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

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ClinicalTrials.gov Identifier: NCT01510769
Recruitment Status : Completed
First Posted : January 16, 2012
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 Tophaceous Gout
Interventions Drug: Lesinurad
Drug: Placebo
Drug: Febuxostat
Enrollment 330
Recruitment Details  
Pre-assignment Details 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
Hide Arm/Group Description [Not Specified] [Not Specified] [Not Specified]
Period Title: Overall Study
Started 106 109 109
Completed 79 84 87
Not Completed 27 25 22
Reason Not Completed
Adverse Event             7             6             4
Gout Flare             0             3             1
Protocol Violation             11             10             9
Lost to Follow-up             5             1             5
Withdrawal by Subject             3             4             3
Death             1             1             0
Arm/Group Title Lesinurad 200 mg + Febuxostat Lesinurad 400 mg + Febuxostat Placebo + Febuxostat Total
Hide Arm/Group Description [Not Specified] [Not Specified] [Not Specified] Total of all reporting groups
Overall Number of Baseline Participants 106 109 109 324
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 106 participants 109 participants 109 participants 324 participants
54.2  (11.0) 53.3  (11.2) 54.6  (10.9) 54.1  (11.0)
Age, Customized   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 106 participants 109 participants 109 participants 324 participants
<65 Years 89 90 89 268
>=65 Years 17 19 20 56
[1]
Measure Description: <65 Years, >=65 Years
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 106 participants 109 participants 109 participants 324 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  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 106 participants 109 participants 109 participants 324 participants
Australia 6 6 4 16
Canada 9 2 6 17
New Zealand 2 6 5 13
Poland 8 10 14 32
Switzerland 0 1 1 2
United States 81 84 79 244
1.Primary Outcome
Title Subjects With a Serum Urate (sUA) Level That is < 5.0 mg/dL by Month 6
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 106 109 109
Measure Type: Number
Unit of Measure: Proportion of Subjects
0.566 0.761 0.468
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lesinurad 200 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1298
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.10
Confidence Interval (2-Sided) 95%
-0.03 to 0.23
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Lesinurad 400 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
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 0.29
Confidence Interval (2-Sided) 95%
0.17 to 0.42
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Complete Resolution of at Least One Target Tophus
Hide Description Proportion of subjects who experience complete resolution of at least 1 target tophus by Month 12
Time Frame 12 Months
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 106 109 109
Measure Type: Number
Unit of Measure: Proportion of Subjects
0.255 0.303 0.211
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lesinurad 200 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4453
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.04
Confidence Interval (2-Sided) 95%
-0.07 to 0.16
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Lesinurad 400 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1149
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.09
Confidence Interval (2-Sided) 95%
-0.02 to 0.21
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Complete or Partial Response of at Least One Tophus
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 106 109 109
Measure Type: Number
Unit of Measure: Proportion of Subjects
0.566 0.587 0.505
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lesinurad 200 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6450
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value 0.03
Confidence Interval (2-Sided) 95%
-0.10 to 0.17
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Lesinurad 400 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4118
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%
-0.08 to 0.19
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Quality of Life
Hide 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
Hide Outcome Measure Data
Hide 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
Hide 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
Overall Number of Participants Analyzed 77 78 80
Measure Type: Number
Unit of Measure: Proportion of Subjects
0.442 0.333 0.525
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Lesinurad 200 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.3034
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -0.08
Confidence Interval (2-Sided) 95%
-0.24 to 0.07
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Lesinurad 400 mg + Febuxostat 80 mg, Placebo + Febuxostat 80 mg
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0210
Comments [Not Specified]
Method Cochran-Mantel-Haenszel
Comments [Not Specified]
Method of Estimation Estimation Parameter Risk Difference (RD)
Estimated Value -0.19
Confidence Interval (2-Sided) 95%
-0.34 to -0.04
