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

• Sponsor: Ironwood Pharmaceuticals, Inc. (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03226899
• Collaborator: Medpace, Inc. (Industry)
• Enrollment: 242
• Locations: 116
• Arms: 2
• Actual Duration (Months): 19.3
• Patients Per Site: 2.1
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Gout; Chronic Kidney Disease (CKD)	Drug: Lesinurad; Drug: XOI; Drug: Placebo; Drug: colchicine; Drug: corticosteroids	Phase 4

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 Design

• Study Type: Interventional
• Actual Enrollment: 242 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Randomized, Double-Blind, Multicenter, Placebo-ControlledRandomized, Double-Blind, Multicenter, Placebo-Controlled
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: active vs placebo visually identical tablets
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Jul 19, 2017
• Actual Primary Completion Date: Feb 25, 2019
• Actual Study Completion Date: Feb 25, 2019

Arms and Interventions

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: Placebo; matching placebo oral tablet; 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

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Achieve Serum Urate (sUA) < 6.0 mg/dL at Month 6 [Month 6]

Secondary Outcome Measures

1. Percentage of Participants Who Achieve sUA < 6.0 mg/dL Over Time [Baseline, Months 1, 3, 6, 9, 12, 15, 18]

2. Change From Baseline in sUA Over Time, Including the Last Value On and Off Treatment [Baseline, Months 1, 3, 6, 9, 12, 15, 18]

3. 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]

4. Change From Baseline in Estimated Creatinine Clearance (eCrCl) at Month 24 [Baseline, 24 months]

   The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight.

5. Percent Change From Baseline in eCrCl at Month 24 [Baseline, 24 months]

   The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight.

6. Change From Baseline in eCrCl Over the Study Period, Including the Last Value On and Off Treatment [Baseline, Months 1, 3, 6, 9, 12, 15, 18]

   The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight.

7. Percent Change From Baseline in eCrCl Over the Study Period, Including the Last Value On and Off Treatment [Baseline, Months 1, 3, 6, 9, 12, 15, 18]

   The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight.

8. Percentage of Participants With Serum Creatinine (sCr) Elevations (≥1.5 × Baseline) Over the Study Period [up to 18 months]

9. Percentage of Participants Meeting Criteria (eg, Based on sCr or eCrCl Criteria) for Treatment Discontinuations Over the Study Period [up to 18 months]

   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).

10. Percentage of Participants Renal-Related and Kidney Stone Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [From first dose of study drug through each participant's study duration, up to approximately 18 months.]

    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.

11. 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.]

12. Percentage of Participants With Cardiac Event Adjudication Committee (CEAC)-Adjudicated Major Adverse Cardiovascular Events (MACEs) [From first dose of study drug through each participant's study duration, up to approximately 18 months.]

    MACEs are defined as Cardiovascular Death, Nonfatal Myocardial Infarction, and Nonfatal Stroke.

13. Incidence of CEAC-Adjudicated MACEs or Hospitalization for Unstable Angina (MACE+) [From first dose of study drug through each participant's study duration, up to approximately 18 months.]

    MACEs are defined as Cardiovascular Death, Nonfatal Myocardial Infarction, and Nonfatal Stroke.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

9. 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).

10. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Central Alabama Research	Birmingham	Alabama	United States	35209
2	Southern Arizona VA Health Care System	Tucson	Arizona	United States	85723
3	Medvin Clinical Research	Covina	California	United States	91722
4	Northern California Research	Sacramento	California	United States	95821
5	Capital Nephrology Medical Group	Sacramento	California	United States	95825
6	Inland Rheumatology Clinical Trials, Inc	Upland	California	United States	91786
7	Medvin Clinical Research - Whittier	Whittier	California	United States	90602
8	Western Nephrology-Westminster	Westminster	Colorado	United States	80031
9	New England Research Associates, Llc	Trumbull	Connecticut	United States	06611
10	Arthritis, Autoimmune, & Allergy LLC	Daytona Beach	Florida	United States	32117
11	Riverside Clinical Research	Edgewater	Florida	United States	32132
12	Florida Medical Research Institute	Gainesville	Florida	United States	32607
13	Eastern Research	Hialeah	Florida	United States	33013
14	Savin Medical Group	Miami Lakes	Florida	United States	33014
15	San Marcus Research Clinic Inc	Miami	Florida	United States	33015
16	LCC Medical Research Institute, LLC	Miami	Florida	United States	33126
17	Rheumatology Associates of Central Florida	Orlando	Florida	United States	32806
18	Omega Research Consultants, LLC	Orlando	Florida	United States	32810
19	BayCare Medical Group, Inc.	Tampa	Florida	United States	33614
20	Meridien Research - Tampa	Tampa	Florida	United States	33634
21	The Kaufmann Clinic, Inc	Atlanta	Georgia	United States	30308
22	Ellipsis Group	Atlanta	Georgia	United States	30342
23	Rocky Mountain Diabetes and Osteoporosis Center PA	Idaho Falls	Idaho	United States	83404
24	Clinical Investigation Specialists, Inc. - Gurnee	Gurnee	Illinois	United States	60031
25	Nephrology Specialists	Merrillville	Indiana	United States	46410
26	Kansas Nephrology Research Institute	Wichita	Kansas	United States	67214
27	Center for Arthritis & Osteoporosis	Elizabethtown	Kentucky	United States	42701
28	Four Rivers Clinical Research	Paducah	Kentucky	United States	42003
29	Ochsner Clinic Foundation	Baton Rouge	Louisiana	United States	70809
30	Clinical Trials Management, LLC - Northshore	Covington	Louisiana	United States	70433
31	Clinical Trials Management LLC - Southshore	Metairie	Louisiana	United States	70006
32	Arthritis and Diabetes Clinic	Monroe	Louisiana	United States	71203
33	Northwest Louisiana Nephrology	Shreveport	Louisiana	United States	71101
34	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts	United States	01605
35	University of Michigan	Ann Arbor	Michigan	United States	48109
36	Michigan Kidney Consultants	Pontiac	Michigan	United States	48341
37	St. Clair Nephrology Research	Roseville	Michigan	United States	48066
38	CRC of Jackson, LLC	Jackson	Mississippi	United States	39202
39	VA Medical Center - Kansas City	Kansas City	Missouri	United States	64128
40	Meridian Clinical Research - Norfolk, NE	Norfolk	Nebraska	United States	68701
41	New Mexico Clinical Research & Osteoporosis Center Inc.	Albuquerque	New Mexico	United States	87106
42	Ellipsis Research Group, LLC	Brooklyn	New York	United States	11215
43	Buffalo VA Medical Center	Buffalo	New York	United States	14215
44	Winthrop University Hospital	Mineola	New York	United States	11501
45	DJL Clinical Research PLLC	Charlotte	North Carolina	United States	28210
46	PhysiqueMed Clinical Trials	Greensboro	North Carolina	United States	27405
47	Burke Primary Care	Morganton	North Carolina	United States	28655
48	Trial Management Associates, LLC	Wilmington	North Carolina	United States	28403
49	Sterling Research Group, Ltd. - Auburn	Cincinnati	Ohio	United States	45219
50	Sterling Research Group, Ltd. - Cincinnati	Cincinnati	Ohio	United States	45246
51	Prestige Clinical Research	Franklin	Ohio	United States	45005
52	Columbia Research Group, Inc.	Portland	Oregon	United States	97239
53	Northeast Clinical Research Center	Bethlehem	Pennsylvania	United States	18017
54	Altoona Center for Clinical Research	Duncansville	Pennsylvania	United States	16635
55	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
56	Rhode Island Hospital	East Providence	Rhode Island	United States	02914
