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

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

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.

Study Overview

• Status: Completed
• Conditions: Tophaceous Gout
• Intervention / Treatment: Drug: Lesinurad; Drug: Lesinurad; Drug: Febuxostat; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 330
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
  • South Australia
    • Woodville South, South Australia, Australia, 5011
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
  • Western Australia
    • Shenton Park, Western Australia, Australia, 6008
• Canada
  • Quebec, Canada, G1V 3M7
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 3G8
    • Victoria, British Columbia, Canada, V8V 3N7
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3K 2M5
  • Ontario
    • London, Ontario, Canada, N6A 5R8
    • Mississauga, Ontario, Canada, L5M 2V8
    • Toronto, Ontario, Canada, M9W 4L6
• New Zealand
  • Hamilton, New Zealand, 3240
  • Auckland
    • Grafton, Auckland, New Zealand, 1010
  • Bay of Plenty
    • Tauranga, Bay of Plenty, New Zealand, 3143
• Poland
  • Biatystok, Poland, 15-430
  • Elblag, Poland, 82-300
  • Katowice, Poland, 40-954
  • Konskie, Poland, 26-200
  • Krakow, Poland, 31-501
  • Krakow, Poland, 30-510
  • Poznan, Poland, 60-539
  • Poznan, Poland, 60-773
  • Lodz Province
    • Kutno, Lodz Province, Poland, 99-300
• Switzerland
  • Fribourg, Switzerland, 1708
  • Vlaud
    • Lausanne, Vlaud, Switzerland, 1011
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35211
  • Arizona
    • Goodyear, Arizona, United States, 85395
    • Peoria, Arizona, United States, 85381
    • Pheonix, Arizona, United States, 85023
    • Tucson, Arizona, United States, 85724
  • Arkansas
    • Little Rock, Arkansas, United States, 72204
    • Little Rock, Arkansas, United States, 72223
  • California
    • Glendale, California, United States, 91204
    • Huntington Beach, California, United States, 92646
    • Irvine, California, United States, 92618
    • La Jolla, California, United States, 92037
    • Los Angeles, California, United States, 90048
    • Rancho Cucamonga, California, United States, 91730
    • San Diego, California, United States, 92108
  • Colorado
    • Denver, Colorado, United States, 80220
    • Denver, Colorado, United States, 80230
    • Englewood, Colorado, United States, 80113
  • Connecticut
    • Trumball, Connecticut, United States, 06611
  • District of Columbia
    • Washington, District of Columbia, United States, 20422
  • Florida
    • Boynton Beach, Florida, United States, 33472
    • Brooksville, Florida, United States, 34601
    • East Brandenton, Florida, United States, 34208
    • Fleming Island, Florida, United States, 32003
    • Miami, Florida, United States, 33135
    • Napels, Florida, United States, 34102
    • Pembroke Pines, Florida, United States, 33027
    • Pembroke Pines, Florida, United States, 33029
    • Port Orange, Florida, United States, 32127
    • Tampa, Florida, United States, 33606
    • Tampa, Florida, United States, 33607
    • Tampa, Florida, United States, 33614
    • Vero Beach, Florida, United States, 32960
    • Winter Haven, Florida, United States, 33880
  • Georgia
    • Conyers, Georgia, United States, 30013
    • Johns Creek, Georgia, United States, 30097
    • Newman, Georgia, United States, 30265
    • Savannah, Georgia, United States, 31406
  • Hawaii
    • Honolulu, Hawaii, United States, 96814
  • Idaho
    • Meridian, Idaho, United States, 83642
    • Meridian, Idaho, United States, 83646
  • Illinois
    • Chicago, Illinois, United States, 60637
    • Chicago, Illinois, United States, 60624
    • Gurnee, Illinois, United States, 60031
    • Springfield, Illinois, United States, 62704
    • Springfield, Illinois, United States, 62711
  • Kentucky
    • Elizabethtown, Kentucky, United States, 42701
    • Lexington, Kentucky, United States, 40504
  • Maryland
    • Frederick, Maryland, United States, 21702
  • Michigan
    • Kalamazoo, Michigan, United States, 49009
    • Southfield, Michigan, United States, 48034
  • Mississippi
    • Jackson, Mississippi, United States, 39202
    • Olive Branch, Mississippi, United States, 38654
  • Missouri
    • Jefferson City, Missouri, United States, 65109
    • Saint Louis, Missouri, United States, 63117
  • Montana
    • Missoula, Montana, United States, 59808
  • New York
    • Mineola, New York, United States, 11501
    • New York, New York, United States, 10016
  • North Carolina
    • Calabash, North Carolina, United States, 28467
    • Durham, North Carolina, United States, 27710
    • Greenville, North Carolina, United States, 27834
    • Wilmington, North Carolina, United States, 28401
    • Winston-Salem, North Carolina, United States, 27103
  • North Dakota
    • Fargo, North Dakota, United States, 58103
  • Ohio
    • Columbus, Ohio, United States, 43203
    • Middleburg, Ohio, United States, 44130
    • Wadsworth, Ohio, United States, 44281
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
    • Oklahoma City, Oklahoma, United States, 73103
  • Pennsylvania
    • Belle Vernon, Pennsylvania, United States, 15012
    • Clairton, Pennsylvania, United States, 15025
    • Duncansville, Pennsylvania, United States, 16635
    • Jenkintown, Pennsylvania, United States, 19046
    • Lansdale, Pennsylvania, United States, 19446
    • Pittsburgh, Pennsylvania, United States, 15206
    • Scottdale, Pennsylvania, United States, 15683
    • Sellersville, Pennsylvania, United States, 18960
  • South Carolina
    • Columbia, South Carolina, United States, 29204
    • Greenville, South Carolina, United States, 29615
    • Mount Pleasant, South Carolina, United States, 29464
    • Spartanburg, South Carolina, United States, 29303
  • Tennessee
    • Jackson, Tennessee, United States, 38305
    • Memphis, Tennessee, United States, 38119
  • Texas
    • Austin, Texas, United States, 78705
    • Austin, Texas, United States, 78758
    • Corpus Christi, Texas, United States, 78413
    • Dallas, Texas, United States, 75218
    • Houston, Texas, United States, 77004
    • Houston, Texas, United States, 77074
    • San Antonio, Texas, United States, 78229
    • Sugar Land, Texas, United States, 77479
    • Victoria, Texas, United States, 77901
    • Waco, Texas, United States, 76708
  • Virginia
    • Chesapeake, Virginia, United States, 23320
    • Danville, Virginia, United States, 24541
    • Richmond, Virginia, United States, 23235
    • Suffolk, Virginia, United States, 23435
    • Virginia Beach, Virginia, United States, 23462
  • Washington
    • Seattle, Washington, United States, 98104
  • West Virginia
    • Morgantown, West Virginia, United States, 26505

