CLEAR 1: Combining Lesinurad With Allopurinol in Inadequate Responders

• Sponsor: Ardea Biosciences, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01510158
• Collaborator: (none)
• Enrollment: 607
• Locations: 166
• Arms: 3
• Duration (Months): 31
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study that compare the serum uric acid lowering effects, clinical benefits, and safety of lesinurad in combination with allopurinol to allopurinol alone in subjects with gout who have had an inadequate response to allopurinol.

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

Detailed Description

Allopurinol is the standard of care for the treatment of gout. Nevertheless, most patients treated with allopurinol do not achieve the recommended serum urate (sUA) target of < 6.0 mg/dL and need additional therapy to achieve the target. Probenecid and benzbromarone are uric acid transporter 1 (URAT1) inhibitors, generally recommended as second-line agents for patients who are either resistant to or intolerant of allopurinol. However, benzbromarone is not available in the US and probenecid is rarely used. Consequently, there is a clear unmet medical need for a new safe and effective therapy for gout, such as lesinurad, a potent URAT1 inhibitor, that can be used in combination with allopurinol in patients not responding adequately to allopurinol monotherapy so that very high rates of response can be achieved by nearly all gout patients, rather than a minority.The subjects selected for this study will have moderate to severe gout with an inadequate response to allopurinol

Study Design

• Study Type: Interventional
• Actual Enrollment: 607 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• 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 Allopurinol Compared to Allopurinol Alone in Subjects With Gout Who Have Had an Inadequate Hypouricemic Response to Standard of Care Allopurinol.
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: lesinurad 200 mg + allopurinol	Drug: Lesinurad; Tablets, 200 mg once daily (qd); Drug: Allopurinol; Tablets, ≥ 300 mg QD (≥ 200 mg qd for subjects with moderate renal impairment)
Experimental: lesinurad 400 mg + allopurinol	Drug: Lesinurad; Tablets, 400 mg qd; Drug: Allopurinol; Tablets, ≥ 300 mg QD (≥ 200 mg qd for subjects with moderate renal impairment)
Placebo Comparator: Placebo + allopurinol	Drug: Placebo; Tablets, Placebo qd; Drug: Allopurinol; Tablets, ≥ 300 mg QD (≥ 200 mg qd for subjects with moderate renal impairment)

Outcome Measures

Primary Outcome Measures

1. Proportion of Subjects With an sUA Level That is < 6.0 mg/dL [6 Months, analysis after all subjects complete 12 months]

Secondary Outcome Measures

1. Gout Flares [12 Months]

   Mean rate of gout flares requiring treatment for the 6-month period from the end of Month 6 to the end of Month 12

2. Tophus [12 Months]

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

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 meets the diagnosis of gout as per the American Rheumatism Association Criteria for the Classification of Acute Arthritis of Primary Gout.

• Subject has been taking allopurinol as the sole urate-lowering therapy indicated for the treatment of gout for at least 8 weeks prior to the Screening Visit at a stable, medically appropriate dose, as determined by the investigator, of at least 300 mg per day (at least 200 mg for subjects with moderate renal impairment).

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

• Subject has an sUA level ≥ 6.5 mg/dL at the Screening Visit and ≥ 6.0 mg/dL at Day -7 Visit.

• Subject has reported at least 2 gout flares in the prior 12 months.

• Body mass index (BMI) < 45 kg/m2

Exclusion Criteria:

• Subject with known hypersensitivity or allergy to allopurinol.

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

• Subject who is pregnant or breastfeeding.

• 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 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 class III or IV heart failure, myocardial infarction, stroke, or deep venous thrombosis; or subjects currently receiving anticoagulants.

• Subject with uncontrolled hypertension.