57	Low Country Rheumatology	Charleston	South Carolina	United States	29406
58	Piedmont Research Partners, LLC	Fort Mill	South Carolina	United States	29707
59	Mountain View Clinical Research - Greer	Greer	South Carolina	United States	29651
60	Knoxville Kidney Center, PLLC	Knoxville	Tennessee	United States	37923
61	Discovery Alliance International Inc. d/b/a Tennessee Health Research Alliance LLC	Nashville	Tennessee	United States	37203
62	Nephrology Associates, P.C.	Nashville	Tennessee	United States	37205
63	FMC Science	Lampasas	Texas	United States	76550
64	P&I Clinical Research	Lufkin	Texas	United States	75904
65	Clinical Advancement Center, PLLC	San Antonio	Texas	United States	78215
66	Briggs Clinical Research, Inc.	San Antonio	Texas	United States	78224
67	3rd Coast Research Associates	Victoria	Texas	United States	77901
68	Spectrum Medical, Inc.	Danville	Virginia	United States	24541
69	Manassas Clinical Research Center	Manassas	Virginia	United States	20110
70	Clinical Research Partners, LLC	Richmond	Virginia	United States	23235
71	CCBR Czech Brno, s. r. o	Brno		Czechia	60200
72	REVMACLINIC s.r.o. - Revmatologicka ambulance	Brno		Czechia	611 41
73	DTTO Faculty Hospital Brno	Brno		Czechia	62500
74	Revmatologie MUDr. Bilkova s.r.o.	Olomouc		Czechia	779 00
75	CCBR Ostrava s.r.o.	Ostrava		Czechia	70200
76	CCBR Clinical Research, Pardubice	Pardubice		Czechia	53002
77	CCBR Czech Prague s.r.o.	Prague		Czechia	130 00
78	MEDICAL PLUS, s.r.o. - Revmatologicka ambulance	Uherske Hradiste		Czechia	686 01
79	Krajska zdravotni, a.s. - Masarykova nemocnice v Usti nad Labem, o.z.	Usti nad Labem		Czechia	40113
80	PV - MEDICAL, s.r.o.	Zlín		Czechia	760 01
81	Nemocnice Znojmo p.o - Interni oddeleni	Znojmo		Czechia	66902
82	Bajai Szent Rokus Korhaz	Baja		Hungary	6500
83	DRC Gyogyszervizsgalo Kozpont Kft	Balatonfüred		Hungary	8230
84	Clinexpert Kft.	Budapest		Hungary	1033
85	Dr Lakatos Ferenc Belgyogyaszati-Kardiologiai Maganrendelo	Békéscsaba		Hungary	5600
86	Vaszary Kolos Korhaz Esztergom - Reumatologiai osztaly	Esztergom		Hungary	2500
87	BKS Research Kft.	Hatvan		Hungary	3000
88	Kalocsai Szent Kereszt Korhaz	Kalocsa		Hungary	6300
89	Selye Janos Hospital - Rheumatology Department	Komárom		Hungary	2921
90	CRU Hungary Kft.	Miskolc		Hungary	3529
91	Clinfan Ltd SMO	Szekszárd		Hungary	7100
92	Allergo-Derm Bakos Kft.	Szolnok		Hungary	5000
93	Mentahaz Maganorvosi Kozpont (SMO)	Székesfehérvár		Hungary	8000
94	Medical Expert Kft.	Veszprem		Hungary	8200
95	Stacja Dializ Zyrardow	Zyrardow	Zyrardo	Poland	96-300
96	B_Serwis Popenda Sp. J.	Chorzów		Poland	41-500
97	Centrum Kliniczno Badawcze J. Brzezicki B. Gornikiewicz - Brzezicka Lekarze Sp. p.	Elbląg		Poland	82-300
98	MCBK s.c.	Grodzisk Mazowiecki		Poland	05-825
99	NZOZ Praktyka Lekarza Rodzinnego Elzbieta Kelm	Katowice		Poland	40-040
100	Centrum Medyczne Pratia Krakow	Kraków		Poland	30-002
101	Malopolskie Centrum Medyczne	Kraków		Poland	30-510
102	Centrum Medyczne Chodzki	Lublin		Poland	20-093
103	Alfa Specjalistyczne Gabinety Lekarskie Ewa Moroz	Nowy Sącz		Poland	33-300
104	Centrum Zdrowia Metabolicznego Pawel Bogdanski	Poznań		Poland	60-589
105	Centrum Badan Klinicznych s.c.	Poznań		Poland	60-773
106	Praktyka Lekarska Ewa Krzyzagorska	Poznań		Poland	61-655
107	Prywatny Gabinet Lekarski NZOZ Centrum Medyczne Aeskulap	Radom		Poland	26-610
108	Centrum Medyczne Pratia Warszawa	Warszawa		Poland	01-868
109	Centrum Medyczne K2J2	Wołomin		Poland	05-200
110	KO - MED Centra Kliniczne Sp. z o.o., Osrodek Badan Klinicznych w Zamosciu	Zamość		Poland	22-400
111	Samodzielny Publiczny ZOZ Uniwersytecki Szpital Kliniczny nr 1 im. Norberta Barlickiego Uniwersytetu Medycznego w Lodzi, Oddzial Kliniczny Nefrologii, Hipertensjologii i Transplantologii Nerek	Łódź		Poland	90-153
112	Centrum Terapii Wspolczesnej J. M. Jasnorzewska Spolka Komandytowo Akcyjna	Łódź		Poland	90-242
113	AppleTreeClinics Sp. z o.o.	Łódź		Poland	90-349
114	Centrum Medyczne AMED Oddzial w Lodzi	Łódź		Poland	91-363
115	NZOZ All - Med Centrum Medyczne Specjalistyczne Gabinety Lekarskie Marcin Ogorek	Łódź		Poland	94-048
116	Centrum Dializa Sp. z o.o. - Zyrardow	Żyrardów		Poland	96-300

