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

Gout Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03226899
• Other study ID #: RDEA594-401
• Status: Terminated
• Phase: Phase 4
• Start date: July 19, 2017
• Est. completion date: February 25, 2019

Study information

• Verified date: October 2021
• Source: Ironwood Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 242
• Est. completion date: February 25, 2019
• Est. primary completion date: February 25, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Kidney Disease (CKD)
• Gout
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Drug:
• Lesinurad
200 mg oral tablet
• 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.
• Placebo
matching placebo oral tablet
• 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.
• 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

Locations

Country	Name	City	State
Czechia	CCBR Czech Brno, s. r. o	Brno
Czechia	DTTO Faculty Hospital Brno	Brno
Czechia	REVMACLINIC s.r.o. - Revmatologicka ambulance	Brno
Czechia	Revmatologie MUDr. Bilkova s.r.o.	Olomouc
Czechia	CCBR Ostrava s.r.o.	Ostrava
Czechia	CCBR Clinical Research, Pardubice	Pardubice
Czechia	CCBR Czech Prague s.r.o.	Prague
Czechia	MEDICAL PLUS, s.r.o. - Revmatologicka ambulance	Uherske Hradiste
Czechia	Krajska zdravotni, a.s. - Masarykova nemocnice v Usti nad Labem, o.z.	Usti nad Labem
Czechia	PV - MEDICAL, s.r.o.	Zlín
Czechia	Nemocnice Znojmo p.o - Interni oddeleni	Znojmo
Hungary	Bajai Szent Rokus Korhaz	Baja
Hungary	DRC Gyogyszervizsgalo Kozpont Kft	Balatonfüred
Hungary	Dr Lakatos Ferenc Belgyogyaszati-Kardiologiai Maganrendelo	Békéscsaba
Hungary	Clinexpert Kft.	Budapest
Hungary	Vaszary Kolos Korhaz Esztergom - Reumatologiai osztaly	Esztergom
Hungary	BKS Research Kft.	Hatvan
Hungary	Kalocsai Szent Kereszt Korhaz	Kalocsa
Hungary	Selye Janos Hospital - Rheumatology Department	Komárom
Hungary	CRU Hungary Kft.	Miskolc
Hungary	Mentahaz Maganorvosi Kozpont (SMO)	Székesfehérvár
Hungary	Clinfan Ltd SMO	Szekszárd
Hungary	Allergo-Derm Bakos Kft.	Szolnok
Hungary	Medical Expert Kft.	Veszprem
Poland	B_Serwis Popenda Sp. J.	Chorzów
Poland	Centrum Kliniczno Badawcze J. Brzezicki B. Gornikiewicz - Brzezicka Lekarze Sp. p.	Elblag
Poland	MCBK s.c.	Grodzisk Mazowiecki
Poland	NZOZ Praktyka Lekarza Rodzinnego Elzbieta Kelm	Katowice
Poland	Centrum Medyczne Pratia Krakow	Kraków
Poland	Malopolskie Centrum Medyczne	Kraków
Poland	AppleTreeClinics Sp. z o.o.	Lódz
Poland	Centrum Medyczne AMED Oddzial w Lodzi	Lódz
Poland	Centrum Terapii Wspolczesnej J. M. Jasnorzewska Spolka Komandytowo Akcyjna	Lódz
Poland	NZOZ All - Med Centrum Medyczne Specjalistyczne Gabinety Lekarskie Marcin Ogorek	Lódz
Poland	Samodzielny Publiczny ZOZ Uniwersytecki Szpital Kliniczny nr 1 im. Norberta Barlickiego Uniwersytetu Medycznego w Lodzi, Oddzial Kliniczny Nefrologii, Hipertensjologii i Transplantologii Nerek	Lódz
Poland	Centrum Medyczne Chodzki	Lublin
Poland	Alfa Specjalistyczne Gabinety Lekarskie Ewa Moroz	Nowy Sacz
Poland	Centrum Badan Klinicznych s.c.	Poznan
Poland	Centrum Zdrowia Metabolicznego Pawel Bogdanski	Poznan
Poland	Praktyka Lekarska Ewa Krzyzagorska	Poznan
Poland	Prywatny Gabinet Lekarski NZOZ Centrum Medyczne Aeskulap	Radom
Poland	Centrum Medyczne Pratia Warszawa	Warszawa
Poland	Centrum Medyczne K2J2	Wolomin
Poland	KO - MED Centra Kliniczne Sp. z o.o., Osrodek Badan Klinicznych w Zamosciu	Zamosc
Poland	Stacja Dializ Zyrardow	Zyrardow	Zyrardo
Poland	Centrum Dializa Sp. z o.o. - Zyrardow	Zyrardów
United States	New Mexico Clinical Research & Osteoporosis Center Inc.	Albuquerque	New Mexico
United States	University of Michigan	Ann Arbor	Michigan
United States	Ellipsis Group	Atlanta	Georgia
United States	The Kaufmann Clinic, Inc	Atlanta	Georgia
United States	Ochsner Clinic Foundation	Baton Rouge	Louisiana
United States	Northeast Clinical Research Center	Bethlehem	Pennsylvania
United States	Central Alabama Research	Birmingham	Alabama
United States	Ellipsis Research Group, LLC	Brooklyn	New York
United States	Buffalo VA Medical Center	Buffalo	New York
United States	Low Country Rheumatology	Charleston	South Carolina
United States	DJL Clinical Research PLLC	Charlotte	North Carolina
United States	Sterling Research Group, Ltd. - Auburn	Cincinnati	Ohio
United States	Sterling Research Group, Ltd. - Cincinnati	Cincinnati	Ohio
United States	Medvin Clinical Research	Covina	California
