Combining Lesinurad With Allopurinol in Inadequate Responders (CLEAR 2)

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ClinicalTrials.gov Identifier: NCT01493531

Recruitment Status : Completed

First Posted : December 16, 2011

Results First Posted : May 26, 2016

Last Update Posted : May 26, 2016

Sponsor:

Information provided by (Responsible Party):

Ardea Biosciences, Inc.

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition	Gout
Interventions	Drug: Lesinurad Drug: Placebo Drug: Allopurinol
Enrollment	610

Participant Flow

Recruitment Details
Pre-assignment Details


Arm/Group Title	Lesinurad 200 mg + Allopurinol	Lesinurad 400 mg + Allopurinol	Placebo + Allopurinol
Arm/Group Description	lesinurad 200 mg qd plus allopurino...	lesinurad 400 mg qd plus allopurino...
Arm/Group Description	lesinurad 200 mg qd plus allopurinol	lesinurad 400 mg qd plus allopurinol	[Not Specified]
Period Title: Overall Study
Started	204	200	206
Completed	163	150	158
Not Completed	41	50	48
Reason Not Completed
Adverse Event	4	12	9
Gout flare	3	0	2
Protocol Violation	8	15	12
Sponsor terminated study	5	2	3
Lost to Follow-up	5	7	11
Withdrawal by Subject	16	13	11
Death	0	1	0

Baseline Characteristics

Arm/Group Title		Lesinurad 200 mg + Allopurinol	Lesinurad 400 mg + Allopurinol	Placebo + Allopurinol	Total
Arm/Group Description		lesinurad 200 mg qd plus allopurino...	lesinurad 400 mg qd plus allopurino...	[Not Specified]	Total of all reporting groups
Arm/Group Description		lesinurad 200 mg qd plus allopurinol	lesinurad 400 mg qd plus allopurinol	[Not Specified]	Total of all reporting groups
Overall Number of Baseline Participants		204	200	206	610
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	204 participants	200 participants	206 participants	610 participants
		51.0 (11.1)	51.3 (11.1)	51.4 (10.6)	51.2 (10.9)
Age, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	204 participants	200 participants	206 participants	610 participants
<65		184	175	185	544
>=65		20	25	21	66
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	204 participants	200 participants	206 participants	610 participants
	Female	7 3.4%	6 3.0%	10 4.9%	23 3.8%
	Male	197 96.6%	194 97.0%	196 95.1%	587 96.2%
Region of Enrollment Measure Type: Number Unit of measure: Participants	Number Analyzed	204 participants	200 participants	206 participants	610 participants
Australia		4	9	4	17
Belgium		1	1	2	4
Canada		7	6	12	25
Germany		9	8	8	25
New Zealand		12	7	7	26
Poland		5	11	6	22
South Africa		30	36	33	99
Spain		2	4	2	8
Switzerland		1	0	0	1
Ukraine		25	24	25	74
United States		108	94	107	309

Outcome Measures

1.Primary Outcome


Title	Subjects With a Serum Urate (sUA) < 6.0 mg/dL by Month 6.
Description	Proportion of subjects with an sUA level that is < 6.0 mg/dL by Mon...
Description	Proportion of subjects with an sUA level that is < 6.0 mg/dL by Month 6.
Time Frame	6 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 allopurino...	lesinurad 400 mg qd plus allopurino...	placebo qd plus allopurinol
Arm/Group Description:	lesinurad 200 mg qd plus allopurinol	lesinurad 400 mg qd plus allopurinol	placebo qd plus allopurinol
Overall Number of Participants Analyzed	204	200	206
Measure Type: Number Unit of Measure: Proportion of Subjects
	0.554	0.665	0.233

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 200 mg + Allopurinol, Placebo + Allopurinol
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.32
	Confidence Interval	(2-Sided) 95% 0.23 to 0.41
	Parameter Dispersion	Type: Standard Error of the mean Value: 0.05
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 400 mg + Allopurinol, Placebo + Allopurinol
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	0.43
	Confidence Interval	(2-Sided) 95% 0.34 to 0.52
	Parameter Dispersion	Type: Standard Error of the mean Value: 0.05
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Gout Flares
Description	Mean rate of gout flares requiring treatment for the 6-month period fr...
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 allopurino...	lesinurad 400 mg qd plus allopurino...	placebo qd plus allopurinol
Arm/Group Description:	lesinurad 200 mg qd plus allopurinol	lesinurad 400 mg qd plus allopurinol	placebo qd plus allopurinol
Overall Number of Participants Analyzed	204	200	206
Mean (Standard Deviation) Unit of Measure: Gout Flares
	0.7 (1.4)	0.8 (1.7)	0.9 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 200 mg + Allopurinol, Placebo + Allopurinol
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.5716
	Comments	[Not Specified]
	Method	Negative Binomial Regression
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95% 0.57 to 1.37
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 400 mg + Allopurinol, Placebo + Allopurinol
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7454
	Comments	[Not Specified]
	Method	Negative Binomial Regression
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95% 0.60 to 1.45
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Subjects With ≥ 1 Target Tophus at Baseline Who Experience Complete Resolution of at Least 1 Target Tophus by Month 12
Description	Proportion of subjects with ≥ 1 target tophus at Baseline who ex...
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 allopurino...	lesinurad 400 mg qd plus allopurino...	placebo qd plus allopurinol
Arm/Group Description:	lesinurad 200 mg qd plus allopurinol	lesinurad 400 mg qd plus allopurinol	placebo qd plus allopurinol
Overall Number of Participants Analyzed	35	29	33
Measure Type: Number Unit of Measure: Proportion of Subjects
	0.314	0.276	0.333