Sponsors and Collaborators

• Ironwood Pharmaceuticals, Inc.
• Medpace, Inc.

Investigators

• Study Chair: Ironwood Study Chair, Ironwood Pharmaceuticals, Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 21, 2017

More Information

Publications

None provided.

• Responsible Party: Ironwood Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03226899
• Other Study ID Numbers: RDEA594-401
• First Posted: Jul 24, 2017
• Last Update Posted: Nov 4, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Gout; Kidney Diseases; Renal Insufficiency, Chronic; Colchicine; Allopurinol; Febuxostat; Lesinurad

Study Results

Participant Flow

Arm/Group Title	Placebo + XOI	Lesinurad + XOI
Arm/Group Description	Placebo oral tablet once daily (QD) plus a stable, medically appropriate dose of an xanthine oxidase inhibitor (XOI)	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
Period Title: Overall Study
STARTED	118	124
COMPLETED	0	0
NOT COMPLETED	118	124

Baseline Characteristics

Arm/Group Title	Placebo + XOI	Lesinurad + XOI	Total
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI	Total of all reporting groups
Overall Participants	118	124	242
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.3 (8.00)	66.4 (10.10)	66.8 (9.12)
Sex: Female, Male (Count of Participants)
Female	22 18.6%	28 22.6%	50 20.7%
Male	96 81.4%	96 77.4%	192 79.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	26 22%	20 16.1%	46 19%
Not Hispanic or Latino	92 78%	104 83.9%	196 81%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 0.8%	2 1.6%	3 1.2%
Native Hawaiian or Other Pacific Islander	2 1.7%	1 0.8%	3 1.2%
Black or African American	14 11.9%	24 19.4%	38 15.7%
White	99 83.9%	95 76.6%	194 80.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	2 1.7%	2 1.6%	4 1.7%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat (mITT) Population: all randomized participants who received at least 1 dose of study drug. Participants with a value at Month 6.

Arm/Group Title	Placebo + XOI	Lesinurad + XOI
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
Measure Participants	80	80
Number [percentage of participants]	33.8 28.6%	58.8 47.4%

2. Secondary Outcome

Title	Percentage of Participants Who Achieve sUA < 6.0 mg/dL Over Time
Time Frame	Baseline, Months 1, 3, 6, 9, 12, 15, 18

Outcome Measure Data

Analysis Population Description

mITT Population: all randomized participants who received at least 1 dose of study drug. Participants with a value at baseline and given time point.

Arm/Group Title	Placebo + XOI	Lesinurad + XOI
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
Measure Participants	116	123
Baseline	10.3 8.7%	10.6 8.5%
Month 1	35.1 29.7%	58.8 47.4%
Month 3	36.4 30.8%	52.5 42.3%
Month 6	33.8 28.6%	58.8 47.4%
Month 9	34.0 28.8%	42.9 34.6%
Month 12	42.9 36.4%	56.5 45.6%
Month 15	45.5 38.6%	62.5 50.4%
Month 18	0.0 0%

3. Secondary Outcome

Title	Change From Baseline in sUA Over Time, Including the Last Value On and Off Treatment
Time Frame	Baseline, Months 1, 3, 6, 9, 12, 15, 18

Outcome Measure Data

Analysis Population Description

Safety Population: all randomized participants who received at least 1 dose of lesinurad or placebo. Participants with a value at baseline and given time point.

