A Phase 4 Safety and Efficacy Study to Evaluate Lesinurad 200 mg in Participants With Gout and Renal Impairment

A Phase 4, Study to Evaluate the Safety and Efficacy of Lesinurad 200 mg in Combination With a Xanthine Oxidase Inhibitor (XOI), Compared With an XOI Alone, in Subjects With Gout and Estimated Creatinine Clearance (eCrCl) 30 to <60 mL/Min Who Have Not Achieved Target Serum Uric Acid Levels (sUA) on an XOI Alone

This study evaluates the safety and efficacy of lesinurad administered with an XOI versus a placebo plus an XOI in gout participants who have moderate renal impairment and who are not at target level of serum urate (sUA).

Study Overview

• Status: Terminated
• Conditions: Gout; Chronic Kidney Disease (CKD)
• Intervention / Treatment: Drug: Lesinurad; Drug: XOI; Drug: colchicine; Drug: corticosteroids; Drug: Placebo

Detailed Description

This postmarketing study is a randomized, double-blind, placebo-controlled study to evaluate safety (with particular focus on renal and cardiovascular events) and efficacy of lesinurad 200 mg once daily (QD) in combination with an XOI for up to 24 months compared with XOI monotherapy, in participants with gout and moderate renal impairment who have not reached target sUA levels (<6.0 mg/dL) on an XOI alone.

