CRYSTAL: Combination Treatment Study in Subjects With Tophaceous Gout With Lesinurad and Febuxostat

• Sponsor: Ardea Biosciences, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01510769
• Collaborator: (none)
• Enrollment: 330
• Locations: 124
• Arms: 3
• Duration (Months): 29
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study will compare the serum uric acid lowering effects, clinical benefits, and safety of lesinurad in combination with febuxostat to febuxostat alone in patients with tophaceaous gout.

Condition or Disease	Intervention/Treatment	Phase
Tophaceous Gout	Drug: Lesinurad; Drug: Lesinurad; Drug: Placebo; Drug: Febuxostat	Phase 3

Detailed Description

Febuxostat is an XO (Xanthine Oxidase) Inhibitor approved Urate Lowering Therapy (ULT) for patients with gout. Although febuxostat has been demonstrated to be superior to allopurinol in lowering serum urate (sUA) to < 6mg/dL in 3 randomized, controlled clinical trials, proportions of subjects experiencing a reduction in tophus area and gout flares were not significantly different compared to allopurinol. Although this study will allow subjects who are naïve to ULT to enroll, it is anticipated that the majority of subjects will currently be taking or have previously experienced XO Inhibitor therapy. This trial will enroll a population of subjects with high uric acid body burden, as all must demonstrate the presence of tophi.

Study Design

• Study Type: Interventional
• Actual Enrollment: 330 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Randomized, Double-Blind, Multicenter, Placebo- Controlled, Combination Study to Evaluate the Efficacy and Safety of Lesinurad and Febuxostat Compared to Febuxostat Alone at Lowering Serum Uric Acid and Resolving Tophi in Subjects With Tophaceous Gout
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Jun 1, 2014
• Actual Study Completion Date: Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: lesinurad 400 mg + febuxostat 80 mg	Drug: Lesinurad; Tablets, 400 mg once daily (QD); Drug: Febuxostat; 80 mg
Experimental: lesinurad 200 mg + febuxostat 80 mg	Drug: Lesinurad; Tablets, 200 mg QD; Drug: Febuxostat; 80 mg
Placebo Comparator: placebo + febuxostat 80 mg	Drug: Placebo; Tablets, Placebo QD; Drug: Febuxostat; 80 mg

Outcome Measures

Primary Outcome Measures

1. Subjects With a Serum Urate (sUA) Level That is < 5.0 mg/dL by Month 6 [6 months, analysis after all subjects complete 12 months]

   Proportion of subjects with an sUA level that is < 5.0 mg/dL by Month 6

Secondary Outcome Measures

1. Complete Resolution of at Least One Target Tophus [12 Months]

   Proportion of subjects who experience complete resolution of at least 1 target tophus by Month 12

2. Complete or Partial Response of at Least One Tophus [12 Months]

   Proportion of subjects with a best tophus response on at least 1 target tophus of complete (disappearance of at least 1 target tophus) or partial (≥ 50% decrease in the area of at least 1 target tophus) resolution by Month 12

3. Quality of Life [12 Months]

   Proportion of subjects with an improvement from Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) of at least 0.25 at Month 12. The HAQ-DI assesses a patient's level of functional ability with items scores ranging from 0-3 with 0 being the least disability.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subject is able to understand the study procedures, the risks involved and willing to provide written informed consent before the first study related activity.

• Subject is willing to adhere to the visit/protocol schedules.

• Subject meets the diagnosis of gout as per the American Rheumatism Association

• Criteria for the Classification of Acute Arthritis of Primary Gout.

• Subject meets one of the following criteria:

• Subjects who are not currently taking an approved ULT must have an sUA value of ≥ 8 mg/dL (476 µmol/L).

• Subjects entering the study on a medically appropriate dose of febuxostat or allopurinol must have an sUA value of ≥ 6.0 mg/dL (357 µmol/L).

• Subject must be able to take gout flare prophylaxis with colchicine or non-steroidal anti-inflammatory drug (NSAID) (including Cox-2 selective NSAID) ± PPI.