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

• 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 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		Athens	Alabama	United States	35611
2		Birmingham	Alabama	United States	35209
3		Birmingham	Alabama	United States	35213
4		Birmingham	Alabama	United States	35242
5		Birmingham	Alabama	United States	35294
6		Gulf Shores	Alabama	United States	36542
7		Mobile	Alabama	United States	36604
8		Mobile	Alabama	United States	36608
9		Pinson	Alabama	United States	35126
10		Glendale	Arizona	United States	85308
11		Goodyear	Arizona	United States	85395
12		Little Rock	Arizona	United States	72204
13		Little Rock	Arizona	United States	72211
14		Peoria	Arizona	United States	85381
15		Phoenix	Arizona	United States	85050
16		Tucson	Arizona	United States	85704
17		Tuscon	Arizona	United States	85723
18		Little Rock	Arkansas	United States	72206
19		Covina	California	United States	91723
20		Glendale	California	United States	91204
21		Huntington Beach	California	United States	92646
22		Inglewood	California	United States	90301
23		Lancaster	California	United States	93534
24		Lincoln	California	United States	95648
25		Orange	California	United States	92868
26		Sacramento	California	United States	95825
27		San Leandro	California	United States	94578
28		Santa Maria	California	United States	93454
29		Colorado Springs	Colorado	United States	80907
30		Colorado Springs	Colorado	United States	80918
31		Denver	Colorado	United States	80230
32		Englewood	Colorado	United States	80113
33		Milford	Connecticut	United States	06460
34		New London	Connecticut	United States	06320
35		Brooksville	Florida	United States	34601
36		Clearwater	Florida	United States	33765
37		Daytona Beach	Florida	United States	32114
38		East Bradenton	Florida	United States	34208
39		Gainesville	Florida	United States	32607
40		Miami	Florida	United States	33125
41		Miami	Florida	United States	33135
42		Miami	Florida	United States	33143
43		Miami	Florida	United States	33165
44		Miami	Florida	United States	33186
45		Naples	Florida	United States	34102
46		Ocala	Florida	United States	34474
47		Ormond Beach	Florida	United States	32174
48		Pembroke Pines	Florida	United States	33027
49		Pembroke Pines	Florida	United States	33029
50		Port Orange	Florida	United States	32127
51		Tampa	Florida	United States	33614
52		Vero Beach	Florida	United States	32960
53		Atlanta	Georgia	United States	30308
54		Atlanta	Georgia	United States	30328
55		Augusta	Georgia	United States	30909
56		Conyers	Georgia	United States	30013
57		Johns Creek	Georgia	United States	30097
58		Marietta	Georgia	United States	30060
59		Newman	Georgia	United States	30265
60		Newnan	Georgia	United States	30265
61		Honolulu	Hawaii	United States	96814
62		Idaho Falls	Idaho	United States	83404
63		Meridian	Idaho	United States	83642
64		Meridian	Idaho	United States	83646
65		Chicago	Illinois	United States	60612
66		Gurnee	Illinois	United States	60031
67		Evansville	Indiana	United States	47714
68		Franklin	Indiana	United States	46131
69		LaPorte	Indiana	United States	46350
70		Cedar Rapids	Iowa	United States	52403
71		Shawnee	Kansas	United States	66218
72		Elizabethtown	Kentucky	United States	41701
73		Paducah	Kentucky	United States	42003
74		Eunice	Louisiana	United States	70535
75		Metairie	Louisiana	United States	70006
76		Monroe	Louisiana	United States	71203
77		Natchitoches	Louisiana	United States	71457
78		Worcester	Massachusetts	United States	01605
79		Ann Arbor	Michigan	United States	48106
80		Kalamazoo	Michigan	United States	49009
81		Southfield	Michigan	United States	48034
82		Traverse City	Michigan	United States	49684
83		Jackson	Mississippi	United States	39202
84		Florissant	Missouri	United States	63031
85		Hazelwood	Missouri	United States	63042
86		Jefferson City	Missouri	United States	65109
87		Kansas City	Missouri	United States	64114
88		Saint Louis	Missouri	United States	63117
89		St. Louis	Missouri	United States	63128
90		Washington	Missouri	United States	63090
91		Missoula	Montana	United States	59808
92		Las Vegas	Nevada	United States	89119
93		Las Vegas	Nevada	United States	89183
94		Albuquerque	New Mexico	United States	87102
95		Endwell	New York	United States	13760
96		New York	New York	United States	10016
97		Syracuse	New York	United States	13210
98		Williamsville	New York	United States	14221
99		Greensboro	North Carolina	United States	27405
100		Raleigh	North Carolina	United States	27609
101		Raleigh	North Carolina	United States	27612
102		Shelby	North Carolina	United States	28150
103		Tabor City	North Carolina	United States	28463
104		Wilmington	North Carolina	United States	28401
105		Winston-Salem	North Carolina	United States	27103
106		Columbus	Ohio	United States	43235
107		Dayton	Ohio	United States	45417
108		Perrysburgh	Ohio	United States	43551
109		Willoughby Hills	Ohio	United States	44904
110		Oklahoma City	Oklahoma	United States	73103
111		Tulsa	Oklahoma	United States	74104
112		Ashland	Oregon	United States	97520
113		Altoona	Pennsylvania	United States	16602
114		Belle Vernon	Pennsylvania	United States	15012
115		Clairton	Pennsylvania	United States	15025
116		Duncansville	Pennsylvania	United States	16635
117		Jenkintown	Pennsylvania	United States	19046
118		Lansdale	Pennsylvania	United States	19446
119		Pittsburgh	Pennsylvania	United States	15206
120		Sellersville	Pennsylvania	United States	18960
121		Upper St. Clair	Pennsylvania	United States	15241
122		Wexford	Pennsylvania	United States	15090
123		Columbia	South Carolina	United States	29204
124		Mount Pleasant	South Carolina	United States	29464
125		Myrtle Beach	South Carolina	United States	29588
126		Rock Hill	South Carolina	United States	29732
127		Spartanburg	South Carolina	United States	29303
128		Brentwood	Tennessee	United States	37027
129		Jackson	Tennessee	United States	38305
130		Knoxville	Tennessee	United States	37923
131		Memphis	Tennessee	United States	38119
132		Austin	Texas	United States	78756
133		Corpus Christi	Texas	United States	78414
134		Dallas	Texas	United States	75218
135		El Paso	Texas	United States	79902
136		Fort Worth	Texas	United States	76135
137		Houston	Texas	United States	77004
138		Houston	Texas	United States	77043
139		Houston	Texas	United States	77062
140		Houston	Texas	United States	77098
141		Kingwood	Texas	United States	77339
142		Nassau Bay	Texas	United States	77058
143		Plabo	Texas	United States	75024
144		Plano	Texas	United States	75075
145		San Angelo	Texas	United States	76904
146		San Antonio	Texas	United States	78209
147		San Antonio	Texas	United States	78215
148		San Antonio	Texas	United States	78229
149		Sealy	Texas	United States	77474
150		Waco	Texas	United States	76708
151		Bountiful	Utah	United States	84010
152		Salt Lake City	Utah	United States	84102
153		West Jordan	Utah	United States	84088
154		Chesapeake	Virginia	United States	23320
155		Manassas	Virginia	United States	20110
156		Midlothian	Virginia	United States	23114
157		Richmond	Virginia	United States	23233
158		Richmond	Virginia	United States	23235
159		Suffolk	Virginia	United States	23435
160		Virginia Beach	Virginia	United States	23462
161		Port Orchard	Washington	United States	98366
162		Spokane	Washington	United States	99204
163		Spokane	Washington	United States	99208
164		Morgantown	West Virginia	United States	26505
165		Milwaukee	Wisconsin	United States	53226
166		Monroe	Wisconsin	United States	53566