Arm/Group Title	Placebo + XOI	Lesinurad + XOI
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
Measure Participants	116	123
Change at Month 1	-57.0 (96.2)	-120.3 (105.3)
Change at Month 3	-59.8 (98.6)	-106.8 (116.2)
Change at Month 6	-54.6 (103.1)	-125.8 (140.0)
Change at Month 9	-70.6 (128.4)	-95.9 (106.5)
Change at Month 12	-78.7 (122.4)	-69.6 (110.4)
Change at Month 15	-92.6 (91.4)	-116.6 (76.3)
Change at Month 18	0.00 (NA)
Change at Last On-Treatment Visit	-57.0 (104.7)	-125.5 (121.4)
Change at Last Off-Treatment Visit	-70.7 (105.4)	-156.6 (149.2)

4. Secondary Outcome

Title	Percent Change From Baseline in sUA Over Time, Including the Last Value On and Off Treatment
Time Frame	Baseline, Months 1, 3, 6, 9, 12, 15, 18

Outcome Measure Data

Analysis Population Description

Safety Population: all randomized participants who received at least 1 dose of lesinurad or placebo. Participants with a value at baseline and given time point.

Arm/Group Title	Placebo + XOI	Lesinurad + XOI
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
Measure Participants	116	123
Change at Month 1	-11.3 (18.8)	-24.0 (19.3)
Change at Month 3	-11.4 (18.8)	-21.2 (21.7)
Change at Month 6	-10.0 (21.7)	-23.9 (24.4)
Change at Month 9	-12.6 (27.3)	-18.6 (20.2)
Change at Month 12	-15.2 (22.8)	-14.7 (26.7)
Change at Month 15	-18.9 (17.5)	-26.1 (16.3)
Change at Month 18	0.00 (NA)
Change at Last On-Treatment Visit	-10.6 (22.1)	-24.8 (22.8)
Change at Last Off-Treatment Visit	-16.1 (25.8)	-27.3 (22.6)

5. Secondary Outcome

Title	Change From Baseline in Estimated Creatinine Clearance (eCrCl) at Month 24
Description	The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight.
Time Frame	Baseline, 24 months

Outcome Measure Data

Analysis Population Description

Due to early study termination, no participant reached Month 24. Therefore these data are not available.

Arm/Group Title	Placebo + XOI	Lesinurad + XOI
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
Measure Participants	0	0

6. Secondary Outcome

Title	Percent Change From Baseline in eCrCl at Month 24
Description	The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight.
Time Frame	Baseline, 24 months

Outcome Measure Data

Analysis Population Description

Due to early study termination, no participant reached Month 24. Therefore these data are not available.

Arm/Group Title	Placebo + XOI	Lesinurad + XOI
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
Measure Participants	0	0

7. Secondary Outcome

Title	Change From Baseline in eCrCl Over the Study Period, Including the Last Value On and Off Treatment
Description	The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight.
Time Frame	Baseline, Months 1, 3, 6, 9, 12, 15, 18

Outcome Measure Data

Analysis Population Description

Safety Population: all randomized participants who received at least 1 dose of lesinurad or placebo. Participants with a value at baseline and given time point.

