Efficacy and Safety of Extended Release and Immediate Release Febuxostat in Participants With Gout and Moderate Renal Impairment

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02128490
• Collaborator: (none)
• Enrollment: 189
• Locations: 89
• Arms: 5
• Duration (Months): 17
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of febuxostat 40 mg extended release (XR) and 80 mg XR in comparison with febuxostat 40 mg immediate release (IR) and 80 mg IR, respectively, in gout participants with moderate renal impairment.

Condition or Disease	Intervention/Treatment	Phase
Gout; Moderate Renal Impairment	Drug: Febuxostat IR; Drug: Febuxostat XR; Drug: Febuxostat placebo; Drug: Colchicine; Drug: Naproxen; Drug: Lansoprazole	Phase 2

Detailed Description

The drug being tested in this study is called febuxostat. Febuxostat is being tested to decrease and maintain serum urate in people who have gout with moderate renal impairment. This study will look at serum urate levels in people who take febuxostat extended release (XR) capsules compared to febuxostat immediate release (IR) capsules and placebo.

The study will enroll approximately 200 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the five treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

• Febuxostat 40 mg XR

• Febuxostat 80 mg XR

• Febuxostat 40 mg IR

• Febuxostat 80 mg IR

• Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient.

All participants will be asked to take one capsule at the same time each day throughout the study, and will be asked to call an interactive voice response system any time they are having a gout flare up. In addition to study medication, participants will also take 0.6 mg of colchicine every other day or naproxen 250 mg twice a day with lansoprazole 15 mg once a day to prevent gout flare ups.

This multi-center trial will be conducted in the United States. The overall time to participate in this study is up to approximately 4 months and participants will make up to 7 visits to the clinic.

Study Design

• Study Type: Interventional
• Actual Enrollment: 189 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double Blind, Multicenter, Placebo Controlled Study to Evaluate the Efficacy and Safety of Febuxostat 40 mg XR, 80 mg XR, 40 mg IR and 80 mg IR in Subjects With Gout and Moderate Renal Impairment
• Study Start Date: May 1, 2014
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Oct 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Febuxostat IR 40 mg Febuxostat Immediate Release (IR) 40 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Drug: Febuxostat IR; Febuxostat IR over-encapsulated tablets; Other Names: Uloric ; Drug: Colchicine; Colchicine tablets; Drug: Naproxen; Naproxen tablets; Drug: Lansoprazole; Lansoprazole capsules
Active Comparator: Febuxostat IR 80 mg Febuxostat IR 80 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Drug: Febuxostat IR; Febuxostat IR over-encapsulated tablets; Other Names: Uloric ; Drug: Colchicine; Colchicine tablets; Drug: Naproxen; Naproxen tablets; Drug: Lansoprazole; Lansoprazole capsules
Experimental: Febuxostat XR 40 mg Febuxostat Extended Release (XR) 40 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Drug: Febuxostat XR; Febuxostat over-encapsulated capsules; Drug: Colchicine; Colchicine tablets; Drug: Naproxen; Naproxen tablets; Drug: Lansoprazole; Lansoprazole capsules
Experimental: Febuxostat XR 80 mg Febuxostat XR 80 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Drug: Febuxostat XR; Febuxostat over-encapsulated capsules; Drug: Colchicine; Colchicine tablets; Drug: Naproxen; Naproxen tablets; Drug: Lansoprazole; Lansoprazole capsules
Placebo Comparator: Placebo Febuxostat placebo-matching capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Drug: Febuxostat placebo; Febuxostat IR and XR placebo-matching capsules; Drug: Colchicine; Colchicine tablets; Drug: Naproxen; Naproxen tablets; Drug: Lansoprazole; Lansoprazole capsules

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Serum Urate <5.0 mg/dL at Month 3 [Month 3]

Secondary Outcome Measures

1. Percentage of Participants With at Least One Gout Flare Requiring Treatment [Baseline to Month 3]

   A participant was considered to have a gout flare if the following criteria were met: Participant-reported acute particular pain typical of a gout attack that was deemed by participant and/or investigator to require treatment and was treated with colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids, Participant experienced at least 3 or more of: 1) Joint swelling, 2) Redness, 3) Tenderness, 4) Pain, Participant experienced at least one or more of: 1) Rapid onset of pain, 2) Decreased range of motion, 3) Joint warmth, 4) Other symptoms similar to a prior gout flare.