Estimation Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Lesinurad 200 mg + Febuxostat Lesinurad 400 mg + Febuxostat Placebo + Febuxostat
Hide Arm/Group Description [Not Specified] [Not Specified] [Not Specified]
All-Cause Mortality
Lesinurad 200 mg + Febuxostat Lesinurad 400 mg + Febuxostat Placebo + Febuxostat
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide 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 (5.66%)      9/109 (8.26%)      10/109 (9.17%)    
Cardiac disorders       
Acute myocardial infarction  1  0/106 (0.00%)  0 1/109 (0.92%)  1 0/109 (0.00%)  0
Angina pectoris  1  0/106 (0.00%)  0 1/109 (0.92%)  2 0/109 (0.00%)  0
Arrhythmia  1  0/106 (0.00%)  0 0/109 (0.00%)  0 1/109 (0.92%)  1
Atrial fibrillation  1  1/106 (0.94%)  1 0/109 (0.00%)  0 0/109 (0.00%)  0
Cardiac failure acute  1  0/106 (0.00%)  0 1/109 (0.92%)  1 0/109 (0.00%)  0
Cardiac failure congestive  1  0/106 (0.00%)  0 1/109 (0.92%)  1 0/109 (0.00%)  0
Coronary artery disease  1  1/106 (0.94%)  1 1/109 (0.92%)  2 0/109 (0.00%)  0
Pulseless electrical activity  1  1/106 (0.94%)  1 0/109 (0.00%)  0 0/109 (0.00%)  0
Ear and labyrinth disorders       
Vertigo  1  0/106 (0.00%)  0 1/109 (0.92%)  1 1/109 (0.92%)  1
Gastrointestinal disorders       
Gastritis  1  1/106 (0.94%)  1 0/109 (0.00%)  0 0/109 (0.00%)  0
General disorders       
Non-cardiac chest pain  1  0/106 (0.00%)  0 0/109 (0.00%)  0 1/109 (0.92%)  1
Hepatobiliary disorders       
Cholecystitis acute  1  0/106 (0.00%)  0 1/109 (0.92%)  1 0/109 (0.00%)  0
Infections and infestations       
Pneumonia  1  0/106 (0.00%)  0 0/109 (0.00%)  0 1/109 (0.92%)  1
Injury, poisoning and procedural complications       
Subdural haematoma  1  0/106 (0.00%)  0 0/109 (0.00%)  0 1/109 (0.92%)  1
Laceration  1  1/106 (0.94%)  1 0/109 (0.00%)  0 0/109 (0.00%)  0
Metabolism and nutrition disorders       
Dehydration  1  0/106 (0.00%)  0 1/109 (0.92%)  1 0/109 (0.00%)  0
Gout  1  0/106 (0.00%)  0 1/109 (0.92%)  1 0/109 (0.00%)  0
Type 2 diabetes mellitus  1  1/106 (0.94%)  1 0/109 (0.00%)  0 0/109 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Joint contracture  1  0/106 (0.00%)  0 0/109 (0.00%)  0 1/109 (0.92%)  1
Osteoarthritis  1  0/106 (0.00%)  0 0/109 (0.00%)  0 1/109 (0.92%)  1
Spinal column stenosis  1  0/106 (0.00%)  0 1/109 (0.92%)  1 0/109 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)       
Prostate cancer  1  0/106 (0.00%)  0 0/109 (0.00%)  0 1/109 (0.92%)  1
Renal and urinary disorders       
Nephrolithiasis  1  0/106 (0.00%)  0 0/109 (0.00%)  0 1/109 (0.92%)  1
Renal failure acute  1  0/106 (0.00%)  0 1/109 (0.92%)  1 1/109 (0.92%)  1
Renal failure chronic  1  0/106 (0.00%)  0 1/109 (0.92%)  1 0/109 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Chronic obstructive pulmonary disease  1  0/106 (0.00%)  0 0/109 (0.00%)  0 1/109 (0.92%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0.02%
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 (47.17%)      59/109 (54.13%)      34/109 (31.19%)    
Gastrointestinal disorders       
Dental caries  1  0/106 (0.00%)  0 3/109 (2.75%)  3 0/109 (0.00%)  0
Toothache  1  1/106 (0.94%)  1 3/109 (2.75%)  3 0/109 (0.00%)  0
General disorders       
Non-cardiac chest pain  1  1/106 (0.94%)  1 3/109 (2.75%)  4 0/109 (0.00%)  0
Pyrexia  1  1/106 (0.94%)  1 7/109 (6.42%)  7 4/109 (3.67%)  4
Infections and infestations       
Influenza  1  6/106 (5.66%)  6 2/109 (1.83%)  4 2/109 (1.83%)  2
Nasopharyngitis  1  10/106 (9.43%)  10 15/109 (13.76%)  15 9/109 (8.26%)  12
Injury, poisoning and procedural complications       
Contusion  1  2/106 (1.89%)  2 7/109 (6.42%)  9 3/109 (2.75%)  3
Excoriation  1  3/106 (2.83%)  3 2/109 (1.83%)  2 0/109 (0.00%)  0
Joint sprain  1  4/106 (3.77%)  4 6/109 (5.50%)  6 2/109 (1.83%)  2
Laceration  1  3/106 (2.83%)  3 8/109 (7.34%)  12 4/109 (3.67%)  5
Investigations       
Blood creatine phosphokinase increased  1  6/106 (5.66%)  8 4/109 (3.67%)  4 3/109 (2.75%)  3
Blood creatinine increased  1  7/106 (6.60%)  7 8/109 (7.34%)  11 3/109 (2.75%)  3
Metabolism and nutrition disorders       
Type 2 diabetes mellitus  1  4/106 (3.77%)  4 1/109 (0.92%)  1 1/109 (0.92%)  1
Musculoskeletal and connective tissue disorders       
Back pain  1  8/106 (7.55%)  9 6/109 (5.50%)  7 5/109 (4.59%)  6
Pain in extremity  1  6/106 (5.66%)  9 9/109 (8.26%)  9 4/109 (3.67%)  4
Nervous system disorders       
Headache  1  10/106 (9.43%)  11 6/109 (5.50%)  7 8/109 (7.34%)  12
Respiratory, thoracic and mediastinal disorders       
Cough  1  4/106 (3.77%)  4 9/109 (8.26%)  9 3/109 (2.75%)  3
Sinus congestion  1  4/106 (3.77%)  4 0/109 (0.00%)  0 0/109 (0.00%)  0
Vascular disorders       
Hypertension  1  6/106 (5.66%)  6 12/109 (11.01%)  13 8/109 (7.34%)  8
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.0
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: Maple Fung, MD
Organization: Ardea Biosciences, Inc.
Phone: 1-858-652-6671
EMail: mfung@ardeabio.com
Layout table for additonal information
Responsible Party: Ardea Biosciences, Inc.
ClinicalTrials.gov Identifier: NCT01510769     History of Changes
Other Study ID Numbers: RDEA594-304
2011-003768-55 ( EudraCT Number )
First Submitted: January 12, 2012
First Posted: January 16, 2012
Results First Submitted: January 14, 2016
Results First Posted: May 26, 2016
Last Update Posted: May 26, 2016