• Study Type: Interventional
• Enrollment (Actual): 242
• Phase: Phase 4

Contacts and Locations

Study Locations

• Czechia
  • Brno, Czechia, 60200
    • CCBR Czech Brno, s. r. o
  • Brno, Czechia, 611 41
    • REVMACLINIC s.r.o. - Revmatologicka ambulance
  • Brno, Czechia, 62500
    • DTTO Faculty Hospital Brno
  • Olomouc, Czechia, 779 00
    • Revmatologie MUDr. Bilkova s.r.o.
  • Ostrava, Czechia, 70200
    • CCBR Ostrava s.r.o.
  • Pardubice, Czechia, 53002
    • CCBR Clinical Research, Pardubice
  • Prague, Czechia, 130 00
    • CCBR Czech Prague s.r.o.
  • Uherske Hradiste, Czechia, 686 01
    • MEDICAL PLUS, s.r.o. - Revmatologicka ambulance
  • Usti nad Labem, Czechia, 40113
    • Krajská zdravotní, a.s. - Masarykova nemocnice v Ústí nad Labem, o.z.
  • Zlín, Czechia, 760 01
    • PV - MEDICAL, s.r.o.
  • Znojmo, Czechia, 66902
    • Nemocnice Znojmo p.o - Interni oddeleni
• Hungary
  • Baja, Hungary, 6500
    • Bajai Szent Rókus Kórház
  • Balatonfüred, Hungary, 8230
    • DRC Gyogyszervizsgalo Kozpont Kft
  • Budapest, Hungary, 1033
    • Clinexpert Kft.
  • Békéscsaba, Hungary, 5600
    • Dr Lakatos Ferenc Belgyogyaszati-Kardiologiai Maganrendelo
  • Esztergom, Hungary, 2500
    • Vaszary Kolos Korhaz Esztergom - Reumatologiai osztaly
  • Hatvan, Hungary, 3000
    • BKS Research Kft.
  • Kalocsa, Hungary, 6300
    • Kalocsai Szent Kereszt Korhaz
  • Komárom, Hungary, 2921
    • Selye Janos Hospital - Rheumatology Department
  • Miskolc, Hungary, 3529
    • CRU Hungary Kft.
  • Szekszárd, Hungary, 7100
    • Clinfan Ltd SMO
  • Szolnok, Hungary, 5000
    • Allergo-Derm Bakos Kft.
  • Székesfehérvár, Hungary, 8000
    • Mentahaz Maganorvosi Kozpont (SMO)
  • Veszprem, Hungary, 8200
    • Medical Expert Kft.
• Poland
  • Chorzów, Poland, 41-500
    • B_Serwis Popenda Sp. J.
  • Elbląg, Poland, 82-300
    • Centrum Kliniczno Badawcze J. Brzezicki B. Gornikiewicz - Brzezicka Lekarze Sp. p.
  • Grodzisk Mazowiecki, Poland, 05-825
    • McBk S.C.
  • Katowice, Poland, 40-040
    • NZOZ Praktyka Lekarza Rodzinnego Elzbieta Kelm
  • Kraków, Poland, 30-510
    • Malopolskie Centrum Medyczne
  • Kraków, Poland, 30-002
    • Centrum Medyczne Pratia Krakow
  • Lublin, Poland, 20-093
    • Centrum Medyczne Chodzki
  • Nowy Sącz, Poland, 33-300
    • Alfa Specjalistyczne Gabinety Lekarskie Ewa Moroz
  • Poznań, Poland, 61-655
    • Praktyka Lekarska Ewa Krzyzagorska
  • Poznań, Poland, 60-773
    • Centrum Badan Klinicznych S.C.
  • Poznań, Poland, 60-589
    • Centrum Zdrowia Metabolicznego Pawel Bogdanski
  • Radom, Poland, 26-610
    • Prywatny Gabinet Lekarski NZOZ Centrum Medyczne Aeskulap
  • Warszawa, Poland, 01-868
    • Centrum Medyczne Pratia Warszawa
  • Wołomin, Poland, 05-200
    • Centrum Medyczne K2J2
  • Zamość, Poland, 22-400
    • KO - MED Centra Kliniczne Sp. z o.o., Osrodek Badan Klinicznych w Zamosciu
  • Łódź, Poland, 90-349
    • AppleTreeClinics Sp. z o.o.
  • Łódź, Poland, 90-153
    • Samodzielny Publiczny ZOZ Uniwersytecki Szpital Kliniczny nr 1 im. Norberta Barlickiego Uniwersytetu Medycznego w Lodzi, Oddzial Kliniczny Nefrologii, Hipertensjologii i Transplantologii Nerek
  • Łódź, Poland, 90-242
    • Centrum Terapii Wspolczesnej J. M. Jasnorzewska Spolka Komandytowo Akcyjna
  • Łódź, Poland, 91-363
    • Centrum Medyczne AMED Oddzial w Lodzi
  • Łódź, Poland, 94-048
    • NZOZ All - Med Centrum Medyczne Specjalistyczne Gabinety Lekarskie Marcin Ogorek
  • Żyrardów, Poland, 96-300
    • Centrum Dializa Sp. z o.o. - Zyrardow
  • Zyrardo
    • Zyrardow, Zyrardo, Poland, 96-300
      • Stacja Dializ Zyrardow
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Central Alabama Research
  • Arizona
    • Tucson, Arizona, United States, 85723
      • Southern Arizona VA Health Care System
  • California
    • Covina, California, United States, 91722
      • Medvin Clinical Research
    • Sacramento, California, United States, 95821
      • Northern California Research
    • Sacramento, California, United States, 95825
      • Capital Nephrology Medical Group
    • Upland, California, United States, 91786
      • Inland Rheumatology Clinical Trials, Inc
    • Whittier, California, United States, 90602
      • Medvin Clinical Research - Whittier
  • Colorado
    • Westminster, Colorado, United States, 80031
      • Western Nephrology-Westminster
  • Connecticut
    • Trumbull, Connecticut, United States, 06611
      • New England Research Associates, LLC
  • Florida
    • Daytona Beach, Florida, United States, 32117
      • Arthritis, Autoimmune, & Allergy LLC
    • Edgewater, Florida, United States, 32132
      • Riverside Clinical Research
    • Gainesville, Florida, United States, 32607
      • Florida Medical Research Institute
    • Hialeah, Florida, United States, 33013
      • Eastern Research
    • Miami, Florida, United States, 33126
      • LCC Medical Research Institute, LLC
    • Miami, Florida, United States, 33015
      • San Marcus Research Clinic Inc