2. Percentage of Participants With Serum Urate <6.0 mg/dL at Month 3 [Month 3]

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements.

2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedure.

3. Has a history or presence of gout defined as having one or more of the American

Rheumatism Association (ARA) criteria for the diagnosis of gout:

1. A tophus proven to contain urate crystals by chemical or polarized light microscopic means, AND/OR;

2. Characteristic urate crystals in the joint fluid, AND/OR;

3. History of at least 6 of the following clinical, laboratory, and x-ray phenomena:

1. more than one attack of acute arthritis, ii. maximum inflammation developed within 1 day, iii. monoarticular arthritis, iv. redness observed over joints, v. first metatarsophalangeal joint painful or swollen, vi. unilateral first metatarsophalangeal joint attack, vii. unilateral tarsal joint attack, viii. tophus (proven or suspected),

1. Hyperuricemia, x. asymmetric swelling within a joint on x-ray, xi. subcortical cysts without erosions on x-ray, xii. joint fluid culture negative for organisms during attack.

1. Is male or female at least 18 years of age, inclusive.

2. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study.

3. Have a serum urate (sUA) level ≥8.0 mg/dL at the Day -4 Visit or at the retest visit.

4. Has an estimated Glomerular Filtration Rate (eGRF) [Modification of Diet in Renal Disease (MDRD)] ≥30 mL/min and <60 mL/min at Screening visit (Day -21 for participants on urate lowering therapy (ULT) and Day -4 for participants not on ULT) or at the retest visit.

5. Has at least one gout flare within 12 months prior to Screening visit.

Exclusion Criteria:

1. Has received any investigational compound within 30 days prior to Screening.

2. Is an immediate family member, study site employee, or is in a dependant relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.

3. Is breastfeeding or pregnant.

4. Has secondary hyperuricemia (eg, due to myeloproliferative disorder).

5. Has a history of xanthinuria.

6. Has received ULT (ie, allopurinol, probenecid, etc.) within 20 days prior to Day 1/Randomization Visit.

7. Has a known hypersensitivity to febuxostat or any components of their formulation; has a known hypersensitivity to naproxen, any other nonsteroidal anti-inflammatory drug (NSAID), aspirin, lansoprazole, colchicine or any components in their formulation.

8. Has active peptic ulcer disease.

9. Has a history of cancer (other than basal cell carcinoma of the skin) within 5 years prior to the Screening Visit.

10. Has alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values >2 x the upper limit of normal (ULN).

11. Has rheumatoid arthritis which requires treatment.

12. Has a significant medical condition and/or conditions that would interfere with the treatment, safety, or compliance with the protocol.

13. Has experienced either a myocardial infarction (MI), stroke, hospitalized unstable angina, cardiac or cerebrovascular revascularization procedure or hospitalized transient ischemic attack (TIA).