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: NCT01510158
• Other Study ID Numbers: RDEA594-301
• First Posted: Jan 13, 2012
• Last Update Posted: Aug 18, 2016
• Last Verified: Jul 1, 2016

• Additional relevant MeSH terms: Gout; Allopurinol; Lesinurad

Study Results

Participant Flow

Arm/Group Title	Lesinurad 200 mg + Allopurinol	Lesinurad 400 mg + Allopurinol	Placebo + Allopurinol
Arm/Group Description	lesinurad 200 mg qd plus allopurinol	lesinurad 400 mg qd plus allopurinol	placebo qd plus allopurinol
Period Title: Overall Study
STARTED	202	203	202
COMPLETED	151	150	152
NOT COMPLETED	51	53	50

Baseline Characteristics

Arm/Group Title	Lesinurad 200 mg + Allopurinol	Lesinurad 400 mg + Allopurinol	Placebo + Allopurinol	Total
Arm/Group Description	lesinurad 200 mg qd plus allopurinol	lesinurad 400 mg qd plus allopurinol	placebo qd plus allopurinol	Total of all reporting groups
Overall Participants	201	201	201	603
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	51.6 (10.7)	52.3 (11.5)	51.7 (11.7)	51.9 (11.3)
Age, Customized (Number) [Number]
<65	181 90%	168 83.6%	169 84.1%	518 85.9%
>=65	20 10%	33 16.4%	32 15.9%	85 14.1%
Sex: Female, Male (Count of Participants)
Female	9 4.5%	15 7.5%	12 6%	36 6%
Male	192 95.5%	186 92.5%	189 94%	567 94%
Region of Enrollment (Number) [Number]
United States	201 100%	201 100%	201 100%	603 100%

Outcome Measures

1. Primary Outcome

Title	Proportion of Subjects With an sUA Level That is < 6.0 mg/dL
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 + Allopurinol	Lesinurad 400 mg + Allopurinol	Placebo + Allopurinol
Arm/Group Description	lesinurad 200 mg qd plus allopurinol	lesinurad 400 mg qd plus allopurinol	placebo qd plus allopurinol
Measure Participants	201	201	201
Number [Proportion of Subjects]	0.542	0.592	0.279

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 200 mg + Allopurinol, Placebo + Allopurinol
	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	0.26
	Confidence Interval	(2-Sided) 95%; 0.17 to 0.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.05
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 400 mg + Allopurinol, Placebo + Allopurinol
	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	0.31
	Confidence Interval	(2-Sided) 95%; 0.22 to 0.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.05
	Estimation Comments

2. Secondary Outcome

Title	Gout Flares
Description	Mean rate of gout flares requiring treatment for the 6-month period from the end of Month 6 to the end of Month 12
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lesinurad 200 mg + Allopurinol	Lesinurad 400 mg + Allopurinol	Placebo + Allopurinol
Arm/Group Description	lesinurad 200 mg qd plus allopurinol	lesinurad 400 mg qd plus allopurinol	placebo qd plus allopurinol
Measure Participants	201	201	201
Mean (Standard Deviation) [Gout Flares]	.60 (1.2)	.50 (1.2)	.60 (1.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 200 mg + Allopurinol, Placebo + Allopurinol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9796
	Comments
	Method	Negative Binomial Regression
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 400 mg + Allopurinol, Placebo + Allopurinol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6125
	Comments
	Method	Negative Binomial Regression
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.54 to 1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Tophus
Description	Proportion of subjects with ≥ 1 target tophus at Baseline who experience complete resolution of at least 1 target tophus by Month 12
Time Frame	12 Months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lesinurad 200 mg + Allopurinol	Lesinurad 400 mg + Allopurinol	Placebo + Allopurinol
Arm/Group Description	lesinurad 200 mg qd plus allopurinol	lesinurad 400 mg qd plus allopurinol	placebo qd plus allopurinol
Measure Participants	18	19	17
Number [Proportion of Subjects]	0	0.211	0.294