Arm/Group Title	Placebo + XOI	Lesinurad + XOI
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
Measure Participants	116	123
Change at Month 1	0.13 (9.67)	-1.29 (6.45)
Change at Month 3	-0.69 (7.41)	-1.53 (8.65)
Change at Month 6	-1.84 (7.58)	-1.80 (7.02)
Change at Month 9	-0.78 (6.85)	-2.10 (7.97)
Change at Month 12	-2.14 (7.03)	-4.30 (6.34)
Change at Month 15	0.36 (6.07)	-6.00 (8.49)
Change at Month 18	-19.0 (NA)
Change at Last On-Treatment Visit	-1.03 (6.97)	-1.91 (8.19)
Change at Last Off-Treatment Visit	2.33 (5.61)	-2.45 (5.41)

8. Secondary Outcome

Title	Percent Change From Baseline in eCrCl Over the Study Period, Including the Last Value On and Off Treatment
Description	The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight.
Time Frame	Baseline, Months 1, 3, 6, 9, 12, 15, 18

Outcome Measure Data

Analysis Population Description

Safety Population: all randomized participants who received at least 1 dose of lesinurad or placebo. Participants with a value at baseline and given time point.

Arm/Group Title	Placebo + XOI	Lesinurad + XOI
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
Measure Participants	116	123
Change at Month 1	1.16 (19.90)	-2.07 (15.30)
Change at Month 3	-0.18 (17.70)	-2.14 (20.12)
Change at Month 6	-2.49 (17.96)	-3.01 (15.32)
Change at Month 9	-0.26 (18.67)	-3.42 (17.05)
Change at Month 12	-3.38 (15.71)	-8.1 (12.9)
Change at Month 15	3.67 (18.6)	-11.0 (16.5)
Change at Month 18	-31.7 (NA)
Change at Last On-Treatment Visit	-1.13 (16.86)	-3.04 (18.21)
Change at Last Off-Treatment Visit	4.14 (13.67)	-5.35 (13.52)

9. Secondary Outcome

Title	Percentage of Participants With Serum Creatinine (sCr) Elevations (≥1.5 × Baseline) Over the Study Period
Time Frame	up to 18 months

Outcome Measure Data

Analysis Population Description

Safety Population: all randomized participants who received at least 1 dose of lesinurad or placebo.

Arm/Group Title	Placebo + XOI	Lesinurad + XOI
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
Measure Participants	116	123
Number [percentage of participants]	5.2 4.4%	7.3 5.9%

10. Secondary Outcome

Title	Percentage of Participants Meeting Criteria (eg, Based on sCr or eCrCl Criteria) for Treatment Discontinuations Over the Study Period
Description	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).
Time Frame	up to 18 months

Outcome Measure Data

Analysis Population Description

Safety Population: all randomized participants who received at least 1 dose of lesinurad or placebo.

Arm/Group Title	Placebo + XOI	Lesinurad + XOI
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
Measure Participants	116	123
Number [percentage of participants]	0.0 0%	0.0 0%

11. Secondary Outcome

Title	Percentage of Participants Renal-Related and Kidney Stone Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	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.
Time Frame	From first dose of study drug through each participant's study duration, up to approximately 18 months.

Outcome Measure Data

Analysis Population Description

All Randomized Participants

Arm/Group Title	Placebo + XOI	Lesinurad + XOI
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
Measure Participants	118	124
Treatment-Emergent SAEs	0.0 0%	0.8 0.6%
Treatment-Emergent AEs	4.2 3.6%	5.6 4.5%

12. Secondary Outcome

Title	Percentage of Participants With Contributing Factors to Renal SAEs as Adjudicated by the Renal Event Adjudication Committee (REAC)
Time Frame	From first dose of study drug through each participant's study duration, up to approximately 18 months.

Outcome Measure Data

Analysis Population Description

This was not analyzed; no events were adjudicated since the study was terminated early.

Arm/Group Title	Placebo + XOI	Lesinurad + XOI
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
Measure Participants	0	0

13. Secondary Outcome

Title	Percentage of Participants With Cardiac Event Adjudication Committee (CEAC)-Adjudicated Major Adverse Cardiovascular Events (MACEs)
Description	MACEs are defined as Cardiovascular Death, Nonfatal Myocardial Infarction, and Nonfatal Stroke.
Time Frame	From first dose of study drug through each participant's study duration, up to approximately 18 months.

Outcome Measure Data

Analysis Population Description

This was not analyzed; no events were adjudicated since the study was terminated early.

Arm/Group Title	Placebo + XOI	Lesinurad + XOI
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
Measure Participants	0	0

14. Secondary Outcome

Title	Incidence of CEAC-Adjudicated MACEs or Hospitalization for Unstable Angina (MACE+)
Description	MACEs are defined as Cardiovascular Death, Nonfatal Myocardial Infarction, and Nonfatal Stroke.
Time Frame	From first dose of study drug through each participant's study duration, up to approximately 18 months.