    • Miami Lakes, Florida, United States, 33014
      • Savin Medical Group
    • Orlando, Florida, United States, 32806
      • Rheumatology Associates of Central Florida
    • Orlando, Florida, United States, 32810
      • Omega Research Consultants, LLC
    • Tampa, Florida, United States, 33634
      • Meridien Research - Tampa
    • Tampa, Florida, United States, 33614
      • BayCare Medical Group, Inc.
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • The Kaufmann Clinic, Inc
    • Atlanta, Georgia, United States, 30342
      • Ellipsis Group
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Rocky Mountain Diabetes and Osteoporosis Center PA
  • Illinois
    • Gurnee, Illinois, United States, 60031
      • Clinical Investigation Specialists, Inc. - Gurnee
  • Indiana
    • Merrillville, Indiana, United States, 46410
      • Nephrology Specialists
  • Kansas
    • Wichita, Kansas, United States, 67214
      • Kansas Nephrology Research Institute
  • Kentucky
    • Elizabethtown, Kentucky, United States, 42701
      • Center for Arthritis & Osteoporosis
    • Paducah, Kentucky, United States, 42003
      • Four Rivers Clinical Research
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70809
      • Ochsner Clinic Foundation
    • Covington, Louisiana, United States, 70433
      • Clinical Trials Management, LLC - Northshore
    • Metairie, Louisiana, United States, 70006
      • Clinical Trials Management LLC - Southshore
    • Monroe, Louisiana, United States, 71203
      • Arthritis and Diabetes Clinic
    • Shreveport, Louisiana, United States, 71101
      • Northwest Louisiana Nephrology
  • Massachusetts
    • Worcester, Massachusetts, United States, 01605
      • University of Massachusetts Memorial Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Pontiac, Michigan, United States, 48341
      • Michigan Kidney Consultants
    • Roseville, Michigan, United States, 48066
      • St. Clair Nephrology Research
  • Mississippi
    • Jackson, Mississippi, United States, 39202
      • CRC of Jackson, LLC
  • Missouri
    • Kansas City, Missouri, United States, 64128
      • VA Medical Center - Kansas City
  • Nebraska
    • Norfolk, Nebraska, United States, 68701
      • Meridian Clinical Research - Norfolk, NE
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • New Mexico Clinical Research & Osteoporosis Center Inc.
  • New York
    • Brooklyn, New York, United States, 11215
      • Ellipsis Research Group, LLC
    • Buffalo, New York, United States, 14215
      • Buffalo VA Medical Center
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
  • North Carolina
    • Charlotte, North Carolina, United States, 28210
      • DJL Clinical Research PLLC
    • Greensboro, North Carolina, United States, 27405
      • PhysiqueMed Clinical Trials
    • Morganton, North Carolina, United States, 28655
      • Burke Primary Care
    • Wilmington, North Carolina, United States, 28403
      • Trial Management Associates, LLC
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Sterling Research Group, Ltd. - Auburn
    • Cincinnati, Ohio, United States, 45246
      • Sterling Research Group, Ltd. - Cincinnati
    • Franklin, Ohio, United States, 45005
      • Prestige Clinical Research
  • Oregon
    • Portland, Oregon, United States, 97239
      • Columbia Research Group, Inc.
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18017
      • Northeast Clinical Research Center
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Center for Clinical Research
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Rhode Island
    • East Providence, Rhode Island, United States, 02914
      • Rhode Island Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29406
      • Low Country Rheumatology
    • Fort Mill, South Carolina, United States, 29707
      • Piedmont Research Partners, LLC
    • Greer, South Carolina, United States, 29651
      • Mountain View Clinical Research - Greer
  • Tennessee
    • Knoxville, Tennessee, United States, 37923
      • Knoxville Kidney Center, PLLC
    • Nashville, Tennessee, United States, 37205
      • Nephrology Associates, P.C.
    • Nashville, Tennessee, United States, 37203
      • Discovery Alliance International Inc. d/b/a Tennessee Health Research Alliance LLC
  • Texas
    • Lampasas, Texas, United States, 76550
      • FMC Science
    • Lufkin, Texas, United States, 75904
      • P&I Clinical Research
    • San Antonio, Texas, United States, 78215
      • Clinical Advancement Center, PLLC
    • San Antonio, Texas, United States, 78224
      • Briggs Clinical Research, Inc.
    • Victoria, Texas, United States, 77901
      • 3rd Coast Research Associates
  • Virginia
    • Danville, Virginia, United States, 24541
      • Spectrum Medical, Inc.
    • Manassas, Virginia, United States, 20110
      • Manassas Clinical Research Center
    • Richmond, Virginia, United States, 23235
      • Clinical Research Partners, LLC