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 200 mg + Allopurinol, Placebo + Allopurinol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0183
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.51 to -0.08
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 400 mg + Allopurinol, Placebo + Allopurinol
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5974
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.37 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Adverse Event Reporting Description	Overall number of baseline participants used to determine number of participants at risk.
Arm/Group Title	Lesinurad 200 mg + Allopurinol		Lesinurad 400 mg + Allopurinol		Placebo + Allopurinol
Arm/Group Description	lesinurad 200 mg qd plus allopurinol		lesinurad 400 mg qd plus allopurinol		placebo qd plus allopurinol
All Cause Mortality
	Lesinurad 200 mg + Allopurinol		Lesinurad 400 mg + Allopurinol		Placebo + Allopurinol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Lesinurad 200 mg + Allopurinol		Lesinurad 400 mg + Allopurinol		Placebo + Allopurinol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/201 (4.5%)		16/201 (8%)		11/201 (5.5%)
Cardiac disorders
Acute myocardial infarction	1/201 (0.5%)	1	3/201 (1.5%)	3	0/201 (0%)	0
Angina pectoris	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Atrial flutter	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Cardiac arrest	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Cardiac failure congestive	1/201 (0.5%)	1	2/201 (1%)	3	0/201 (0%)	0
Coronary artery disease	2/201 (1%)	2	0/201 (0%)	0	0/201 (0%)	0
Myocardial infarction	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Myocardial ischaemia	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Gastrointestinal disorders
Alcoholic pancreatitis	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Pancreatitis acute	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
General disorders
Non-cardiac chest pain	1/201 (0.5%)	1	0/201 (0%)	0	1/201 (0.5%)	2
Systemic inflammatory response syndrome	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Hepatobiliary disorders
Bile duct stone	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Cholecystitis acute	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Infections and infestations
Abscess limb	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Cellulitis	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Escherichia infection	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Influenza	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Pneumonia	0/201 (0%)	0	1/201 (0.5%)	1	1/201 (0.5%)	1
Vulval abscess	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Vulval cellulitis	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Injury, poisoning and procedural complications
Clavicle fracture	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Concussion	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Coronary artery restenosis	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Facial bones fracture	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Metabolism and nutrition disorders
Dehydration	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Gout	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Lung neoplasm malignant	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Metastatic neoplasm	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Nervous system disorders
Cerebrovascular accident	0/201 (0%)	0	0/201 (0%)	0	2/201 (1%)	2
Transient ischaemic attack	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	2
Vascular dementia	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Vocal cord paralysis	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Psychiatric disorders
Suicide attempt	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Renal and urinary disorders
Calculus ureteric	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Renal failure	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Stag horn calculus	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Urinary retention	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Lesinurad 200 mg + Allopurinol		Lesinurad 400 mg + Allopurinol		Placebo + Allopurinol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	147/201 (73.1%)		156/201 (77.6%)		138/201 (68.7%)
Blood and lymphatic system disorders
Anaemia	0/201 (0%)	0	3/201 (1.5%)	3	1/201 (0.5%)	1
Leukocytosis	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Thrombocytopenia	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Thrombocytosis	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Cardiac disorders
Angina pectoris	2/201 (1%)	2	2/201 (1%)	2	0/201 (0%)	0
Arrhythmia	1/201 (0.5%)	1	0/201 (0%)	0	1/201 (0.5%)	1
Atrial fibrillation	0/201 (0%)	0	1/201 (0.5%)	1	1/201 (0.5%)	1
Atrial flutter	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Atrioventricular block first degree	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Bradycardia	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Coronary artery disease	0/201 (0%)	0	1/201 (0.5%)	1	1/201 (0.5%)	1
Hypertensive heart disease	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Myocardial ischaemia	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Tachycardia	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Ventricular extrasystoles	0/201 (0%)	0	1/201 (0.5%)	1	1/201 (0.5%)	1
Congenital, familial and genetic disorders
Hydrocele	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Ear and labyrinth disorders
Deafness transitory	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	2
Eustachian tube dysfunction	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Inner ear inflammation	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Middle ear effusion	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Otorrhoea	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Tinnitus	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Vertigo	1/201 (0.5%)	1	2/201 (1%)	2	1/201 (0.5%)	1
Endocrine disorders
Androgen deficiency	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Hyperparathyroidism primary	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Hyperthyroidism	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Hypogonadism	1/201 (0.5%)	1	1/201 (0.5%)	1	0/201 (0%)	0