• Subject with at least 1 measurable tophus on the hands/wrists and/or feet/ankles ≥ 5 mm and ≤ 20 mm in the longest diameter.

• Body mass index (BMI) < 45 kg/m2

Exclusion Criteria:

• Subject with known hypersensitivity or allergy to febuxostat.

• Subject who is taking any approved urate-lowering medication other than allopurinol or febuxostat that is indicated for the treatment of gout within 8 weeks of the Screening Visit.

• Subject who previously received pegloticase.

• Subject who consumes more than 14 drinks of alcohol per week (eg, 1 drink = 5 oz [150 mL] of wine, 12 oz [360 mL] of beer, or 1.5 oz [45 mL] of hard liquor).

• Subject with a history or suspicion of drug abuse within the past 5 years.

• Subject with a history of myositis/myopathy or rhabdomyolysis.

• Subject that requires or may require systemic immunosuppressive or immunomodulatory treatment.

• Subject with known or suspected human immunodeficiency virus (HIV) infection.

• Subject with a positive test for active hepatitis B or hepatitis C infection.

• Subject with a history of malignancy within the previous 5 years with the exception of non-melanoma skin cancer that has been treated with no evidence of recurrence, treated cervical dysplasia or treated in situ Grade 1 cervical cancer.

• Subject within the last 12 months with: unstable angina, New York Heart Association thrombosis; or subjects currently receiving anticoagulants.

• Subject with uncontrolled hypertension.

• Subject with an estimated creatinine clearance < 30 mL/min.

• Subjects with a creatine kinase > 2.5 x ULN at any time during the Screening Period.

• Subject with active peptic ulcer disease requiring treatment.

• Subject with a history of xanthinuria, active liver disease, or hepatic dysfunction.

• Subject receiving chronic treatment with more than 325 mg of salicylates per day.

• Subject taking valpromide, progabide, or valproic acid.

• Subject who has received an investigational therapy within 8 weeks or 5 half-lives (whichever is longer) prior to the Screening Visit.