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 200 mg + Allopurinol, Placebo + Allopurinol
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.8466
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95% -0.24 to 0.2
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lesinurad 400 mg + Allopurinol, Placebo + Allopurinol
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.6301
	Comments	[Not Specified]
	Method	Cochran-Mantel-Haenszel
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Risk Difference (RD)
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95% -0.29 to 0.17
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]

Arm/Group Title	Lesinurad 200 mg + Allopurinol		Lesinurad 400 mg + Allopurinol		Placebo + Allopurinol
Arm/Group Description	lesinurad 200 mg qd plus allopurino...		lesinurad 400 mg qd plus allopurino...		[Not Specified]
Arm/Group Description	lesinurad 200 mg qd plus allopurinol		lesinurad 400 mg qd plus allopurinol		[Not Specified]
All-Cause Mortality
	Lesinurad 200 mg + Allopurinol		Lesinurad 400 mg + Allopurinol		Placebo + Allopurinol
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--
Serious Adverse Events 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	9/204 (4.41%)		19/200 (9.50%)		8/206 (3.88%)
Cardiac disorders
Coronary artery disease ^† 1	0/204 (0.00%)	0	1/200 (0.50%)	1	0/206 (0.00%)	0
Myocardial infarction ^† 1	0/204 (0.00%)	0	3/200 (1.50%)	3	0/206 (0.00%)	0
Atrial fibrillation ^† 1	1/204 (0.49%)	1	0/200 (0.00%)	0	0/206 (0.00%)	0
Intracardiac thrombus ^† 1	0/204 (0.00%)	0	1/200 (0.50%)	1	0/206 (0.00%)	0
Gastrointestinal disorders
Duodenal ulcer haemorrhage ^† 1	0/204 (0.00%)	0	1/200 (0.50%)	1	1/206 (0.49%)	1
Gastrointestinal haemorrhage ^† 1	1/204 (0.49%)	1	0/200 (0.00%)	0	0/206 (0.00%)	0
General disorders
Adverse drug reaction ^† 1	1/204 (0.49%)	1	0/200 (0.00%)	0	0/206 (0.00%)	0
Non-cardiac chest pain ^† 1	1/204 (0.49%)	1	0/200 (0.00%)	0	0/206 (0.00%)	0
Infections and infestations
Pneumonia ^† 1	2/204 (0.98%)	2	0/200 (0.00%)	0	0/206 (0.00%)	0
Bronchopneumonia ^† 1	0/204 (0.00%)	0	1/200 (0.50%)	1	0/206 (0.00%)	0
Cellulitis ^† 1	0/204 (0.00%)	0	1/200 (0.50%)	1	0/206 (0.00%)	0
Empyema ^† 1	1/204 (0.49%)	1	0/200 (0.00%)	0	0/206 (0.00%)	0
Pyelonephritis chronic ^† 1	0/204 (0.00%)	0	1/200 (0.50%)	1	0/206 (0.00%)	0
Sinobronchitis ^† 1	1/204 (0.49%)	1	0/200 (0.00%)	0	0/206 (0.00%)	0
Abscess limb ^† 1	0/204 (0.00%)	0	0/200 (0.00%)	0	1/206 (0.49%)	1
Appendicitis ^† 1	0/204 (0.00%)	0	0/200 (0.00%)	0	1/206 (0.49%)	1
Diverticulitis ^† 1	0/204 (0.00%)	0	0/200 (0.00%)	0	1/206 (0.49%)	1
Injury, poisoning and procedural complications
Multiple drug overdose ^† 1	1/204 (0.49%)	1	0/200 (0.00%)	0	0/206 (0.00%)	0
Multiple injuries ^† 1	1/204 (0.49%)	1	0/200 (0.00%)	0	0/206 (0.00%)	0
Femur fracture ^† 1	0/204 (0.00%)	0	0/200 (0.00%)	0	1/206 (0.49%)	1
Metabolism and nutrition disorders
Gout ^† 1	0/204 (0.00%)	0	2/200 (1.00%)	4	0/206 (0.00%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis ^† 1	0/204 (0.00%)	0	2/200 (1.00%)	2	0/206 (0.00%)	0
Arthralgia ^† 1	1/204 (0.49%)	1	0/200 (0.00%)	0	0/206 (0.00%)	0
Back pain ^† 1	1/204 (0.49%)	1	0/200 (0.00%)	0	0/206 (0.00%)	0
Flank pain ^† 1	1/204 (0.49%)	1	0/200 (0.00%)	0	0/206 (0.00%)	0
Intervertebral disc degeneration ^† 1	0/204 (0.00%)	0	1/200 (0.50%)	1	0/206 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma ^† 1	0/204 (0.00%)	0	1/200 (0.50%)	1	0/206 (0.00%)	0