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

15. Has participated in another investigational study within the 30 days prior to the Screening Visit.

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

17. Is required to take excluded medications.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Muscle Shoals	Alabama	United States
3		Phoenix	Arizona	United States
4	Benny Green MD PA Family Practice	Little Rock	Arkansas	United States	72223
5		Little Rock	Arkansas	United States
6		Bellflower	California	United States
7		Escondido	California	United States
8		Harbor City	California	United States
9		Huntington Park	California	United States
10		Irvine	California	United States
11		Lomita	California	United States
12	Long Beach Center for Clinical Research	Long Beach	California	United States	90807
13		Long Beach	California	United States
14		Los Angeles	California	United States
15	Brigid Freyne MD	Murrieta	California	United States	92563
16		Murrieta	California	United States
17		Orange	California	United States
18		Rancho Cucamonga	California	United States
19		Redondo Beach	California	United States
20		Sacramento	California	United States
21		San Jose	California	United States
22		San Ramon	California	United States
23		Clearwater	Florida	United States
24		Coral Gables	Florida	United States
25		Coral Springs	Florida	United States
26	Riverside Clinical Research	Edgewater	Florida	United States	32141
27		Edgewater	Florida	United States
28		Hialeah	Florida	United States
29		Miami Beach	Florida	United States
30		Miami Lakes	Florida	United States
31		Miami	Florida	United States
32		Orlando	Florida	United States
33		Pembroke Pines	Florida	United States
34		Plantation	Florida	United States
35		Port Charlotte	Florida	United States
36		Saint Cloud	Florida	United States
37		Vero Beach	Florida	United States
38		Atlanta	Georgia	United States
39		Dunwoody	Georgia	United States
40		East Point	Georgia	United States
41		Suwanee	Georgia	United States
42	East West Medical Research Institute	Honolulu	Hawaii	United States	96814
43		Honolulu	Hawaii	United States
44		Brownsburg	Indiana	United States
45		Manhattan	Kansas	United States
46		Wichita	Kansas	United States
47		Elizabethtown	Kentucky	United States
48	Central Kentucy Reseach Associates	Lexington	Kentucky	United States	40509
49		Lexington	Kentucky	United States
50		Paducah	Kentucky	United States
51		Mandeville	Louisiana	United States
52		Metairie	Louisiana	United States
53		Fall River	Massachusetts	United States
54		Detroit	Michigan	United States
55		Kalamazoo	Michigan	United States
56		Hazelwood	Missouri	United States
57		Washington	Missouri	United States
58		Las Vegas	Nevada	United States
59		Albuquerque	New Mexico	United States
60		Columbiana	North Carolina	United States
61		Greensboro	North Carolina	United States
62		Salisbury	North Carolina	United States
63		Wilmington	North Carolina	United States
64		Fargo	North Dakota	United States
65		Franklin	Ohio	United States
66	COR Clinical Research LLC	Oklahoma City	Oklahoma	United States	73103
67		Oklahoma City	Oklahoma	United States
68		Portland	Oregon	United States
69		Columbia	South Carolina	United States
70		Greer	South Carolina	United States
71		Indian Land	South Carolina	United States
72		Clarksville	Tennessee	United States
73		Knoxville	Tennessee	United States
74	Remesh C Gupta MD	Memphis	Tennessee	United States	38119
75		Memphis	Tennessee	United States
76		Austin	Texas	United States
77		Bellaire	Texas	United States
78	3rd Coast Research Associates	Corpus Christi	Texas	United States	78413
79		Corpus Christi	Texas	United States
80		Nassau Bay	Texas	United States
81		Plano	Texas	United States
82	Sun Research Institute	San Antonio	Texas	United States	78215
83	Briggs Clinical Research LLC	San Antonio	Texas	United States	78224
84		San Antonio	Texas	United States
85		Bountiful	Utah	United States
86		Newport News	Virginia	United States
87		Norfolk	Virginia	United States
88		Richmond	Virginia	United States
89		Virginia Beach	Virginia	United States

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director Clinical Science, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02128490
• Other Study ID Numbers: FEB-XR_201; U1111-1152-3942
• First Posted: May 1, 2014
• Last Update Posted: Nov 3, 2016
• Last Verified: Sep 1, 2016

• Keywords provided by Takeda: Drug therapy
• Additional relevant MeSH terms: Gout; Renal Insufficiency; Naproxen; Colchicine; Febuxostat; Lansoprazole; Dexlansoprazole

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 65 investigative sites in the United States from 5 May 2014 to 23 October 2015.
Pre-assignment Detail	Participants with a diagnosis of gout were enrolled equally in 1 of 5 treatment groups once a day: placebo, febuxostat 40 mg extended release (XR), febuxostat 80 mg XR, febuxostat 40 mg immediate release (IR) or febuxostat 80 mg IR.