• Subject with any other medical or psychological condition, which in the opinion of the Investigator and/or Medical Monitor, might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements, or to complete the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States	35211
2		Goodyear	Arizona	United States	85395
3		Peoria	Arizona	United States	85381
4		Pheonix	Arizona	United States	85023
5		Tucson	Arizona	United States	85724
6		Little Rock	Arkansas	United States	72204
7		Little Rock	Arkansas	United States	72223
8		Glendale	California	United States	91204
9		Huntington Beach	California	United States	92646
10		Irvine	California	United States	92618
11		La Jolla	California	United States	92037
12		Los Angeles	California	United States	90048
13		Rancho Cucamonga	California	United States	91730
14		San Diego	California	United States	92108
15		Denver	Colorado	United States	80220
16		Denver	Colorado	United States	80230
17		Englewood	Colorado	United States	80113
18		Trumball	Connecticut	United States	06611
19		Washington	District of Columbia	United States	20422
20		Boynton Beach	Florida	United States	33472
21		Brooksville	Florida	United States	34601
22		East Brandenton	Florida	United States	34208
23		Fleming Island	Florida	United States	32003
24		Miami	Florida	United States	33135
25		Napels	Florida	United States	34102
26		Pembroke Pines	Florida	United States	33027
27		Pembroke Pines	Florida	United States	33029
28		Port Orange	Florida	United States	32127
29		Tampa	Florida	United States	33606
30		Tampa	Florida	United States	33607
31		Tampa	Florida	United States	33614
32		Vero Beach	Florida	United States	32960
33		Winter Haven	Florida	United States	33880
34		Conyers	Georgia	United States	30013
35		Johns Creek	Georgia	United States	30097
36		Newman	Georgia	United States	30265
37		Savannah	Georgia	United States	31406
38		Honolulu	Hawaii	United States	96814
39		Meridian	Idaho	United States	83642
40		Meridian	Idaho	United States	83646
41		Chicago	Illinois	United States	60624
42		Chicago	Illinois	United States	60637
43		Gurnee	Illinois	United States	60031
44		Springfield	Illinois	United States	62704
45		Springfield	Illinois	United States	62711
46		Elizabethtown	Kentucky	United States	42701
47		Lexington	Kentucky	United States	40504
48		Frederick	Maryland	United States	21702
49		Kalamazoo	Michigan	United States	49009
50		Southfield	Michigan	United States	48034
51		Jackson	Mississippi	United States	39202
52		Olive Branch	Mississippi	United States	38654
53		Jefferson City	Missouri	United States	65109
54		Saint Louis	Missouri	United States	63117
55		Missoula	Montana	United States	59808
56		Mineola	New York	United States	11501
57		New York	New York	United States	10016
58		Calabash	North Carolina	United States	28467
59		Durham	North Carolina	United States	27710
60		Greenville	North Carolina	United States	27834
61		Wilmington	North Carolina	United States	28401
62		Winston-Salem	North Carolina	United States	27103
63		Fargo	North Dakota	United States	58103
64		Columbus	Ohio	United States	43203
65		Middleburg	Ohio	United States	44130
66		Wadsworth	Ohio	United States	44281
67		Oklahoma City	Oklahoma	United States	73103
68		Oklahoma City	Oklahoma	United States	73112
69		Belle Vernon	Pennsylvania	United States	15012
70		Clairton	Pennsylvania	United States	15025
71		Duncansville	Pennsylvania	United States	16635
72		Jenkintown	Pennsylvania	United States	19046
73		Lansdale	Pennsylvania	United States	19446
74		Pittsburgh	Pennsylvania	United States	15206
75		Scottdale	Pennsylvania	United States	15683
76		Sellersville	Pennsylvania	United States	18960
77		Columbia	South Carolina	United States	29204
78		Greenville	South Carolina	United States	29615
79		Mount Pleasant	South Carolina	United States	29464
80		Spartanburg	South Carolina	United States	29303
81		Jackson	Tennessee	United States	38305
82		Memphis	Tennessee	United States	38119
83		Austin	Texas	United States	78705
84		Austin	Texas	United States	78758
85		Corpus Christi	Texas	United States	78413
86		Dallas	Texas	United States	75218
87		Houston	Texas	United States	77004
88		Houston	Texas	United States	77074
89		San Antonio	Texas	United States	78229
90		Sugar Land	Texas	United States	77479
91		Victoria	Texas	United States	77901
92		Waco	Texas	United States	76708
93		Chesapeake	Virginia	United States	23320
94		Danville	Virginia	United States	24541
95		Richmond	Virginia	United States	23235
96		Suffolk	Virginia	United States	23435
97		Virginia Beach	Virginia	United States	23462
98		Seattle	Washington	United States	98104
99		Morgantown	West Virginia	United States	26505
100		Camperdown	New South Wales	Australia	2050
101		Woodville South	South Australia	Australia	5011
102		Hobart	Tasmania	Australia	7000
103		Shenton Park	Western Australia	Australia	6008
104		Kelowna	British Columbia	Canada	V1Y 3G8
105		Victoria	British Columbia	Canada	V8V 3N7
106		Halifax	Nova Scotia	Canada	B3K 2M5
107		London	Ontario	Canada	N6A 5R8
108		Mississauga	Ontario	Canada	L5M 2V8
109		Toronto	Ontario	Canada	M9W 4L6
110		Quebec		Canada	G1V 3M7
111		Grafton	Auckland	New Zealand	1010
112		Tauranga	Bay of Plenty	New Zealand	3143
113		Hamilton		New Zealand	3240
114		Kutno	Lodz Province	Poland	99-300
115		Biatystok		Poland	15-430
116		Elblag		Poland	82-300
117		Katowice		Poland	40-954
118		Konskie		Poland	26-200
119		Krakow		Poland	30-510
120		Krakow		Poland	31-501
121		Poznan		Poland	60-539
122		Poznan		Poland	60-773
123		Lausanne	Vlaud	Switzerland	1011
124		Fribourg		Switzerland	1708

Sponsors and Collaborators

• Ardea Biosciences, Inc.

