Clinical trial NCT03226899: A Phase 4 Safety and Efficacy Study to Evaluate Lesinurad 200 mg in Participants With Gout and Renal Impairment
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE4
Conditions: Gout
Chronic Kidney Disease (CKD)
Lead sponsor: Ironwood Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Medpace, Inc.
First posted: 2017-07-24
Enrollment: 242
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, Double-Blind, Multicenter, Placebo-Controlled
Primary purpose: TREATMENT

Brief summary: 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).

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants Who Achieve Serum Urate (sUA) < 6.0 mg/dL at Month 6
timeFrame: Month 6
Secondary outcomes:
measure: Percentage of Participants Who Achieve sUA < 6.0 mg/dL Over Time
timeFrame: Baseline, Months 1, 3, 6, 9, 12, 15, 18
measure: Change From Baseline in sUA Over Time, Including the Last Value On and Off Treatment
timeFrame: Baseline, Months 1, 3, 6, 9, 12, 15, 18
measure: Percent Change From Baseline in sUA Over Time, Including the Last Value On and Off Treatment
timeFrame: Baseline, Months 1, 3, 6, 9, 12, 15, 18
measure: Change From Baseline in Estimated Creatinine Clearance (eCrCl) at Month 24
timeFrame: Baseline, 24 months
measure: Percent Change From Baseline in eCrCl at Month 24
timeFrame: Baseline, 24 months
measure: Change From Baseline in eCrCl Over the Study Period, Including the Last Value On and Off Treatment
timeFrame: Baseline, Months 1, 3, 6, 9, 12, 15, 18
measure: Percent Change From Baseline in eCrCl Over the Study Period, Including the Last Value On and Off Treatment
timeFrame: Baseline, Months 1, 3, 6, 9, 12, 15, 18
measure: Percentage of Participants With Serum Creatinine (sCr) Elevations (≥1.5 × Baseline) Over the Study Period
timeFrame: up to 18 months
measure: Percentage of Participants Meeting Criteria (eg, Based on sCr or eCrCl Criteria) for Treatment Discontinuations Over the Study Period
timeFrame: up to 18 months
measure: Percentage of Participants Renal-Related and Kidney Stone Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From first dose of study drug through each participant's study duration, up to approximately 18 months.
measure: Percentage of Participants With Contributing Factors to Renal SAEs as Adjudicated by the Renal Event Adjudication Committee (REAC)
timeFrame: From first dose of study drug through each participant's study duration, up to approximately 18 months.
measure: Percentage of Participants With Cardiac Event Adjudication Committee (CEAC)-Adjudicated Major Adverse Cardiovascular Events (MACEs)
timeFrame: From first dose of study drug through each participant's study duration, up to approximately 18 months.
measure: Incidence of CEAC-Adjudicated MACEs or Hospitalization for Unstable Angina (MACE+)
timeFrame: From first dose of study drug through each participant's study duration, up to approximately 18 months.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Central Alabama Research
state: Alabama
city: Tucson
country: United States
facility: Southern Arizona VA Health Care System
state: Arizona
city: Covina
country: United States
facility: Medvin Clinical Research
state: California
city: Sacramento
country: United States
facility: Northern California Research
state: California
city: Sacramento
country: United States
facility: Capital Nephrology Medical Group
state: California
city: Upland
country: United States
facility: Inland Rheumatology Clinical Trials, Inc
state: California
city: Whittier
country: United States
facility: Medvin Clinical Research - Whittier
state: California
city: Westminster
country: United States
facility: Western Nephrology-Westminster
state: Colorado
city: Trumbull
country: United States
facility: New England Research Associates, Llc
state: Connecticut
city: Daytona Beach
country: United States
facility: Arthritis, Autoimmune, & Allergy LLC
state: Florida
city: Edgewater
country: United States
facility: Riverside Clinical Research
state: Florida
city: Gainesville
country: United States
facility: Florida Medical Research Institute
state: Florida
city: Hialeah
country: United States
facility: Eastern Research
state: Florida
city: Miami Lakes
country: United States
facility: Savin Medical Group
state: Florida
city: Miami
country: United States
facility: San Marcus Research Clinic Inc
state: Florida
city: Miami
country: United States
facility: LCC Medical Research Institute, LLC
state: Florida
city: Orlando
country: United States
facility: Rheumatology Associates of Central Florida
state: Florida
city: Orlando
country: United States
facility: Omega Research Consultants, LLC
state: Florida
city: Tampa
country: United States
facility: BayCare Medical Group, Inc.