Arm/Group Title	Placebo	Febuxostat IR 40 mg	Febuxostat XR 40 mg	Febuxostat IR 80 mg	Febuxostat XR 80 mg
Arm/Group Description	Febuxostat placebo-matching capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat Immediate Release (IR) 40 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat Extended Release (XR) 40 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat IR 80 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat XR 80 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Period Title: Overall Study
STARTED	38	37	39	37	38
COMPLETED	33	31	34	31	31
NOT COMPLETED	5	6	5	6	7

Baseline Characteristics

Arm/Group Title	Placebo	Febuxostat IR 40 mg	Febuxostat XR 40 mg	Febuxostat IR 80 mg	Febuxostat XR 80 mg	Total
Arm/Group Description	Febuxostat placebo-matching capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat Immediate Release (IR) 40 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat Extended Release (XR) 40 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat IR 80 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat XR 80 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Total of all reporting groups
Overall Participants	38	37	39	37	38	189
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.6 (12.78)	61.3 (10.09)	64.4 (11.21)	63.5 (10.33)	61.4 (12.17)	63.1 (11.34)
Age, Customized (participants) [Number]
< 45 years	1 2.6%	3 8.1%	1 2.6%	0 0%	4 10.5%	9 4.8%
45 to < 65 years	14 36.8%	16 43.2%	15 38.5%	18 48.6%	18 47.4%	81 42.9%
>= 65 years	23 60.5%	18 48.6%	23 59%	19 51.4%	16 42.1%	99 52.4%
Age, Customized (participants) [Number]
18 to < 65 years	15 39.5%	19 51.4%	16 41%	18 48.6%	22 57.9%	90 47.6%
65 to < 85 years	21 55.3%	18 48.6%	23 59%	19 51.4%	16 42.1%	97 51.3%
>= 85 years	2 5.3%	0 0%	0 0%	0 0%	0 0%	2 1.1%
Sex: Female, Male (Count of Participants)
Female	12 31.6%	12 32.4%	13 33.3%	9 24.3%	9 23.7%	55 29.1%
Male	26 68.4%	25 67.6%	26 66.7%	28 75.7%	29 76.3%	134 70.9%
Race/Ethnicity, Customized (participants) [Number]
Asian	0 0%	2 5.4%	1 2.6%	2 5.4%	4 10.5%	9 4.8%
Black or African American	4 10.5%	10 27%	10 25.6%	12 32.4%	10 26.3%	46 24.3%
Native Hawaiian or Other Pacific Islander	1 2.6%	0 0%	1 2.6%	2 5.4%	0 0%	4 2.1%
White	33 86.8%	24 64.9%	26 66.7%	21 56.8%	22 57.9%	126 66.7%
Other: Multi-racial	0 0%	1 2.7%	1 2.6%	0 0%	2 5.3%	4 2.1%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	2 5.3%	1 2.7%	7 17.9%	7 18.9%	7 18.4%	24 12.7%
Not Hispanic or Latino	36 94.7%	36 97.3%	32 82.1%	30 81.1%	31 81.6%	165 87.3%
Region of Enrollment (participants) [Number]
United States	38 100%	37 100%	39 100%	37 100%	38 100%	189 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	171.5 (10.47)	172.8 (10.39)	171.6 (9.99)	170.7 (11.16)	173.4 (9.63)	172.0 (10.27)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	100.76 (25.675)	108.52 (25.451)	103.75 (27.027)	96.43 (21.749)	98.44 (22.844)	101.58 (24.749)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	34.08 (6.993)	36.53 (9.036)	35.23 (8.655)	33.10 (7.220)	32.62 (6.609)	34.31 (7.810)
Smoking History (participants) [Number]
Never Smoked	20 52.6%	21 56.8%	19 48.7%	20 54.1%	16 42.1%	96 50.8%
Current Smoker	2 5.3%	3 8.1%	4 10.3%	5 13.5%	5 13.2%	19 10.1%
Ex-Smoker	16 42.1%	13 35.1%	16 41%	12 32.4%	17 44.7%	74 39.2%
Alcohol Classification (participants) [Number]
Never Drank	8 21.1%	14 37.8%	14 35.9%	19 51.4%	20 52.6%	75 39.7%
Current Drinker	22 57.9%	15 40.5%	15 38.5%	14 37.8%	13 34.2%	79 41.8%
Ex-Drinker	8 21.1%	8 21.6%	10 25.6%	4 10.8%	5 13.2%	35 18.5%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Serum Urate <5.0 mg/dL at Month 3
Time Frame	Month 3

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) included all participants who were randomized and received at least 1 dose of double-blind study medication. Participants who discontinued double-blind study drug prior to the Month 3 visit were considered treatment failures, i.e. to have serum urate ≥ 5.0 mg/dL.