Investigators

• Study Director: Chris Storgard, MD, Ardea Biosciences, Inc.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Ardea Biosciences, Inc.
• ClinicalTrials.gov Identifier: NCT01510769
• Other Study ID Numbers: RDEA594-304; 2011-003768-55
• First Posted: Jan 16, 2012
• Last Update Posted: May 26, 2016
• Last Verified: Apr 1, 2016

• Additional relevant MeSH terms: Gout; Febuxostat; Lesinurad

Study Results

Participant Flow

Pre-assignment Detail	330 participants were randomized and 324 participants were included in the Intent-to-Treat (ITT) population (ie, 6 subjects were randomized but not treated).

Arm/Group Title	Lesinurad 200 mg + Febuxostat	Lesinurad 400 mg + Febuxostat	Placebo + Febuxostat
Arm/Group Description
Period Title: Overall Study
STARTED	106	109	109
COMPLETED	79	84	87
NOT COMPLETED	27	25	22

Baseline Characteristics

Arm/Group Title	Lesinurad 200 mg + Febuxostat	Lesinurad 400 mg + Febuxostat	Placebo + Febuxostat	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	106	109	109	324
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.2 (11.0)	53.3 (11.2)	54.6 (10.9)	54.1 (11.0)
Age, Customized (Number) [Number]
<65 Years	89 84%	90 82.6%	89 81.7%	268 82.7%
>=65 Years	17 16%	19 17.4%	20 18.3%	56 17.3%
Sex: Female, Male (Count of Participants)
Female	6 5.7%	7 6.4%	2 1.8%	15 4.6%
Male	100 94.3%	102 93.6%	107 98.2%	309 95.4%
Region of Enrollment (Number) [Number]
Australia	6 5.7%	6 5.5%	4 3.7%	16 4.9%
Canada	9 8.5%	2 1.8%	6 5.5%	17 5.2%
New Zealand	2 1.9%	6 5.5%	5 4.6%	13 4%
Poland	8 7.5%	10 9.2%	14 12.8%	32 9.9%
Switzerland	0 0%	1 0.9%	1 0.9%	2 0.6%
United States	81 76.4%	84 77.1%	79 72.5%	244 75.3%

Outcome Measures

1. Primary Outcome

Title	Subjects With a Serum Urate (sUA) Level That is < 5.0 mg/dL by Month 6
Description	Proportion of subjects with an sUA level that is < 5.0 mg/dL by Month 6
Time Frame	6 months, analysis after all subjects complete 12 months

Outcome Measure Data

Analysis Population Description

Intent-to-Treat Population

Arm/Group Title	Lesinurad 200 mg + Febuxostat 80 mg	Lesinurad 400 mg + Febuxostat 80 mg	Placebo + Febuxostat 80 mg
Arm/Group Description	lesinurad 200 mg once daily (qd) plus febuxostat 80 mg	lesinurad 400 mg qd plus febuxostat 80 mg	placebo qd plus febuxostat 80 mg
Measure Participants	106	109	109
Number [Proportion of Subjects]	0.566	0.761	0.468

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 200 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1298
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.10
	Confidence Interval	(2-Sided) 95%; -0.03 to 0.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 400 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 95%; 0.17 to 0.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Complete Resolution of at Least One Target Tophus
Description	Proportion of subjects who experience complete resolution of at least 1 target tophus by Month 12
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

Intent-to-Treat Population

Arm/Group Title	Lesinurad 200 mg + Febuxostat 80 mg	Lesinurad 400 mg + Febuxostat 80 mg	Placebo + Febuxostat 80 mg
Arm/Group Description	lesinurad 200 mg once daily (qd) plus febuxostat 80 mg	lesinurad 400 mg qd plus febuxostat 80 mg	placebo qd plus febuxostat 80 mg
Measure Participants	106	109	109
Number [Proportion of Subjects]	0.255	0.303	0.211

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 200 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4453
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 400 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1149
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Complete or Partial Response of at Least One Tophus
Description	Proportion of subjects with a best tophus response on at least 1 target tophus of complete (disappearance of at least 1 target tophus) or partial (≥ 50% decrease in the area of at least 1 target tophus) resolution by Month 12
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