Hypothyroidism	1/201 (0.5%)	1	1/201 (0.5%)	1	1/201 (0.5%)	1
Thyroid disorder	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Eye disorders
Astigmatism	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Blepharitis	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Cataract	1/201 (0.5%)	2	1/201 (0.5%)	1	1/201 (0.5%)	1
Conjunctival haemorrhage	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Conjunctivitis	2/201 (1%)	2	0/201 (0%)	0	0/201 (0%)	0
Eye pain	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Glaucoma	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Iridocyclitis	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Iritis	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Myopia	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Ocular hyperaemia	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Ocular icterus	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Posterior capsule opacification	0/201 (0%)	0	1/201 (0.5%)	3	0/201 (0%)	0
Presbyopia	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Retinal tear	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Vision blurred	1/201 (0.5%)	1	2/201 (1%)	2	0/201 (0%)	0
Visual impairment	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Gastrointestinal disorders
Abdominal discomfort	2/201 (1%)	3	1/201 (0.5%)	1	0/201 (0%)	0
Abdominal pain	0/201 (0%)	0	1/201 (0.5%)	1	2/201 (1%)	2
Abdominal pain upper	3/201 (1.5%)	3	4/201 (2%)	4	2/201 (1%)	3
Constipation	4/201 (2%)	4	6/201 (3%)	6	3/201 (1.5%)	3
Dental caries	1/201 (0.5%)	1	2/201 (1%)	3	2/201 (1%)	3
Diarrhoea	8/201 (4%)	8	8/201 (4%)	8	8/201 (4%)	8
Diverticulum intestinal	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Dry mouth	1/201 (0.5%)	1	1/201 (0.5%)	1	2/201 (1%)	2
Dyspepsia	1/201 (0.5%)	1	1/201 (0.5%)	1	3/201 (1.5%)	3
Dysphagia	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Eructation	1/201 (0.5%)	2	0/201 (0%)	0	0/201 (0%)	0
Flatulence	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Food poisoning	1/201 (0.5%)	1	1/201 (0.5%)	1	1/201 (0.5%)	1
Frequent bowel movements	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Gastric disorder	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Gastritis	1/201 (0.5%)	1	1/201 (0.5%)	1	0/201 (0%)	0
Gastrointestinal disorder	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Gastrooesophageal reflux disease	3/201 (1.5%)	3	3/201 (1.5%)	3	1/201 (0.5%)	1
Gingival pain	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Haematochezia	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Haemorrhoids	0/201 (0%)	0	3/201 (1.5%)	3	1/201 (0.5%)	1
Infrequent bowel movements	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Inguinal hernia	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Irritable bowel syndrome	0/201 (0%)	0	2/201 (1%)	2	0/201 (0%)	0
Loose tooth	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Nausea	2/201 (1%)	2	9/201 (4.5%)	11	9/201 (4.5%)	9
Pancreatitis acute	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Proctalgia	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Rectal haemorrhage	1/201 (0.5%)	1	1/201 (0.5%)	1	1/201 (0.5%)	1
Stomatitis	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Tooth impacted	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Toothache	1/201 (0.5%)	1	1/201 (0.5%)	1	2/201 (1%)	2
Umbilical hernia	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Vomiting	6/201 (3%)	6	6/201 (3%)	6	5/201 (2.5%)	5
General disorders
Chest discomfort	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Chest pain	2/201 (1%)	2	0/201 (0%)	0	1/201 (0.5%)	1
Chills	2/201 (1%)	2	3/201 (1.5%)	3	5/201 (2.5%)	5
Cyst	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Device breakage	1/201 (0.5%)	1	0/201 (0%)	0	1/201 (0.5%)	1
Facial pain	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Fatigue	5/201 (2.5%)	5	5/201 (2.5%)	5	3/201 (1.5%)	4
Gait disturbance	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Influenza like illness	0/201 (0%)	0	0/201 (0%)	0	2/201 (1%)	2
Irritability	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Local swelling	1/201 (0.5%)	1	1/201 (0.5%)	1	2/201 (1%)	2
Non-cardiac chest pain	5/201 (2.5%)	7	2/201 (1%)	2	3/201 (1.5%)	3
Oedema	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Oedema peripheral	4/201 (2%)	4	6/201 (3%)	6	5/201 (2.5%)	6
Pain	3/201 (1.5%)	3	1/201 (0.5%)	1	2/201 (1%)	3
Pyrexia	5/201 (2.5%)	6	6/201 (3%)	6	6/201 (3%)	6
Secretion discharge	1/201 (0.5%)	2	0/201 (0%)	0	0/201 (0%)	0
Thirst	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Xerosis	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Hepatobiliary disorders
Cholelithiasis	2/201 (1%)	2	0/201 (0%)	0	0/201 (0%)	0
Hepatic cyst	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Hepatic function abnormal	0/201 (0%)	0	2/201 (1%)	2	0/201 (0%)	0
Hepatic steatosis	1/201 (0.5%)	1	1/201 (0.5%)	1	1/201 (0.5%)	1
Immune system disorders
Allergy to arthropod sting	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Drug hypersensitivity	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Hypersensitivity	0/201 (0%)	0	1/201 (0.5%)	1	1/201 (0.5%)	1
Seasonal allergy	0/201 (0%)	0	2/201 (1%)	2	4/201 (2%)	4
Infections and infestations
Abscess limb	0/201 (0%)	0	1/201 (0.5%)	2	0/201 (0%)	0
Acute sinusitis	1/201 (0.5%)	1	1/201 (0.5%)	1	2/201 (1%)	2
Arthritis infective	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Beta haemolytic streptococcal infection	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Bronchitis	3/201 (1.5%)	3	7/201 (3.5%)	8	1/201 (0.5%)	1
Cellulitis	1/201 (0.5%)	1	3/201 (1.5%)	3	2/201 (1%)	2
Chronic sinusitis	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Conjunctivitis infective	0/201 (0%)	0	2/201 (1%)	2	0/201 (0%)	0
Cystitis	3/201 (1.5%)	3	0/201 (0%)	0	0/201 (0%)	0
Diarrhoea infectious	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Diverticulitis	0/201 (0%)	0	1/201 (0.5%)	1	1/201 (0.5%)	1
Ear infection	1/201 (0.5%)	1	1/201 (0.5%)	1	1/201 (0.5%)	1
Escherichia urinary tract infection	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Eye infection	2/201 (1%)	2	0/201 (0%)	0	2/201 (1%)	2
Folliculitis	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Fungal infection	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Furuncle	1/201 (0.5%)	1	1/201 (0.5%)	1	0/201 (0%)	0
Gastroenteritis	3/201 (1.5%)	4	5/201 (2.5%)	5	5/201 (2.5%)	5