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:

1. Subject is able to understand the study procedures, the risks involved, and willing to provide written informed consent before the first study related activity.
2. Subject is willing to adhere to the protocol schedule.
3. Subject is ≥ 18 years and ≤ 85 years of age.
4. Subject has a diagnosis of gout.
5. Subject has moderate renal impairment with estimated creatinine clearance (eCrCl; calculated by the Cockcroft-Gault formula using ideal body weight) 25.0 to ≤ 65.0 mL/min at Screening Visits 1 and 2 and an average eCrCl for both screening visits of 30.0 to < 60.0 mL/min.
6. Subject has been taking an XOI as ULT indicated for the treatment of gout for at least 4 weeks prior to Screening at a stable, medically appropriate dose, as determined by the Investigator. The minimum dose of allopurinol is 200 mg daily, and the minimum dose of febuxostat is the lowest approved dose per the local product label.
7. Subject has a serum uric acid level ≥ 6.0 mg/dL (357 µmol/L) at Screening Visits 1 and 2.
8. Subject is male or female; females must not be pregnant or breastfeeding and females of childbearing potential must agree to use nonhormonal contraception during the Screening Period and while taking investigation product (IP).
9. Subject has a body mass index < 45 kg/m^2.

Exclusion Criteria:

1. Subject had unstable angina, New York Heart Association class III or IV heart failure, myocardial infarction, or stroke within the last 6 months prior to randomization; or had a deep venous thrombosis within the previous 3 months prior to randomization.
2. Subject has uncontrolled hypertension (defined as systolic pressure above 160 or diastolic pressure above 95 mm Hg at either Screening Visits 1 or 2).
3. Subject has severe hepatic impairment (defined as Child-Pugh Class C) or is known human immunodeficiency virus (HIV) positive.
4. Subject is a solid organ transplant recipient.
5. Subject has a urine protein of 3+ or higher by dipstick by the central laboratory at Screening Visit 2.
6. Subject has a history of glomerulonephritis.
7. Subject is taking valpromide, progabide, valproic acid, or other known inhibitors of epoxide hydrolase, or subject is taking ranolazine, cyclosporine, azathioprine or mercaptopurine.
8. Subject is receiving chronic treatment with more than 325 mg of salicylates per day.
9. Subject is unable to initiate gout flare prophylaxis with colchicine or low-dose oral corticosteroids at Baseline.
10. Subject is taking any other drug approved for use as a urate-lowering medication other than allopurinol or febuxostat (eg, pegloticase, probenecid, benzbromarone) within 4 weeks prior to Screening or during Screening.
11. For subjects who will be taking colchicine for gout flare prophylaxis: Subject is taking, or anticipated to take during the first 6 months on study, moderate or strong Cytochrome P450 3A4 (CYP3A4) inhibitors (ie, verapamil or diltiazem, clarithromycin, and fluconazole; or grapefruit or grapefruit juice).
12. Subject previously participated in a clinical study involving lesinurad (RDEA594) or verinurad (RDEA3170) and received active treatment or placebo, or has taken commercially-available lesinurad.
13. Subject has a gout flare during the Screening Period.
14. Subject is pregnant or breastfeeding.
15. Subject 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).
16. Subject has a history of malignancy and has been on active treatment within the previous 5 years prior to randomization with the exception of non-melanoma skin cancer, treated in situ Grade 1 cervical cancer, or treated ductal carcinoma in situ of the breast.
17. Subject has been hospitalized (other than for elective surgery) or received intravenous contrast (eg, for computerized tomography (CT) scan or any angiography) within 1 month prior to Screening or during Screening.
18. Subject has participated in a clinical trial within 8 weeks prior to Screening.
19. Subject has any other medical or psychological condition, which in the opinion of the Investigator 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.
20. The maximum number of subjects in the eCrCl stratification subgroup has been reached.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Lesinurad + XOI; lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI	Drug: Lesinurad; 200 mg oral tablet; Other Names: RDEA594; Drug: XOI; All participants must be on a stable, medically appropriate dose of XOI as their sole urate-lowering therapy (ULT) indicated for the treatment of gout for at least 4 weeks prior to Screening and throughout the Screening Period. This stable dose of XOI will be maintained throughout the study period.; Other Names: allopurinol; febuxostat; Drug: colchicine; Gout flare prophylaxis: commercially available colchicine is provided through the Month 6 study visit. Actual colchicine dose (0.5 or 0.6 mg qd) and frequency were adjusted based on the local label, subject medical history, and clinical judgement.; Drug: corticosteroids; Gout flare prophylaxis: Participants unable to take colchicine are permitted to take a short course of low-dose oral corticosteroids up to the Month 3 study visit