Arm/Group Title	Placebo	Febuxostat IR 40 mg	Febuxostat XR 40 mg	Febuxostat IR 80 mg	Febuxostat XR 80 mg
Arm/Group Description	Febuxostat placebo-matching capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat Immediate Release (IR) 40 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat Extended Release (XR) 40 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat IR 80 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat XR 80 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Measure Participants	38	37	39	37	38
Number [percentage of participants]	0 0%	13.5 36.5%	35.9 92.1%	40.5 109.5%	44.7 117.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat XR 40 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportions
	Estimated Value	35.9
	Confidence Interval	(2-Sided) 95%; 20.8 to 51.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat XR 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportions
	Estimated Value	44.7
	Confidence Interval	(2-Sided) 95%; 28.9 to 60.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Febuxostat IR 40 mg, Febuxostat XR 40 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.034
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportions
	Estimated Value	22.4
	Confidence Interval	(2-Sided) 95%; 3.7 to 41.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Febuxostat IR 80 mg, Febuxostat XR 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.817
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportions
	Estimated Value	4.2
	Confidence Interval	(2-Sided) 95%; -18.2 to 26.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants With at Least One Gout Flare Requiring Treatment
Description	A participant was considered to have a gout flare if the following criteria were met: Participant-reported acute particular pain typical of a gout attack that was deemed by participant and/or investigator to require treatment and was treated with colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids, Participant experienced at least 3 or more of: 1) Joint swelling, 2) Redness, 3) Tenderness, 4) Pain, Participant experienced at least one or more of: 1) Rapid onset of pain, 2) Decreased range of motion, 3) Joint warmth, 4) Other symptoms similar to a prior gout flare.
Time Frame	Baseline to Month 3

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized and received at least 1 dose of double-blind study medication.

Arm/Group Title	Placebo	Febuxostat IR 40 mg	Febuxostat XR 40 mg	Febuxostat IR 80 mg	Febuxostat XR 80 mg
Arm/Group Description	Febuxostat placebo-matching capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat Immediate Release (IR) 40 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat Extended Release (XR) 40 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat IR 80 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat XR 80 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Measure Participants	38	37	39	37	38
Number [percentage of participants]	10.5 27.6%	40.5 109.5%	23.1 59.2%	37.8 102.2%	42.1 110.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat XR 40 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.224
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportions
	Estimated Value	12.6
	Confidence Interval	(2-Sided) 95%; -3.9 to 29.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat XR 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportions
	Estimated Value	31.6
	Confidence Interval	(2-Sided) 95%; 13.1 to 50.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Febuxostat IR 40 mg, Febuxostat XR 40 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.139
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportions
	Estimated Value	-17.5
	Confidence Interval	(2-Sided) 95%; -38.1 to 3.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Febuxostat IR 80 mg, Febuxostat XR 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.815
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportions
	Estimated Value	4.3
	Confidence Interval	(2-Sided) 95%; -17.9 to 26.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants With Serum Urate <6.0 mg/dL at Month 3
Time Frame	Month 3

Outcome Measure Data

Analysis Population Description

FAS included all participants who were randomized and received at least 1 dose of double-blind study medication. Participants who discontinued double-blind study drug prior to the Month 3 visit were considered treatment failures, i.e. to have serum urate ≥ 5.0 mg/dL.