Gastroenteritis viral	4/201 (2%)	5	3/201 (1.5%)	3	4/201 (2%)	4
Haemophilus infection	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Helicobacter infection	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Herpes zoster	1/201 (0.5%)	1	1/201 (0.5%)	1	0/201 (0%)	0
Hordeolum	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Infected skin ulcer	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Influenza	5/201 (2.5%)	6	6/201 (3%)	6	8/201 (4%)	10
Localised infection	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Lower respiratory tract infection	0/201 (0%)	0	3/201 (1.5%)	4	1/201 (0.5%)	1
Nail infection	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Nasopharyngitis	17/201 (8.5%)	23	15/201 (7.5%)	18	14/201 (7%)	17
Onychomycosis	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Oral candidiasis	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Oral herpes	1/201 (0.5%)	1	1/201 (0.5%)	3	0/201 (0%)	0
Otitis externa	1/201 (0.5%)	1	1/201 (0.5%)	1	1/201 (0.5%)	1
Paronychia	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Peptostreptococcus infection	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Peritonsillar abscess	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Pharyngitis	2/201 (1%)	2	3/201 (1.5%)	3	3/201 (1.5%)	3
Pharyngitis streptococcal	2/201 (1%)	2	1/201 (0.5%)	1	1/201 (0.5%)	1
Pneumonia	0/201 (0%)	0	2/201 (1%)	2	2/201 (1%)	2
Post procedural infection	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Rash pustular	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Respiratory tract infection	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Respiratory tract infection viral	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Rhinitis	0/201 (0%)	0	1/201 (0.5%)	1	1/201 (0.5%)	1
Sialoadenitis	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Sinusitis	9/201 (4.5%)	11	12/201 (6%)	15	4/201 (2%)	4
Skin candida	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Skin infection	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Staphylococcal infection	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Subcutaneous abscess	3/201 (1.5%)	3	0/201 (0%)	0	0/201 (0%)	0
Tinea cruris	0/201 (0%)	0	1/201 (0.5%)	1	1/201 (0.5%)	1
Tooth abscess	2/201 (1%)	2	4/201 (2%)	4	1/201 (0.5%)	1
Tooth infection	0/201 (0%)	0	2/201 (1%)	2	1/201 (0.5%)	1
Upper respiratory tract infection	22/201 (10.9%)	28	18/201 (9%)	22	11/201 (5.5%)	13
Urinary tract infection	3/201 (1.5%)	3	10/201 (5%)	10	4/201 (2%)	5
Viral infection	3/201 (1.5%)	3	1/201 (0.5%)	1	2/201 (1%)	2
Viral upper respiratory tract infection	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Vulval abscess	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Vulval cellulitis	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Wound infection	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Injury, poisoning and procedural complications
Animal bite	0/201 (0%)	0	2/201 (1%)	2	0/201 (0%)	0
Animal scratch	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Arthropod bite	1/201 (0.5%)	1	4/201 (2%)	4	1/201 (0.5%)	1
Back injury	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Bite	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Clavicle fracture	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Concussion	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Contusion	6/201 (3%)	6	7/201 (3.5%)	10	6/201 (3%)	6
Epicondylitis	1/201 (0.5%)	1	1/201 (0.5%)	1	1/201 (0.5%)	1
Excoriation	2/201 (1%)	2	2/201 (1%)	2	0/201 (0%)	0
Eye injury	0/201 (0%)	0	0/201 (0%)	0	3/201 (1.5%)	3
Facial bones fracture	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Fall	6/201 (3%)	7	6/201 (3%)	7	8/201 (4%)	9
Foot fracture	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Hand fracture	0/201 (0%)	0	2/201 (1%)	2	0/201 (0%)	0
Heat stroke	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Joint injury	0/201 (0%)	0	3/201 (1.5%)	3	2/201 (1%)	2
Joint sprain	1/201 (0.5%)	1	3/201 (1.5%)	4	3/201 (1.5%)	3
Laceration	2/201 (1%)	2	2/201 (1%)	2	3/201 (1.5%)	3
Ligament rupture	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Ligament sprain	0/201 (0%)	0	1/201 (0.5%)	1	2/201 (1%)	2
Limb injury	1/201 (0.5%)	1	0/201 (0%)	0	2/201 (1%)	2
Meniscus lesion	1/201 (0.5%)	1	1/201 (0.5%)	2	2/201 (1%)	2
Muscle injury	0/201 (0%)	0	0/201 (0%)	0	3/201 (1.5%)	3
Muscle rupture	1/201 (0.5%)	1	1/201 (0.5%)	1	2/201 (1%)	2
Muscle strain	10/201 (5%)	10	10/201 (5%)	12	7/201 (3.5%)	9
Nail avulsion	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Periorbital haematoma	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Procedural pain	0/201 (0%)	0	0/201 (0%)	0	2/201 (1%)	2
Road traffic accident	2/201 (1%)	2	3/201 (1.5%)	3	1/201 (0.5%)	1
Scratch	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Skeletal injury	0/201 (0%)	0	1/201 (0.5%)	1	1/201 (0.5%)	1
Soft tissue injury	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Spinal compression fracture	0/201 (0%)	0	2/201 (1%)	2	0/201 (0%)	0
Sunburn	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Traumatic haematoma	0/201 (0%)	0	1/201 (0.5%)	1	1/201 (0.5%)	1
Ulna fracture	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Wound	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	2
Investigations
Alanine aminotransferase increased	2/201 (1%)	2	1/201 (0.5%)	1	0/201 (0%)	0
Aspartate aminotransferase increased	2/201 (1%)	2	0/201 (0%)	0	1/201 (0.5%)	1
Blood alkaline phosphatase increased	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Blood amylase increased	2/201 (1%)	2	1/201 (0.5%)	1	1/201 (0.5%)	1
Blood bicarbonate decreased	3/201 (1.5%)	4	5/201 (2.5%)	7	3/201 (1.5%)	3
Blood cholesterol increased	0/201 (0%)	0	2/201 (1%)	2	1/201 (0.5%)	1
Blood creatine phosphokinase increased	9/201 (4.5%)	10	16/201 (8%)	16	5/201 (2.5%)	5
Blood creatinine increased	7/201 (3.5%)	11	14/201 (7%)	19	2/201 (1%)	2
Blood glucose increased	4/201 (2%)	5	4/201 (2%)	4	1/201 (0.5%)	1
Blood potassium decreased	0/201 (0%)	0	2/201 (1%)	2	0/201 (0%)	0
Blood pressure increased	0/201 (0%)	0	2/201 (1%)	2	1/201 (0.5%)	1
Blood testosterone decreased	1/201 (0.5%)	1	1/201 (0.5%)	1	1/201 (0.5%)	1
Blood triglycerides increased	1/201 (0.5%)	1	6/201 (3%)	6	4/201 (2%)	4
Blood urea increased	2/201 (1%)	4	3/201 (1.5%)	4	2/201 (1%)	2
Blood urine present	0/201 (0%)	0	1/201 (0.5%)	1	1/201 (0.5%)	1
Body temperature decreased	1/201 (0.5%)	4	0/201 (0%)	0	0/201 (0%)	0