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Resolution of at Least One Target Tophus	Proportion of subjects who experience complete resolution of at least 1 target tophus by Month 12	12 Months
Complete or Partial Response of at Least One Tophus	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	12 Months
Quality of Life	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.	12 Months

Collaborators and Investigators

• Sponsor: Ardea Biosciences, Inc.

Publications and helpful links

General Publications

• Topless R, Noorbaloochi S, Merriman TR, Singh JA. Change in serum urate level with urate-lowering therapy initiation associates in the immediate term with patient-reported outcomes in people with gout. Semin Arthritis Rheum. 2022 Oct;56:152057. doi: 10.1016/j.semarthrit.2022.152057. Epub 2022 Jun 29.
• Dalbeth N, Jones G, Terkeltaub R, Khanna D, Fung M, Baumgartner S, Perez-Ruiz F. Efficacy and safety during extended treatment of lesinurad in combination with febuxostat in patients with tophaceous gout: CRYSTAL extension study. Arthritis Res Ther. 2019 Jan 7;21(1):8. doi: 10.1186/s13075-018-1788-4.
• Dalbeth N, Jones G, Terkeltaub R, Khanna D, Kopicko J, Bhakta N, Adler S, Fung M, Storgard C, Baumgartner S, Perez-Ruiz F. Lesinurad, a Selective Uric Acid Reabsorption Inhibitor, in Combination With Febuxostat in Patients With Tophaceous Gout: Findings of a Phase III Clinical Trial. Arthritis Rheumatol. 2017 Sep;69(9):1903-1913. doi: 10.1002/art.40159. Epub 2017 Aug 4.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: January 1, 2012
• Primary Completion (Actual): June 1, 2014
• Study Completion (Actual): June 1, 2014

Study Registration Dates

• First Submitted: January 12, 2012
• First Submitted That Met QC Criteria: January 13, 2012
• First Posted (Estimate): January 16, 2012

Study Record Updates

• Last Update Posted (Estimate): May 26, 2016
• Last Update Submitted That Met QC Criteria: April 20, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Metabolism, Inborn Errors; Crystal Arthropathies; Purine-Pyrimidine Metabolism, Inborn Errors; Gout; Antirheumatic Agents; Gout Suppressants; Renal Agents; Uricosuric Agents; Lesinurad; Febuxostat
• Other Study ID Numbers: RDEA594-304; 2011-003768-55 (EudraCT Number)