United States	Clinical Trials Management, LLC - Northshore	Covington	Louisiana
United States	Spectrum Medical, Inc.	Danville	Virginia
United States	Arthritis, Autoimmune, & Allergy LLC	Daytona Beach	Florida
United States	Altoona Center for Clinical Research	Duncansville	Pennsylvania
United States	Rhode Island Hospital	East Providence	Rhode Island
United States	Riverside Clinical Research	Edgewater	Florida
United States	Center for Arthritis & Osteoporosis	Elizabethtown	Kentucky
United States	Piedmont Research Partners, LLC	Fort Mill	South Carolina
United States	Prestige Clinical Research	Franklin	Ohio
United States	Florida Medical Research Institute	Gainesville	Florida
United States	PhysiqueMed Clinical Trials	Greensboro	North Carolina
United States	Mountain View Clinical Research - Greer	Greer	South Carolina
United States	Clinical Investigation Specialists, Inc. - Gurnee	Gurnee	Illinois
United States	Eastern Research	Hialeah	Florida
United States	Rocky Mountain Diabetes and Osteoporosis Center PA	Idaho Falls	Idaho
United States	CRC of Jackson, LLC	Jackson	Mississippi
United States	VA Medical Center - Kansas City	Kansas City	Missouri
United States	Knoxville Kidney Center, PLLC	Knoxville	Tennessee
United States	FMC Science	Lampasas	Texas
United States	P&I Clinical Research	Lufkin	Texas
United States	Manassas Clinical Research Center	Manassas	Virginia
United States	Nephrology Specialists	Merrillville	Indiana
United States	Clinical Trials Management LLC - Southshore	Metairie	Louisiana
United States	LCC Medical Research Institute, LLC	Miami	Florida
United States	San Marcus Research Clinic Inc	Miami	Florida
United States	Savin Medical Group	Miami Lakes	Florida
United States	Winthrop University Hospital	Mineola	New York
United States	Arthritis and Diabetes Clinic	Monroe	Louisiana
United States	Burke Primary Care	Morganton	North Carolina
United States	Discovery Alliance International Inc. d/b/a Tennessee Health Research Alliance LLC	Nashville	Tennessee
United States	Nephrology Associates, P.C.	Nashville	Tennessee
United States	Meridian Clinical Research - Norfolk, NE	Norfolk	Nebraska
United States	Omega Research Consultants, LLC	Orlando	Florida
United States	Rheumatology Associates of Central Florida	Orlando	Florida
United States	Four Rivers Clinical Research	Paducah	Kentucky
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Michigan Kidney Consultants	Pontiac	Michigan
United States	Columbia Research Group, Inc.	Portland	Oregon
United States	Clinical Research Partners, LLC	Richmond	Virginia
United States	St. Clair Nephrology Research	Roseville	Michigan
United States	Capital Nephrology Medical Group	Sacramento	California
United States	Northern California Research	Sacramento	California
United States	Briggs Clinical Research, Inc.	San Antonio	Texas
United States	Clinical Advancement Center, PLLC	San Antonio	Texas
United States	Northwest Louisiana Nephrology	Shreveport	Louisiana
United States	BayCare Medical Group, Inc.	Tampa	Florida
United States	Meridien Research - Tampa	Tampa	Florida
United States	New England Research Associates, Llc	Trumbull	Connecticut
United States	Southern Arizona VA Health Care System	Tucson	Arizona
United States	Inland Rheumatology Clinical Trials, Inc	Upland	California
United States	3rd Coast Research Associates	Victoria	Texas
United States	Western Nephrology-Westminster	Westminster	Colorado
United States	Medvin Clinical Research - Whittier	Whittier	California
United States	Kansas Nephrology Research Institute	Wichita	Kansas
United States	Trial Management Associates, LLC	Wilmington	North Carolina
United States	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Ironwood Pharmaceuticals, Inc.	Medpace, Inc.

Countries where clinical trial is conducted

United States,  Czechia,  Hungary,  Poland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Who Achieve Serum Urate (sUA) < 6.0 mg/dL at Month 6		Month 6
Secondary	Percentage of Participants Who Achieve sUA < 6.0 mg/dL Over Time		Baseline, Months 1, 3, 6, 9, 12, 15, 18
Secondary	Change From Baseline in sUA Over Time, Including the Last Value On and Off Treatment		Baseline, Months 1, 3, 6, 9, 12, 15, 18
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Percentage of Participants With Serum Creatinine (sCr) Elevations (=1.5 × Baseline) Over the Study Period		up to 18 months
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.