Body temperature increased	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
C-reactive protein increased	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Cardiac murmur	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Cardiac stress test abnormal	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Electrocardiogram qt prolonged	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Electrocardiogram t wave abnormal	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Electrocardiogram abnormal	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Gamma-glutamyltransferase increased	0/201 (0%)	0	3/201 (1.5%)	3	3/201 (1.5%)	6
Glucose urine present	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Glycosylated haemoglobin increased	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Haematocrit increased	0/201 (0%)	0	1/201 (0.5%)	1	1/201 (0.5%)	1
Haemoglobin increased	0/201 (0%)	0	1/201 (0.5%)	1	1/201 (0.5%)	1
Hepatic enzyme increased	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Neutrophil count increased	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Platelet count increased	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Red blood cell count increased	1/201 (0.5%)	1	1/201 (0.5%)	1	1/201 (0.5%)	1
Urine output decreased	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Vitamin b12 decreased	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
White blood cell count decreased	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
White blood cell count increased	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
White blood cells urine positive	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Dehydration	3/201 (1.5%)	3	2/201 (1%)	3	0/201 (0%)	0
Diabetes mellitus	2/201 (1%)	2	1/201 (0.5%)	1	1/201 (0.5%)	1
Diabetes mellitus inadequate control	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Hyperamylasaemia	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Hypercholesterolaemia	2/201 (1%)	2	2/201 (1%)	2	1/201 (0.5%)	1
Hyperglycaemia	0/201 (0%)	0	1/201 (0.5%)	2	2/201 (1%)	2
Hyperkalaemia	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Hyperlipidaemia	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Hypertriglyceridaemia	5/201 (2.5%)	5	2/201 (1%)	2	1/201 (0.5%)	1
Hypocalcaemia	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Hypoglycaemia	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Hypokalaemia	2/201 (1%)	2	1/201 (0.5%)	1	1/201 (0.5%)	1
Hyponatraemia	0/201 (0%)	0	1/201 (0.5%)	1	1/201 (0.5%)	1
Iron deficiency	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Type 2 diabetes mellitus	4/201 (2%)	4	5/201 (2.5%)	5	0/201 (0%)	0
Vitamin b complex deficiency	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Vitamin d deficiency	2/201 (1%)	2	2/201 (1%)	2	0/201 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	8/201 (4%)	9	16/201 (8%)	18	19/201 (9.5%)	23
Arthritis	1/201 (0.5%)	1	4/201 (2%)	5	1/201 (0.5%)	1
Back pain	16/201 (8%)	18	9/201 (4.5%)	12	19/201 (9.5%)	21
Bursitis	3/201 (1.5%)	3	4/201 (2%)	4	1/201 (0.5%)	1
Flank pain	3/201 (1.5%)	4	2/201 (1%)	2	2/201 (1%)	2
Haemarthrosis	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Intervertebral disc degeneration	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Intervertebral disc protrusion	1/201 (0.5%)	1	1/201 (0.5%)	1	0/201 (0%)	0
Joint effusion	0/201 (0%)	0	2/201 (1%)	2	0/201 (0%)	0
Joint hyperextension	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Joint stiffness	1/201 (0.5%)	1	1/201 (0.5%)	1	2/201 (1%)	2
Joint swelling	1/201 (0.5%)	1	3/201 (1.5%)	3	0/201 (0%)	0
Limb discomfort	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Medial tibial stress syndrome	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Muscle spasms	2/201 (1%)	3	4/201 (2%)	5	4/201 (2%)	5
Muscular weakness	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Musculoskeletal chest pain	1/201 (0.5%)	1	1/201 (0.5%)	1	0/201 (0%)	0
Musculoskeletal discomfort	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Musculoskeletal pain	2/201 (1%)	2	2/201 (1%)	2	9/201 (4.5%)	10
Musculoskeletal stiffness	1/201 (0.5%)	1	1/201 (0.5%)	1	0/201 (0%)	0
Myalgia	3/201 (1.5%)	3	8/201 (4%)	8	4/201 (2%)	4
Myalgia intercostal	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Neck pain	1/201 (0.5%)	1	2/201 (1%)	2	2/201 (1%)	2
Nodal osteoarthritis	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Osteoarthritis	2/201 (1%)	2	0/201 (0%)	0	2/201 (1%)	2
Pain in extremity	7/201 (3.5%)	8	5/201 (2.5%)	5	9/201 (4.5%)	11
Polyarthritis	1/201 (0.5%)	1	0/201 (0%)	0	1/201 (0.5%)	1
Psoriatic arthropathy	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Rheumatoid arthritis	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Rotator cuff syndrome	0/201 (0%)	0	1/201 (0.5%)	1	2/201 (1%)	2
Synovial cyst	0/201 (0%)	0	1/201 (0.5%)	1	1/201 (0.5%)	1
Tendon pain	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Tendonitis	5/201 (2.5%)	5	3/201 (1.5%)	3	3/201 (1.5%)	3
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Lipoma	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Lung neoplasm	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Neuroma	0/201 (0%)	0	2/201 (1%)	2	0/201 (0%)	0
Seborrhoeic keratosis	1/201 (0.5%)	1	1/201 (0.5%)	1	0/201 (0%)	0
Skin papilloma	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Squamous cell carcinoma of skin	1/201 (0.5%)	1	1/201 (0.5%)	1	1/201 (0.5%)	1
Thyroid neoplasm	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Nervous system disorders
Carpal tunnel syndrome	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Cataplexy	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Convulsion	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Disturbance in attention	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Dizziness	4/201 (2%)	5	9/201 (4.5%)	9	2/201 (1%)	2
Dysgeusia	2/201 (1%)	2	1/201 (0.5%)	1	0/201 (0%)	0
Headache	7/201 (3.5%)	9	12/201 (6%)	15	5/201 (2.5%)	5
Hypoaesthesia	2/201 (1%)	2	4/201 (2%)	4	0/201 (0%)	0
Loss of consciousness	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Migraine	2/201 (1%)	2	1/201 (0.5%)	1	0/201 (0%)	0
Nerve compression	0/201 (0%)	0	0/201 (0%)	0	2/201 (1%)	2
Neuralgia	1/201 (0.5%)	1	0/201 (0%)	0	1/201 (0.5%)	1
Neuropathy peripheral	1/201 (0.5%)	2	2/201 (1%)	2	0/201 (0%)	0