Intent-to-Treat Population

Arm/Group Title	Lesinurad 200 mg + Febuxostat 80 mg	Lesinurad 400 mg + Febuxostat 80 mg	Placebo + Febuxostat 80 mg
Arm/Group Description	lesinurad 200 mg once daily (qd) plus febuxostat 80 mg	lesinurad 400 mg qd plus febuxostat 80 mg	placebo qd plus febuxostat 80 mg
Measure Participants	106	109	109
Number [Proportion of Subjects]	0.566	0.587	0.505

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 200 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6450
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.10 to 0.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 400 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4118
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.08 to 0.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Quality of Life
Description	Proportion of subjects with an improvement from Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) of at least 0.25 at Month 12. The HAQ-DI assesses a patient's level of functional ability with items scores ranging from 0-3 with 0 being the least disability.
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

Intent-to-Treat Population

Arm/Group Title	Lesinurad 200 mg + Febuxostat 80 mg	Lesinurad 400 mg + Febuxostat 80 mg	Placebo + Febuxostat 80 mg
Arm/Group Description	lesinurad 200 mg once daily (qd) plus febuxostat 80 mg	lesinurad 400 mg qd plus febuxostat 80 mg	placebo qd plus febuxostat 80 mg
Measure Participants	77	78	80
Number [Proportion of Subjects]	0.442	0.333	0.525

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 200 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3034
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.24 to 0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 400 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0210
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.34 to -0.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Arm/Group Title	Lesinurad 200 mg + Febuxostat		Lesinurad 400 mg + Febuxostat		Placebo + Febuxostat
Arm/Group Description
All Cause Mortality
	Lesinurad 200 mg + Febuxostat		Lesinurad 400 mg + Febuxostat		Placebo + Febuxostat
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Lesinurad 200 mg + Febuxostat		Lesinurad 400 mg + Febuxostat		Placebo + Febuxostat
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/106 (5.7%)		9/109 (8.3%)		10/109 (9.2%)
Cardiac disorders
Acute myocardial infarction	0/106 (0%)	0	1/109 (0.9%)	1	0/109 (0%)	0
Angina pectoris	0/106 (0%)	0	1/109 (0.9%)	2	0/109 (0%)	0
Arrhythmia	0/106 (0%)	0	0/109 (0%)	0	1/109 (0.9%)	1
Atrial fibrillation	1/106 (0.9%)	1	0/109 (0%)	0	0/109 (0%)	0
Cardiac failure acute	0/106 (0%)	0	1/109 (0.9%)	1	0/109 (0%)	0
Cardiac failure congestive	0/106 (0%)	0	1/109 (0.9%)	1	0/109 (0%)	0
Coronary artery disease	1/106 (0.9%)	1	1/109 (0.9%)	2	0/109 (0%)	0
Pulseless electrical activity	1/106 (0.9%)	1	0/109 (0%)	0	0/109 (0%)	0
Ear and labyrinth disorders
Vertigo	0/106 (0%)	0	1/109 (0.9%)	1	1/109 (0.9%)	1
Gastrointestinal disorders
Gastritis	1/106 (0.9%)	1	0/109 (0%)	0	0/109 (0%)	0
General disorders
Non-cardiac chest pain	0/106 (0%)	0	0/109 (0%)	0	1/109 (0.9%)	1
Hepatobiliary disorders
Cholecystitis acute	0/106 (0%)	0	1/109 (0.9%)	1	0/109 (0%)	0
Infections and infestations
Pneumonia	0/106 (0%)	0	0/109 (0%)	0	1/109 (0.9%)	1
Injury, poisoning and procedural complications
Subdural haematoma	0/106 (0%)	0	0/109 (0%)	0	1/109 (0.9%)	1
Laceration	1/106 (0.9%)	1	0/109 (0%)	0	0/109 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/106 (0%)	0	1/109 (0.9%)	1	0/109 (0%)	0
Gout	0/106 (0%)	0	1/109 (0.9%)	1	0/109 (0%)	0
Type 2 diabetes mellitus	1/106 (0.9%)	1	0/109 (0%)	0	0/109 (0%)	0
Musculoskeletal and connective tissue disorders
Joint contracture	0/106 (0%)	0	0/109 (0%)	0	1/109 (0.9%)	1
Osteoarthritis	0/106 (0%)	0	0/109 (0%)	0	1/109 (0.9%)	1
Spinal column stenosis	0/106 (0%)	0	1/109 (0.9%)	1	0/109 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer	0/106 (0%)	0	0/109 (0%)	0	1/109 (0.9%)	1
Renal and urinary disorders
Nephrolithiasis	0/106 (0%)	0	0/109 (0%)	0	1/109 (0.9%)	1
Renal failure acute	0/106 (0%)	0	1/109 (0.9%)	1	1/109 (0.9%)	1
Renal failure chronic	0/106 (0%)	0	1/109 (0.9%)	1	0/109 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/106 (0%)	0	0/109 (0%)	0	1/109 (0.9%)	1
Other (Not Including Serious) Adverse Events
	Lesinurad 200 mg + Febuxostat		Lesinurad 400 mg + Febuxostat		Placebo + Febuxostat
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	50/106 (47.2%)		59/109 (54.1%)		34/109 (31.2%)
Gastrointestinal disorders
Dental caries	0/106 (0%)	0	3/109 (2.8%)	3	0/109 (0%)	0
Toothache	1/106 (0.9%)	1	3/109 (2.8%)	3	0/109 (0%)	0
General disorders
Non-cardiac chest pain	1/106 (0.9%)	1	3/109 (2.8%)	4	0/109 (0%)	0
Pyrexia	1/106 (0.9%)	1	7/109 (6.4%)	7	4/109 (3.7%)	4
Infections and infestations
Influenza	6/106 (5.7%)	6	2/109 (1.8%)	4	2/109 (1.8%)	2
Nasopharyngitis	10/106 (9.4%)	10	15/109 (13.8%)	15	9/109 (8.3%)	12
Injury, poisoning and procedural complications
Contusion	2/106 (1.9%)	2	7/109 (6.4%)	9	3/109 (2.8%)	3
Excoriation	3/106 (2.8%)	3	2/109 (1.8%)	2	0/109 (0%)	0
Joint sprain	4/106 (3.8%)	4	6/109 (5.5%)	6	2/109 (1.8%)	2
Laceration	3/106 (2.8%)	3	8/109 (7.3%)	12	4/109 (3.7%)	5
Investigations
Blood creatine phosphokinase increased	6/106 (5.7%)	8	4/109 (3.7%)	4	3/109 (2.8%)	3
Blood creatinine increased	7/106 (6.6%)	7	8/109 (7.3%)	11	3/109 (2.8%)	3
Metabolism and nutrition disorders
Type 2 diabetes mellitus	4/106 (3.8%)	4	1/109 (0.9%)	1	1/109 (0.9%)	1
Musculoskeletal and connective tissue disorders
Back pain	8/106 (7.5%)	9	6/109 (5.5%)	7	5/109 (4.6%)	6
Pain in extremity	6/106 (5.7%)	9	9/109 (8.3%)	9	4/109 (3.7%)	4
Nervous system disorders
Headache	10/106 (9.4%)	11	6/109 (5.5%)	7	8/109 (7.3%)	12
Respiratory, thoracic and mediastinal disorders
Cough	4/106 (3.8%)	4	9/109 (8.3%)	9	3/109 (2.8%)	3
Sinus congestion	4/106 (3.8%)	4	0/109 (0%)	0	0/109 (0%)	0
Vascular disorders
Hypertension	6/106 (5.7%)	6	12/109 (11%)	13	8/109 (7.3%)	8

Limitations/Caveats

[Not Specified]

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

PI shall submit a copy of the Publication to Sponsor for review at least 45 days prior to its proposed submission. Sponsor reserves the right to delay any such publication for an additional period of 60 days. Upon Sponsor's request, PI agrees to delete from the proposed publication any Confidential Information. PI agrees not to release any publication without the prior written permission of Sponsor.