Arm/Group Title	Placebo	Febuxostat IR 40 mg	Febuxostat XR 40 mg	Febuxostat IR 80 mg	Febuxostat XR 80 mg
Arm/Group Description	Febuxostat placebo-matching capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat Immediate Release (IR) 40 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat Extended Release (XR) 40 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat IR 80 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.	Febuxostat XR 80 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
Measure Participants	38	37	39	37	38
Number [percentage of participants]	0 0%	32.4 87.6%	53.8 137.9%	59.5 160.8%	55.3 145.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat XR 40 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportions
	Estimated Value	53.8
	Confidence Interval	(2-Sided) 95%; 38.2 to 69.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Febuxostat XR 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportions
	Estimated Value	55.3
	Confidence Interval	(2-Sided) 95%; 39.5 to 71.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Febuxostat IR 40 mg, Febuxostat XR 40 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.069
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportions
	Estimated Value	21.4
	Confidence Interval	(2-Sided) 95%; -0.3 to 43.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Febuxostat IR 80 mg, Febuxostat XR 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.817
	Comments
	Method	Fisher Exact
	Comments
Method of Estimation	Estimation Parameter	Difference in Proportions
	Estimated Value	-4.2
	Confidence Interval	(2-Sided) 95%; -26.6 to 18.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	First dose of double-blind study drug to 30 days past last dose of double-blind study drug (Up to 4 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	Placebo		Febuxostat IR 40 mg		Febuxostat XR 40 mg		Febuxostat IR 80 mg		Febuxostat XR 80 mg
Arm/Group Description	Febuxostat placebo-matching capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.		Febuxostat Immediate Release (IR) 40 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.		Febuxostat Extended Release (XR) 40 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.		Febuxostat IR 80 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.		Febuxostat XR 80 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every other day, or, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months.
All Cause Mortality
	Placebo		Febuxostat IR 40 mg		Febuxostat XR 40 mg		Febuxostat IR 80 mg		Febuxostat XR 80 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Febuxostat IR 40 mg		Febuxostat XR 40 mg		Febuxostat IR 80 mg		Febuxostat XR 80 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/38 (0%)		1/37 (2.7%)		1/39 (2.6%)		0/37 (0%)		4/38 (10.5%)
Cardiac disorders
Coronary artery disease	0/38 (0%)		0/37 (0%)		0/39 (0%)		0/37 (0%)		1/38 (2.6%)
Sinus node dusfunction	0/38 (0%)		0/37 (0%)		0/39 (0%)		0/37 (0%)		1/38 (2.6%)
Cardiac arrest	0/38 (0%)		0/37 (0%)		0/39 (0%)		0/37 (0%)		1/38 (2.6%)
Hepatobiliary disorders
Cholelithiasis	0/38 (0%)		0/37 (0%)		1/39 (2.6%)		0/37 (0%)		0/38 (0%)
Infections and infestations
Gastroenteritis	0/38 (0%)		1/37 (2.7%)		0/39 (0%)		0/37 (0%)		0/38 (0%)
Gangrene	0/38 (0%)		0/37 (0%)		0/39 (0%)		0/37 (0%)		1/38 (2.6%)
Renal and urinary disorders
Acute kidney injury	0/38 (0%)		1/37 (2.7%)		0/39 (0%)		0/37 (0%)		0/38 (0%)
Vascular disorders
Hypertension	0/38 (0%)		0/37 (0%)		0/39 (0%)		0/37 (0%)		1/38 (2.6%)
Other (Not Including Serious) Adverse Events
	Placebo		Febuxostat IR 40 mg		Febuxostat XR 40 mg		Febuxostat IR 80 mg		Febuxostat XR 80 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/38 (7.9%)		5/37 (13.5%)		4/39 (10.3%)		1/37 (2.7%)		3/38 (7.9%)
Cardiac disorders
Palpitations	0/38 (0%)		0/37 (0%)		2/39 (5.1%)		0/37 (0%)		0/38 (0%)
Gastrointestinal disorders
Diarrhoea	0/38 (0%)		2/37 (5.4%)		0/39 (0%)		0/37 (0%)		0/38 (0%)
Infections and infestations
Urinary tract infection	0/38 (0%)		2/37 (5.4%)		0/39 (0%)		0/37 (0%)		0/38 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	0/38 (0%)		0/37 (0%)		2/39 (5.1%)		0/37 (0%)		0/38 (0%)
Renal and urinary disorders
Renal failure	2/38 (5.3%)		0/37 (0%)		0/39 (0%)		0/37 (0%)		0/38 (0%)
Vascular disorders
Hypertension	1/38 (2.6%)		1/37 (2.7%)		0/39 (0%)		1/37 (2.7%)		3/38 (7.9%)

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.