state: Florida
city: Tampa
country: United States
facility: Meridien Research - Tampa
state: Florida
city: Atlanta
country: United States
facility: The Kaufmann Clinic, Inc
state: Georgia
city: Atlanta
country: United States
facility: Ellipsis Group
state: Georgia
city: Idaho Falls
country: United States
facility: Rocky Mountain Diabetes and Osteoporosis Center PA
state: Idaho
city: Gurnee
country: United States
facility: Clinical Investigation Specialists, Inc. - Gurnee
state: Illinois
city: Merrillville
country: United States
facility: Nephrology Specialists
state: Indiana
city: Wichita
country: United States
facility: Kansas Nephrology Research Institute
state: Kansas
city: Elizabethtown
country: United States
facility: Center for Arthritis & Osteoporosis
state: Kentucky
city: Paducah
country: United States
facility: Four Rivers Clinical Research
state: Kentucky
city: Baton Rouge
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Covington
country: United States
facility: Clinical Trials Management, LLC - Northshore
state: Louisiana
city: Metairie
country: United States
facility: Clinical Trials Management LLC - Southshore
state: Louisiana
city: Monroe
country: United States
facility: Arthritis and Diabetes Clinic
state: Louisiana
city: Shreveport
country: United States
facility: Northwest Louisiana Nephrology
state: Louisiana
city: Worcester
country: United States
facility: University of Massachusetts Memorial Medical Center
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Pontiac
country: United States
facility: Michigan Kidney Consultants
state: Michigan
city: Roseville
country: United States
facility: St. Clair Nephrology Research
state: Michigan
city: Jackson
country: United States
facility: CRC of Jackson, LLC
state: Mississippi
city: Kansas City
country: United States
facility: VA Medical Center - Kansas City
state: Missouri
city: Norfolk
country: United States
facility: Meridian Clinical Research - Norfolk, NE
state: Nebraska
city: Albuquerque
country: United States
facility: New Mexico Clinical Research & Osteoporosis Center Inc.
state: New Mexico
city: Brooklyn
country: United States
facility: Ellipsis Research Group, LLC
state: New York
city: Buffalo
country: United States
facility: Buffalo VA Medical Center
state: New York
city: Mineola
country: United States
facility: Winthrop University Hospital
state: New York
city: Charlotte
country: United States
facility: DJL Clinical Research PLLC
state: North Carolina
city: Greensboro
country: United States
facility: PhysiqueMed Clinical Trials
state: North Carolina
city: Morganton
country: United States
facility: Burke Primary Care
state: North Carolina
city: Wilmington
country: United States
facility: Trial Management Associates, LLC
state: North Carolina
city: Cincinnati
country: United States
facility: Sterling Research Group, Ltd. - Auburn
state: Ohio
city: Cincinnati
country: United States
facility: Sterling Research Group, Ltd. - Cincinnati
state: Ohio
city: Franklin
country: United States
facility: Prestige Clinical Research
state: Ohio
city: Portland
country: United States
facility: Columbia Research Group, Inc.
state: Oregon
city: Bethlehem
country: United States
facility: Northeast Clinical Research Center
state: Pennsylvania
city: Duncansville
country: United States
facility: Altoona Center for Clinical Research
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: East Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Low Country Rheumatology
state: South Carolina
city: Fort Mill
country: United States
facility: Piedmont Research Partners, LLC
state: South Carolina
city: Greer
country: United States
facility: Mountain View Clinical Research - Greer
state: South Carolina
city: Knoxville
country: United States
facility: Knoxville Kidney Center, PLLC
state: Tennessee
city: Nashville
country: United States
facility: Discovery Alliance International Inc. d/b/a Tennessee Health Research Alliance LLC
state: Tennessee
city: Nashville
country: United States
facility: Nephrology Associates, P.C.
state: Tennessee
city: Lampasas
country: United States
facility: FMC Science
state: Texas
city: Lufkin
country: United States
facility: P&I Clinical Research
state: Texas
city: San Antonio
country: United States
facility: Clinical Advancement Center, PLLC
state: Texas
city: San Antonio
country: United States
facility: Briggs Clinical Research, Inc.
state: Texas
city: Victoria
country: United States
facility: 3rd Coast Research Associates
state: Texas
city: Danville
country: United States
facility: Spectrum Medical, Inc.
state: Virginia
city: Manassas
country: United States
facility: Manassas Clinical Research Center
state: Virginia
city: Richmond
country: United States
facility: Clinical Research Partners, LLC
state: Virginia
city: Brno
country: Czechia
facility: CCBR Czech Brno, s. r. o
city: Brno
country: Czechia
facility: REVMACLINIC s.r.o. - Revmatologicka ambulance
city: Brno
country: Czechia
facility: DTTO Faculty Hospital Brno
city: Olomouc
country: Czechia
facility: Revmatologie MUDr. Bilkova s.r.o.
