Combining Lesinurad With Allopurinol in Inadequate Responders (CLEAR 1)

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.

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.

Study Overview

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

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 Type: Interventional
• Enrollment (Actual): 607
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Athens, Alabama, United States, 35611
    • Birmingham, Alabama, United States, 35242
    • Birmingham, Alabama, United States, 35294
    • Birmingham, Alabama, United States, 35209
    • Birmingham, Alabama, United States, 35213
    • Gulf Shores, Alabama, United States, 36542
    • Mobile, Alabama, United States, 36604
    • Mobile, Alabama, United States, 36608
    • Pinson, Alabama, United States, 35126
  • Arizona
    • Glendale, Arizona, United States, 85308
    • Goodyear, Arizona, United States, 85395
    • Little Rock, Arizona, United States, 72204
    • Little Rock, Arizona, United States, 72211
    • Peoria, Arizona, United States, 85381
    • Phoenix, Arizona, United States, 85050
    • Tucson, Arizona, United States, 85704
    • Tuscon, Arizona, United States, 85723
  • Arkansas
    • Little Rock, Arkansas, United States, 72206
  • California
    • Covina, California, United States, 91723
    • Glendale, California, United States, 91204
    • Huntington Beach, California, United States, 92646
    • Inglewood, California, United States, 90301
    • Lancaster, California, United States, 93534
    • Lincoln, California, United States, 95648
    • Orange, California, United States, 92868
    • Sacramento, California, United States, 95825
    • San Leandro, California, United States, 94578
    • Santa Maria, California, United States, 93454
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
    • Colorado Springs, Colorado, United States, 80918
    • Denver, Colorado, United States, 80230
    • Englewood, Colorado, United States, 80113
  • Connecticut
    • Milford, Connecticut, United States, 06460
    • New London, Connecticut, United States, 06320
  • Florida
    • Brooksville, Florida, United States, 34601
    • Clearwater, Florida, United States, 33765
    • Daytona Beach, Florida, United States, 32114
    • East Bradenton, Florida, United States, 34208
    • Gainesville, Florida, United States, 32607
    • Miami, Florida, United States, 33186
    • Miami, Florida, United States, 33165
    • Miami, Florida, United States, 33143
    • Miami, Florida, United States, 33125
    • Miami, Florida, United States, 33135
    • Naples, Florida, United States, 34102
    • Ocala, Florida, United States, 34474
    • Ormond Beach, Florida, United States, 32174
    • Pembroke Pines, Florida, United States, 33027
    • Pembroke Pines, Florida, United States, 33029
    • Port Orange, Florida, United States, 32127
    • Tampa, Florida, United States, 33614
    • Vero Beach, Florida, United States, 32960
  • Georgia
    • Atlanta, Georgia, United States, 30308
    • Atlanta, Georgia, United States, 30328
    • Augusta, Georgia, United States, 30909
    • Conyers, Georgia, United States, 30013
    • Johns Creek, Georgia, United States, 30097
    • Marietta, Georgia, United States, 30060
    • Newman, Georgia, United States, 30265
    • Newnan, Georgia, United States, 30265
  • Hawaii
    • Honolulu, Hawaii, United States, 96814
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
    • Meridian, Idaho, United States, 83642
    • Meridian, Idaho, United States, 83646
  • Illinois
    • Chicago, Illinois, United States, 60612
    • Gurnee, Illinois, United States, 60031
  • Indiana
    • Evansville, Indiana, United States, 47714
    • Franklin, Indiana, United States, 46131
    • LaPorte, Indiana, United States, 46350
  • Iowa
    • Cedar Rapids, Iowa, United States, 52403
  • Kansas
    • Shawnee, Kansas, United States, 66218
  • Kentucky
    • Elizabethtown, Kentucky, United States, 41701
    • Paducah, Kentucky, United States, 42003
  • Louisiana
    • Eunice, Louisiana, United States, 70535
    • Metairie, Louisiana, United States, 70006
    • Monroe, Louisiana, United States, 71203
    • Natchitoches, Louisiana, United States, 71457
  • Massachusetts
    • Worcester, Massachusetts, United States, 01605
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
    • Kalamazoo, Michigan, United States, 49009
    • Southfield, Michigan, United States, 48034
    • Traverse City, Michigan, United States, 49684
  • Mississippi
    • Jackson, Mississippi, United States, 39202
  • Missouri
    • Florissant, Missouri, United States, 63031
    • Hazelwood, Missouri, United States, 63042
    • Jefferson City, Missouri, United States, 65109
    • Kansas City, Missouri, United States, 64114
    • Saint Louis, Missouri, United States, 63117
    • St. Louis, Missouri, United States, 63128
    • Washington, Missouri, United States, 63090
  • Montana
    • Missoula, Montana, United States, 59808
  • Nevada
    • Las Vegas, Nevada, United States, 89119
    • Las Vegas, Nevada, United States, 89183
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
  • New York
    • Endwell, New York, United States, 13760
    • New York, New York, United States, 10016
    • Syracuse, New York, United States, 13210
    • Williamsville, New York, United States, 14221
  • North Carolina
    • Greensboro, North Carolina, United States, 27405
    • Raleigh, North Carolina, United States, 27609
    • Raleigh, North Carolina, United States, 27612
    • Shelby, North Carolina, United States, 28150
    • Tabor City, North Carolina, United States, 28463
    • Wilmington, North Carolina, United States, 28401
    • Winston-Salem, North Carolina, United States, 27103
  • Ohio
    • Columbus, Ohio, United States, 43235
    • Dayton, Ohio, United States, 45417
    • Perrysburgh, Ohio, United States, 43551
    • Willoughby Hills, Ohio, United States, 44904
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73103
    • Tulsa, Oklahoma, United States, 74104
  • Oregon
    • Ashland, Oregon, United States, 97520
  • Pennsylvania
    • Altoona, Pennsylvania, United States, 16602
    • 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
    • Sellersville, Pennsylvania, United States, 18960
    • Upper St. Clair, Pennsylvania, United States, 15241
    • Wexford, Pennsylvania, United States, 15090
  • South Carolina
    • Columbia, South Carolina, United States, 29204
    • Mount Pleasant, South Carolina, United States, 29464
    • Myrtle Beach, South Carolina, United States, 29588
    • Rock Hill, South Carolina, United States, 29732
    • Spartanburg, South Carolina, United States, 29303
  • Tennessee
    • Brentwood, Tennessee, United States, 37027
    • Jackson, Tennessee, United States, 38305
    • Knoxville, Tennessee, United States, 37923
    • Memphis, Tennessee, United States, 38119
  • Texas
    • Austin, Texas, United States, 78756
    • Corpus Christi, Texas, United States, 78414
    • Dallas, Texas, United States, 75218
    • El Paso, Texas, United States, 79902
    • Fort Worth, Texas, United States, 76135
    • Houston, Texas, United States, 77004
    • Houston, Texas, United States, 77098
    • Houston, Texas, United States, 77062
    • Houston, Texas, United States, 77043
    • Kingwood, Texas, United States, 77339
    • Nassau Bay, Texas, United States, 77058
    • Plabo, Texas, United States, 75024
    • Plano, Texas, United States, 75075
    • San Angelo, Texas, United States, 76904
    • San Antonio, Texas, United States, 78229
    • San Antonio, Texas, United States, 78215
    • San Antonio, Texas, United States, 78209
    • Sealy, Texas, United States, 77474
    • Waco, Texas, United States, 76708
  • Utah
    • Bountiful, Utah, United States, 84010
    • Salt Lake City, Utah, United States, 84102
    • West Jordan, Utah, United States, 84088
  • Virginia
    • Chesapeake, Virginia, United States, 23320
    • Manassas, Virginia, United States, 20110
    • Midlothian, Virginia, United States, 23114
    • Richmond, Virginia, United States, 23235
    • Richmond, Virginia, United States, 23233
    • Suffolk, Virginia, United States, 23435
    • Virginia Beach, Virginia, United States, 23462
  • Washington
    • Port Orchard, Washington, United States, 98366
    • Spokane, Washington, United States, 99204
    • Spokane, Washington, United States, 99208
  • West Virginia
    • Morgantown, West Virginia, United States, 26505
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
    • Monroe, Wisconsin, United States, 53566

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 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 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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

Outcome Measure	Measure Description	Time Frame
Gout Flares	Mean rate of gout flares requiring treatment for the 6-month period from the end of Month 6 to the end of Month 12	12 Months
Tophus	Proportion of subjects with ≥ 1 target tophus at Baseline who experience complete resolution of at least 1 target tophus by Month 12	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.
• Saag KG, Fitz-Patrick D, Kopicko J, Fung M, Bhakta N, Adler S, Storgard C, Baumgartner S, Becker MA. Lesinurad Combined With Allopurinol: A Randomized, Double-Blind, Placebo-Controlled Study in Gout Patients With an Inadequate Response to Standard-of-Care Allopurinol (a US-Based Study). Arthritis Rheumatol. 2017 Jan;69(1):203-212. doi: 10.1002/art.39840. Erratum In: Arthritis Rheumatol. 2018 Aug;70(8):1318.

Helpful Links

• Related Info

Study record dates

Study Major Dates

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

Study Registration Dates

• First Submitted: January 11, 2012
• First Submitted That Met QC Criteria: January 11, 2012
• First Posted (Estimate): January 13, 2012

Study Record Updates

• Last Update Posted (Estimate): August 18, 2016
• Last Update Submitted That Met QC Criteria: July 11, 2016
• Last Verified: July 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Antioxidants; Free Radical Scavengers; Gout Suppressants; Renal Agents; Uricosuric Agents; Allopurinol; Lesinurad
• Other Study ID Numbers: RDEA594-301