6%)		0/157 (0%)
Cellulitis	0/157 (0%)		1/157 (0.6%)
Bursitis infective	1/157 (0.6%)		0/157 (0%)
Osteomyelitis	0/157 (0%)		1/157 (0.6%)
Hepatic infection	0/157 (0%)		1/157 (0.6%)
Incision site infection	0/157 (0%)		1/157 (0.6%)
Pneumonia	1/157 (0.6%)		0/157 (0%)
Chest wall abscess	1/157 (0.6%)		0/157 (0%)
Sepsis	1/157 (0.6%)		0/157 (0%)
Pneumonia streptococcal	1/157 (0.6%)		0/157 (0%)
Metabolism and nutrition disorders
Gout	0/157 (0%)		1/157 (0.6%)
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/157 (0%)		1/157 (0.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of lung	1/157 (0.6%)		0/157 (0%)
Malignant melanoma	1/157 (0.6%)		0/157 (0%)
Uterine leiomyoma	1/157 (0.6%)		0/157 (0%)
Nervous system disorders
Dizziness	0/157 (0%)		1/157 (0.6%)
Renal and urinary disorders
Nephropathy	1/157 (0.6%)		0/157 (0%)
Oliguria	1/157 (0.6%)		0/157 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/157 (0%)		2/157 (1.3%)
Chronic obstructive pulmonary disease	1/157 (0.6%)		0/157 (0%)
Acute respiratory failure	1/157 (0.6%)		0/157 (0%)
Skin and subcutaneous tissue disorders
Skin ulcer	0/157 (0%)		1/157 (0.6%)
Vascular disorders
Arteriosclerosis	0/157 (0%)		1/157 (0.6%)
Peripheral vascular disorder	1/157 (0.6%)		0/157 (0%)
Peripheral arterial occlusive disease	1/157 (0.6%)		0/157 (0%)
Other (Not Including Serious) Adverse Events
	Febuxostat 40 mg or 80 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	73/157 (46.5%)		67/157 (42.7%)
Gastrointestinal disorders
Diarrhoea	9/157 (5.7%)		6/157 (3.8%)
General disorders
Oedema peripheral	8/157 (5.1%)		5/157 (3.2%)
Infections and infestations
Upper respiratory tract infection	15/157 (9.6%)		16/157 (10.2%)
Investigations
Aspartate aminotransferase increased	11/157 (7%)		6/157 (3.8%)
Blood creatine phosphokinase increased	9/157 (5.7%)		11/157 (7%)
Alanine aminotransferase increased	10/157 (6.4%)		6/157 (3.8%)
Gamma-glutamyltransferase increased	6/157 (3.8%)		9/157 (5.7%)
Musculoskeletal and connective tissue disorders
Arthralgia	14/157 (8.9%)		10/157 (6.4%)
Pain in extremity	9/157 (5.7%)		13/157 (8.3%)
Back pain	9/157 (5.7%)		6/157 (3.8%)
Musculoskeletal pain	4/157 (2.5%)		8/157 (5.1%)
Nervous system disorders
Headache	5/157 (3.2%)		10/157 (6.4%)
Vascular disorders
Hypertension	8/157 (5.1%)		7/157 (4.5%)

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.