city: Ostrava
country: Czechia
facility: CCBR Ostrava s.r.o.
city: Pardubice
country: Czechia
facility: CCBR Clinical Research, Pardubice
city: Prague
country: Czechia
facility: CCBR Czech Prague s.r.o.
city: Uherske Hradiste
country: Czechia
facility: MEDICAL PLUS, s.r.o. - Revmatologicka ambulance
city: Usti nad Labem
country: Czechia
facility: Krajska zdravotni, a.s. - Masarykova nemocnice v Usti nad Labem, o.z.
city: Zlín
country: Czechia
facility: PV - MEDICAL, s.r.o.
city: Znojmo
country: Czechia
facility: Nemocnice Znojmo p.o - Interni oddeleni
city: Baja
country: Hungary
facility: Bajai Szent Rokus Korhaz
city: Balatonfüred
country: Hungary
facility: DRC Gyogyszervizsgalo Kozpont Kft
city: Budapest
country: Hungary
facility: Clinexpert Kft.
city: Békéscsaba
country: Hungary
facility: Dr Lakatos Ferenc Belgyogyaszati-Kardiologiai Maganrendelo
city: Esztergom
country: Hungary
facility: Vaszary Kolos Korhaz Esztergom - Reumatologiai osztaly
city: Hatvan
country: Hungary
facility: BKS Research Kft.
city: Kalocsa
country: Hungary
facility: Kalocsai Szent Kereszt Korhaz
city: Komárom
country: Hungary
facility: Selye Janos Hospital - Rheumatology Department
city: Miskolc
country: Hungary
facility: CRU Hungary Kft.
city: Szekszárd
country: Hungary
facility: Clinfan Ltd SMO
city: Szolnok
country: Hungary
facility: Allergo-Derm Bakos Kft.
city: Székesfehérvár
country: Hungary
facility: Mentahaz Maganorvosi Kozpont (SMO)
city: Veszprem
country: Hungary
facility: Medical Expert Kft.
city: Zyrardow
country: Poland
facility: Stacja Dializ Zyrardow
state: Zyrardo
city: Chorzów
country: Poland
facility: B_Serwis Popenda Sp. J.
city: Elbląg
country: Poland
facility: Centrum Kliniczno Badawcze J. Brzezicki B. Gornikiewicz - Brzezicka Lekarze Sp. p.
city: Grodzisk Mazowiecki
country: Poland
facility: MCBK s.c.
city: Katowice
country: Poland
facility: NZOZ Praktyka Lekarza Rodzinnego Elzbieta Kelm
city: Kraków
country: Poland
facility: Centrum Medyczne Pratia Krakow
city: Kraków
country: Poland
facility: Malopolskie Centrum Medyczne
city: Lublin
country: Poland
facility: Centrum Medyczne Chodzki
city: Nowy Sącz
country: Poland
facility: Alfa Specjalistyczne Gabinety Lekarskie Ewa Moroz
city: Poznań
country: Poland
facility: Centrum Zdrowia Metabolicznego Pawel Bogdanski
city: Poznań
country: Poland
facility: Centrum Badan Klinicznych s.c.
city: Poznań
country: Poland
facility: Praktyka Lekarska Ewa Krzyzagorska
city: Radom
country: Poland
facility: Prywatny Gabinet Lekarski NZOZ Centrum Medyczne Aeskulap
city: Warszawa
country: Poland
facility: Centrum Medyczne Pratia Warszawa
city: Wołomin
country: Poland
facility: Centrum Medyczne K2J2
city: Zamość
country: Poland
facility: KO - MED Centra Kliniczne Sp. z o.o., Osrodek Badan Klinicznych w Zamosciu
city: Łódź
country: Poland
facility: Samodzielny Publiczny ZOZ Uniwersytecki Szpital Kliniczny nr 1 im. Norberta Barlickiego Uniwersytetu Medycznego w Lodzi, Oddzial Kliniczny Nefrologii, Hipertensjologii i Transplantologii Nerek
city: Łódź
country: Poland
facility: Centrum Terapii Wspolczesnej J. M. Jasnorzewska Spolka Komandytowo Akcyjna
city: Łódź
country: Poland
facility: AppleTreeClinics Sp. z o.o.
city: Łódź
country: Poland
facility: Centrum Medyczne AMED Oddzial w Lodzi
city: Łódź
country: Poland
facility: NZOZ All - Med Centrum Medyczne Specjalistyczne Gabinety Lekarskie Marcin Ogorek
city: Żyrardów
country: Poland
facility: Centrum Dializa Sp. z o.o. - Zyrardow
Study officials:
affiliation: Ironwood Pharmaceuticals, Inc.
name: Ironwood Study Chair
role: STUDY_CHAIR
References: