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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Gout, Chronic Kidney Disease (CKD)

Intervention / Treatment
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* Drug: Lesinurad
* Drug: XOI
* Drug: Placebo
* Drug: colchicine
* Drug: corticosteroids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is able to understand the study procedures, the risks involved, and willing to provide written informed consent before the first study related activity. Subject is willing to adhere to the protocol schedule. Subject is ≥ 18 years and ≤ 85 years of age. Subject has a diagnosis of gout. 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. 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. Subject has a serum uric acid level ≥ 6.0 mg/dL (357 µmol/L) at Screening Visits 1 and 2. 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). Subject has a body mass index < 45 kg/m^2. Exclusion Criteria: 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. Subject has uncontrolled hypertension (defined as systolic pressure above 160 or diastolic pressure above 95 mm Hg at either Screening Visits 1 or 2). Subject has severe hepatic impairment (defined as Child-Pugh Class C) or is known human immunodeficiency virus (HIV) positive. Subject is a solid organ transplant recipient. Subject has a urine protein of 3+ or higher by dipstick by the central laboratory at Screening Visit 2. Subject has a history of glomerulonephritis. Subject is taking valpromide, progabide, valproic acid, or other known inhibitors of epoxide hydrolase, or subject is taking ranolazine, cyclosporine, azathioprine or mercaptopurine. Subject is receiving chronic treatment with more than 325 mg of salicylates per day. Subject is unable to initiate gout flare prophylaxis with colchicine or low-dose oral corticosteroids at Baseline. 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. 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). 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. Subject has a gout flare during the Screening Period. Subject is pregnant or breastfeeding. 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). 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. 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. Subject has participated in a clinical trial within 8 weeks prior to Screening. 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. The maximum number of subjects in the eCrCl stratification subgroup has been reached.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, Double-Blind, Multicenter, Placebo-Controlled
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lesinurad + XOI<br>lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI | Drug: Lesinurad<br>* 200 mg oral tablet<br>* Other names: RDEA594;Drug: XOI<br>* 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.<br>* Other names: febuxostat;Drug: colchicine<br>* 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.<br>Drug: corticosteroids<br>* 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<br>|
| Placebo Comparator: Placebo + XOI<br>placebo tablet QD plus a stable, medically appropriate dose of an XOI | Drug: XOI<br>* 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.<br>* Other names: febuxostat;Drug: Placebo<br>* matching placebo oral tablet<br>Drug: colchicine<br>* 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.<br>Drug: corticosteroids<br>* 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<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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. |