Placebo Comparator: Placebo + XOI; placebo tablet QD plus a stable, medically appropriate dose of an XOI	Drug: XOI; All participants must be on a stable, medically appropriate dose of XOI as their sole urate-lowering therapy (ULT) indicated for the treatment of gout for at least 4 weeks prior to Screening and throughout the Screening Period. This stable dose of XOI will be maintained throughout the study period.; Other Names: allopurinol; febuxostat; Drug: colchicine; Gout flare prophylaxis: commercially available colchicine is provided through the Month 6 study visit. Actual colchicine dose (0.5 or 0.6 mg qd) and frequency were adjusted based on the local label, subject medical history, and clinical judgement.; Drug: corticosteroids; Gout flare prophylaxis: Participants unable to take colchicine are permitted to take a short course of low-dose oral corticosteroids up to the Month 3 study visit; Drug: Placebo; matching placebo oral tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percentage of Participants Who Achieve Serum Urate (sUA) < 6.0 mg/dL at Month 6	Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Achieve sUA < 6.0 mg/dL Over Time		Baseline, Months 1, 3, 6, 9, 12, 15, 18
Change From Baseline in sUA Over Time, Including the Last Value On and Off Treatment		Baseline, Months 1, 3, 6, 9, 12, 15, 18
Percent Change From Baseline in sUA Over Time, Including the Last Value On and Off Treatment		Baseline, Months 1, 3, 6, 9, 12, 15, 18
Change From Baseline in Estimated Creatinine Clearance (eCrCl) at Month 24	The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight.	Baseline, 24 months
Percent Change From Baseline in eCrCl at Month 24	The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight.	Baseline, 24 months
Change From Baseline in eCrCl Over the Study Period, Including the Last Value On and Off Treatment	The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight.	Baseline, Months 1, 3, 6, 9, 12, 15, 18
Percent Change From Baseline in eCrCl Over the Study Period, Including the Last Value On and Off Treatment	The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight.	Baseline, Months 1, 3, 6, 9, 12, 15, 18
Percentage of Participants With Serum Creatinine (sCr) Elevations (≥1.5 × Baseline) Over the Study Period		up to 18 months
Percentage of Participants Meeting Criteria (eg, Based on sCr or eCrCl Criteria) for Treatment Discontinuations Over the Study Period	Kidney function was monitored throughout the study by measuring sCr and calculating eCrCl by Cockcroft-Gault formula using ideal body weight. Treatment discontinuations were required if a participant experienced an absolute sCr ≥4.0 mg/dL or an eCrCl <20 mL/min (based on central laboratory results).	up to 18 months
Percentage of Participants Renal-Related and Kidney Stone Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	Renal-related and kidney stone events were based on Medical Dictionary for Regulatory Activities (MedDRA) "Renal and Urinary Disorders" system organ classification. AEs that started on or after the first dose of study drug in this study, or those AEs with onset prior to the first dose of study drug but worsened after the first dose of study drug, were considered treatment emergent.	From first dose of study drug through each participant's study duration, up to approximately 18 months.
Percentage of Participants With Contributing Factors to Renal SAEs as Adjudicated by the Renal Event Adjudication Committee (REAC)		From first dose of study drug through each participant's study duration, up to approximately 18 months.
Percentage of Participants With Cardiac Event Adjudication Committee (CEAC)-Adjudicated Major Adverse Cardiovascular Events (MACEs)	MACEs are defined as Cardiovascular Death, Nonfatal Myocardial Infarction, and Nonfatal Stroke.	From first dose of study drug through each participant's study duration, up to approximately 18 months.
Incidence of CEAC-Adjudicated MACEs or Hospitalization for Unstable Angina (MACE+)	MACEs are defined as Cardiovascular Death, Nonfatal Myocardial Infarction, and Nonfatal Stroke.	From first dose of study drug through each participant's study duration, up to approximately 18 months.

Collaborators and Investigators

• Sponsor: Ironwood Pharmaceuticals, Inc.
• Collaborators: Medpace, Inc.
• Investigators: Study Chair: Ironwood Study Chair, Ironwood Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2017
• Primary Completion (Actual): February 25, 2019
• Study Completion (Actual): February 25, 2019

Study Registration Dates

• First Submitted: July 20, 2017
• First Submitted That Met QC Criteria: July 20, 2017
• First Posted (Actual): July 24, 2017

Study Record Updates

• Last Update Posted (Actual): November 4, 2021
• Last Update Submitted That Met QC Criteria: October 6, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Urologic Diseases; Renal Insufficiency; Genetic Diseases, Inborn; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Metabolism, Inborn Errors; Crystal Arthropathies; Purine-Pyrimidine Metabolism, Inborn Errors; Kidney Diseases; Renal Insufficiency, Chronic; Gout; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Protective Agents; Antioxidants; Free Radical Scavengers; Gout Suppressants; Renal Agents; Uricosuric Agents; Colchicine; Allopurinol; Lesinurad; Febuxostat
• Other Study ID Numbers: RDEA594-401

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No