Outcome Measure Data

Analysis Population Description

This was not analyzed; no events were adjudicated since the study was terminated early.

Arm/Group Title	Placebo + XOI	Lesinurad + XOI
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI	lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
Measure Participants	0	0

Adverse Events

Time Frame	From first dose of study drug through each participant's study duration, up to approximately 18 months.
Arm/Group Title	Placebo + XOI		Lesinurad + XOI
Arm/Group Description	placebo oral tablet QD plus a stable, medically appropriate dose of an XOI		lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
All Cause Mortality
	Placebo + XOI		Lesinurad + XOI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/118 (0%)		0/124 (0%)
Serious Adverse Events
	Placebo + XOI		Lesinurad + XOI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/118 (5.9%)		13/124 (10.5%)
Blood and lymphatic system disorders
Haemorrhagic anaemia	0/118 (0%)		1/124 (0.8%)
Cardiac disorders
Arteriosclerosis coronary artery	0/118 (0%)		1/124 (0.8%)
Atrial fibrillation	1/118 (0.8%)		0/124 (0%)
Cardiac failure congestive	0/118 (0%)		1/124 (0.8%)
Coronary artery disease	0/118 (0%)		1/124 (0.8%)
Coronary artery occlusion	1/118 (0.8%)		0/124 (0%)
Myocarditis	0/118 (0%)		1/124 (0.8%)
Tricuspid valve incompetence	1/118 (0.8%)		0/124 (0%)
Gastrointestinal disorders
Diverticulum	1/118 (0.8%)		0/124 (0%)
General disorders
Non-cardiac chest pain	0/118 (0%)		2/124 (1.6%)
Asthenia	0/118 (0%)		1/124 (0.8%)
Vascular stent occlusion	1/118 (0.8%)		0/124 (0%)
Hepatobiliary disorders
Bile duct stone	0/118 (0%)		1/124 (0.8%)
Cholecystitis	1/118 (0.8%)		0/124 (0%)
Cholecystitis acute	0/118 (0%)		1/124 (0.8%)
Investigations
Blood creatine phosphokinase increased	0/118 (0%)		1/124 (0.8%)
Weight decreased	0/118 (0%)		1/124 (0.8%)
Metabolism and nutrition disorders
Dehydration	1/118 (0.8%)		0/124 (0%)
Hyponatraemia	0/118 (0%)		1/124 (0.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colon cancer recurrent	0/118 (0%)		1/124 (0.8%)
Nervous system disorders
Syncope	0/118 (0%)		1/124 (0.8%)
Renal and urinary disorders
Acute kidney injury	0/118 (0%)		1/124 (0.8%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/118 (0.8%)		0/124 (0%)
Chronic obstructive pulmonary disease	1/118 (0.8%)		0/124 (0%)
Dyspnoea	0/118 (0%)		1/124 (0.8%)
Emphysema	0/118 (0%)		1/124 (0.8%)
Epistaxis	0/118 (0%)		1/124 (0.8%)
Pulmonary hypertension	0/118 (0%)		1/124 (0.8%)
Other (Not Including Serious) Adverse Events
	Placebo + XOI		Lesinurad + XOI
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/118 (7.6%)		18/124 (14.5%)
Infections and infestations
Viral upper respiratory tract infection	4/118 (3.4%)		5/124 (4%)
Upper respiratory tract infection	0/118 (0%)		4/124 (3.2%)
Metabolism and nutrition disorders
Vitamin D deficiency	0/118 (0%)		3/124 (2.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/118 (0.8%)		3/124 (2.4%)
Vascular disorders
Hypertension	4/118 (3.4%)		3/124 (2.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI may publish or disclose the results of the study 24 months after final data lock provided that sponsor can review the publication prior to public release, sponsor can request removal of confidential information of sponsor (not including results of trial), and sponsor can request a publication delay in order to protect potentially patentable information. Furthermore, if a publication committee is developing an initial publication, PI is to delay disclosure until that publication is published.