Gastric cancer ^† 1	0/204 (0.00%)	0	1/200 (0.50%)	1	0/206 (0.00%)	0
Ovarian adenoma ^† 1	1/204 (0.49%)	1	0/200 (0.00%)	0	0/206 (0.00%)	0
Parathyroid tumour benign ^† 1	1/204 (0.49%)	1	0/200 (0.00%)	0	0/206 (0.00%)	0
Prostate cancer ^† 1	0/204 (0.00%)	0	1/200 (0.50%)	1	0/206 (0.00%)	0
Pancreatic neuroendocrine tumour ^† 1	0/204 (0.00%)	0	0/200 (0.00%)	0	1/206 (0.49%)	1
Nervous system disorders
Subarachnoid haemorrhage ^† 1	0/204 (0.00%)	0	0/200 (0.00%)	0	1/206 (0.49%)	1
Psychiatric disorders
Depression ^† 1	1/204 (0.49%)	1	0/200 (0.00%)	0	0/206 (0.00%)	0
Dissociative disorder ^† 1	0/204 (0.00%)	0	1/200 (0.50%)	1	0/206 (0.00%)	0
Renal and urinary disorders
Nephrolithiasis ^† 1	0/204 (0.00%)	0	2/200 (1.00%)	2	0/206 (0.00%)	0
Renal failure acute ^† 1	0/204 (0.00%)	0	1/200 (0.50%)	1	1/206 (0.49%)	1
Renal impairment ^† 1	0/204 (0.00%)	0	1/200 (0.50%)	1	0/206 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary oedema ^† 1	0/204 (0.00%)	0	1/200 (0.50%)	1	0/206 (0.00%)	0
Vascular disorders
Hypertensive crisis ^† 1	0/204 (0.00%)	0	1/200 (0.50%)	1	0/206 (0.00%)	0
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 14.0
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0.02%
	Lesinurad 200 mg + Allopurinol		Lesinurad 400 mg + Allopurinol		Placebo + Allopurinol
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	85/204 (41.67%)		82/200 (41.00%)		60/206 (29.13%)
Gastrointestinal disorders
Diarrhoea ^† 1	10/204 (4.90%)	13	14/200 (7.00%)	21	7/206 (3.40%)	8
Gastrooesophageal reflux disease ^† 1	10/204 (4.90%)	10	4/200 (2.00%)	4	1/206 (0.49%)	1
Infections and infestations
Upper respiratory tract infection ^† 1	14/204 (6.86%)	16	30/200 (15.00%)	39	21/206 (10.19%)	23
Influenza ^† 1	14/204 (6.86%)	17	8/200 (4.00%)	9	4/206 (1.94%)	4
Bronchitis ^† 1	9/204 (4.41%)	9	4/200 (2.00%)	4	4/206 (1.94%)	5
Injury, poisoning and procedural complications
Joint sprain ^† 1	9/204 (4.41%)	9	2/200 (1.00%)	2	4/206 (1.94%)	4
Investigations
Blood creatinine increased ^† 1	8/204 (3.92%)	9	19/200 (9.50%)	24	7/206 (3.40%)	7
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	24/204 (11.76%)	24	6/200 (3.00%)	7	9/206 (4.37%)	14
Nervous system disorders
Headache ^† 1	10/204 (4.90%)	11	12/200 (6.00%)	13	8/206 (3.88%)	8
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain ^† 1	5/204 (2.45%)	5	1/200 (0.50%)	1	0/206 (0.00%)	0
Vascular disorders
Hypertension ^† 1	17/204 (8.33%)	17	16/200 (8.00%)	16	10/206 (4.85%)	10
† Indicates events were collected by systematic assessment 1 Term from vocabulary, MedDRA 14.0

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Nihar Bhakta, MD
Organization:	Ardea Biosciences, Inc.
Phone:	1-858-652-6671
EMail:	nbhakta@ardeabio.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Bardin T, Keenan RT, Khanna PP, Kopicko J, Fung M, Bhakta N, Adler S, Storgard C, Baumgartner S, So A. Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study). Ann Rheum Dis. 2017 May;76(5):811-820. doi: 10.1136/annrheumdis-2016-209213. Epub 2016 Nov 7.

Layout table for additonal information

Responsible Party:	Ardea Biosciences, Inc.
ClinicalTrials.gov Identifier:	NCT01493531
Other Study ID Numbers:	RDEA594-302 2011-003767-29 ( EudraCT Number )
First Submitted:	December 13, 2011
First Posted:	December 16, 2011
Results First Submitted:	January 14, 2016
Results First Posted:	May 26, 2016
Last Update Posted:	May 26, 2016

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