Paraesthesia	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Presyncope	1/201 (0.5%)	1	0/201 (0%)	0	1/201 (0.5%)	1
Radiculitis brachial	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Restless legs syndrome	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Sciatica	1/201 (0.5%)	1	0/201 (0%)	0	3/201 (1.5%)	3
Sinus headache	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Somnolence	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Syncope	3/201 (1.5%)	3	2/201 (1%)	2	1/201 (0.5%)	1
Tension headache	1/201 (0.5%)	1	1/201 (0.5%)	1	1/201 (0.5%)	1
Tremor	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Viith nerve paralysis	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Vascular dementia	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Psychiatric disorders
Agitation	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Anxiety	2/201 (1%)	2	3/201 (1.5%)	3	1/201 (0.5%)	1
Confusional state	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Depression	1/201 (0.5%)	1	2/201 (1%)	2	3/201 (1.5%)	5
Euphoric mood	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Insomnia	5/201 (2.5%)	5	2/201 (1%)	2	4/201 (2%)	4
Libido decreased	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Libido increased	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Sleep disorder	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Renal and urinary disorders
Acute prerenal failure	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Bladder dysfunction	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Calculus ureteric	0/201 (0%)	0	2/201 (1%)	2	0/201 (0%)	0
Haematuria	4/201 (2%)	4	4/201 (2%)	4	1/201 (0.5%)	1
Hydronephrosis	0/201 (0%)	0	2/201 (1%)	2	0/201 (0%)	0
Nephrolithiasis	2/201 (1%)	2	4/201 (2%)	4	4/201 (2%)	4
Proteinuria	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Pyuria	0/201 (0%)	0	3/201 (1.5%)	3	0/201 (0%)	0
Renal failure	1/201 (0.5%)	1	2/201 (1%)	2	3/201 (1.5%)	3
Stag horn calculus	0/201 (0%)	0	1/201 (0.5%)	3	0/201 (0%)	0
Urethral perforation	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Urinary incontinence	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Urinary retention	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Reproductive system and breast disorders
Acquired hydrocele	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Benign prostatic hyperplasia	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Breast swelling	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Breast tenderness	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Cystocele	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Erectile dysfunction	1/201 (0.5%)	1	2/201 (1%)	2	0/201 (0%)	0
Haematospermia	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Menopausal symptoms	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Postmenopausal haemorrhage	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Sexual dysfunction	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Testicular pain	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Varicocele	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Vulvovaginal pain	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	0/201 (0%)	0	2/201 (1%)	2	1/201 (0.5%)	1
Chronic obstructive pulmonary disease	1/201 (0.5%)	2	0/201 (0%)	0	0/201 (0%)	0
Cough	4/201 (2%)	4	4/201 (2%)	4	5/201 (2.5%)	6
Dyspnoea	2/201 (1%)	2	1/201 (0.5%)	1	5/201 (2.5%)	5
Epistaxis	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Nasal congestion	3/201 (1.5%)	3	2/201 (1%)	2	1/201 (0.5%)	1
Oropharyngeal pain	2/201 (1%)	2	5/201 (2.5%)	5	0/201 (0%)	0
Pleurisy	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Pneumonitis	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Pulmonary congestion	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Respiratory failure	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Respiratory tract congestion	1/201 (0.5%)	3	1/201 (0.5%)	1	1/201 (0.5%)	1
Rhinitis allergic	1/201 (0.5%)	1	1/201 (0.5%)	1	0/201 (0%)	0
Rhinorrhoea	0/201 (0%)	0	1/201 (0.5%)	2	2/201 (1%)	2
Sinus congestion	4/201 (2%)	4	3/201 (1.5%)	3	4/201 (2%)	5
Sleep apnoea syndrome	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Upper-airway cough syndrome	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Vasomotor rhinitis	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Wheezing	0/201 (0%)	0	1/201 (0.5%)	1	2/201 (1%)	2
Skin and subcutaneous tissue disorders
Acne	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Dandruff	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Decubitus ulcer	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Dermal cyst	2/201 (1%)	2	0/201 (0%)	0	0/201 (0%)	0
Dermatitis	1/201 (0.5%)	1	1/201 (0.5%)	2	0/201 (0%)	0
Dermatitis atopic	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Dermatitis contact	1/201 (0.5%)	1	0/201 (0%)	0	2/201 (1%)	2
Dry skin	1/201 (0.5%)	1	0/201 (0%)	0	1/201 (0.5%)	1
Eczema	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Erythema	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Hyperhidrosis	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Night sweats	1/201 (0.5%)	1	0/201 (0%)	0	1/201 (0.5%)	1
Pain of skin	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Photosensitivity reaction	1/201 (0.5%)	1	1/201 (0.5%)	1	0/201 (0%)	0
Pruritus	3/201 (1.5%)	5	1/201 (0.5%)	1	0/201 (0%)	0
Psoriasis	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Rash	7/201 (3.5%)	8	5/201 (2.5%)	5	4/201 (2%)	5
Rash maculo-papular	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Rash pruritic	0/201 (0%)	0	1/201 (0.5%)	1	0/201 (0%)	0
Rash vesicular	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Rosacea	2/201 (1%)	2	0/201 (0%)	0	0/201 (0%)	0
Skin lesion	1/201 (0.5%)	1	0/201 (0%)	0	1/201 (0.5%)	1
Skin ulcer	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1
Urticaria	2/201 (1%)	2	1/201 (0.5%)	1	1/201 (0.5%)	1
Vascular disorders
Haematoma	1/201 (0.5%)	1	2/201 (1%)	2	1/201 (0.5%)	1
Hot flush	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Hyperaemia	1/201 (0.5%)	1	0/201 (0%)	0	0/201 (0%)	0
Hypertension	8/201 (4%)	8	7/201 (3.5%)	7	7/201 (3.5%)	7
Hypotension	2/201 (1%)	2	0/201 (0%)	0	0/201 (0%)	0
Varicose vein	0/201 (0%)	0	0/201 (0%)	0	1/201 (0.5%)	1

Limitations/Caveats

[Not Specified]

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Certain Agreements

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.