Effect of Febuxostat on Renal Function in Patients With Gout and Moderate to Severe Renal Impairment

Study Overview
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Brief Summary
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The purpose of this study is to determine the effect of febuxostat, once daily (QD) or twice daily (BID), on renal function in gout patients with elevated serum urate levels and who have moderate to severe renal impairment.

Detailed Description
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Gout is caused by high levels of uric acid in the body, and is associated with a broad range of conditions including heart disease, chronic kidney disease and high blood pressure. Hyperuricemia, which is defined as an elevation in serum urate levels, develops into gout when urate crystals form in the body and settle in joints and other organs. Approximately 40-60% of patients with hyperuricemia and gout have some degree of renal impairment. Hyperuricemia has long been associated with renal disease, and chronic hyperuricemia as seen in gout can lead to deposition of urate crystals resulting in diminished renal function. This study will evaluate the effect of febuxostat on the renal function of patients with hyperuricemia and gout and moderate to severe renal impairment. All participants must have an average sitting blood pressure measurement less than 160 mmHg systolic and less than 95 mmHg diastolic. All participants must meet the American Rheumatism Association (ARA) diagnostic criteria for gout (subjects with tophi were excluded). Participants are expected to return to the site for approximately 10 visits.

Official Title
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A Multicenter, Randomized, Double-Blind, Phase 2 Study to Evaluate the Effect of Febuxostat Versus Placebo on Renal Function in Gout Subjects With Hyperuricemia and Moderate to Severe Renal Impairment

Conditions
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Renal Impairment

Intervention / Treatment
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* Drug: Febuxostat
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have a serum urate greater than 7 mg/dL and a serum creatinine greater than or equal to 1.5 mg at Day -21 Must have a history or presence of gout defined as having one or more of the American Rheumatism Association criteria for the diagnosis of gout (the criteria related to tophi have been excluded for the purpose of the study) Must have an estimated Glomerular Filtration Rate (eGFR) of 15 or greater, or less than or equal to 50 mL/min, AND a serum creatinine greater than 1.5 mg/dL at Screening Visit Day -21 Exclusion Criteria: Has secondary hyperuricemia (eg, due to myeloproliferative disorder, or organ transplant) Has tophaceous gout Has a history of xanthinuria Has received aspirin greater than 325 mg/day within 35 days prior to Day 1/Randomization Visit Has known hypersensitivity or allergy to allopurinol or any component in its formulation Has known hypersensitivity to febuxostat or colchicine or any components in their formulation Has myocardial infarction or stroke within the 90 days prior to the Screening Visit Has alanine aminotransferase and/or aspartate aminotransferase values greater than 2.0 times the upper limit of normal Has end stage renal disease or is likely to be a candidate for dialysis over the 1 year study period Has a serum creatinine less than or equal to 1.5 mg/dL, or an estimated Glomerular Filtration Rate at Day -21 Screening Visit less than 15 mL/min or greater than 50 mL/min as calculated by the central laboratory Is required to take excluded medications

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo-matching capsules, orally, twice daily for up to 12 months. | Drug: Placebo<br>* Febuxostat placebo-matching capsules<br>|
| Experimental: Febuxostat 30 mg BID<br>Febuxostat 30 mg, capsules, orally, twice daily (BID) for up to 12 months. | Drug: Febuxostat<br>* Febuxostat capsules<br>* Other names: TMX-67;|
| Experimental: Febuxostat 40/80 mg QD<br>Participants initially received febuxostat 40 mg, capsules, once daily (QD) and one placebo-matching capsule QD and remained on this dose for up to 12 months if their serum urate (sUA) was <6.0 mg/dL at the Day 14 visit. Participants whose sUA was ≥6.0 mg/dL at the Day 14 visit received febuxostat 80 mg, capsule, QD, and one placebo-matching capsule QD at the Month 1 visit, and for the remainder of the study. | Drug: Febuxostat<br>* Febuxostat capsules<br>* Other names: TMX-67;Drug: Placebo<br>* Febuxostat placebo-matching capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Month 12 in Serum Creatinine | Renal function was assessed by measuring the change from Baseline in serum creatinine. Analyses were conducted by the Central Laboratory. | Baseline and Month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Month 12 in Estimated Glomerular Filtration Rate (eGFR) | Change from baseline to Month 12 in estimated Glomerular Filtration Rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula (as calculated by the central laboratory). | Baseline and Month 12 | 
| Percentage of Participants With Serum Urate (sUA) Less Than 6 mg/dL at Month 12 | Serum urate concentrations were determined using the enzymatic method as performed by the Central Laboratory. | Month 12 | 
| Mean Clearance (CL/F) of Febuxostat at Steady State | Mean CL/F at steady state were estimated using a population pharmacokinetic (PK) approach, based on 2 PK samples collected prior to dosing, and 4 PK samples collected postdose. | The 2 pre-dose PK samples collected were collected at any 2 of the following visits: Months 3, 6, 9, and/or 12, at -0.25 to 0 hours. The 4 postdose PK samples were collected at Months 3, 6, and/or 9, at 0.25; 0.75 to 2.0; 2.5 to 4.0; and 5 to 12 hours. | 
| Mean Area Under the Concentration-Time Curve During the Dosing Interval (AUC[0-τ]) of Febuxostat at Steady State | Mean AUC during the dosing interval at steady state was estimated using a population pharmacokinetic (PK) approach, based on 2 PK samples collected prior to dosing, and 4 PK samples collected postdose. | The 2 pre-dose PK samples collected were collected at any 2 of the following visits: Months 3, 6, 9, and/or 12, at -0.25 to 0 hours. The 4 postdose PK samples were collected at Months 3, 6, and/or 9, at 0.25; 0.75 to 2.0; 2.5 to 4.0; and 5 to 12 hours. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gout, physiology, Hyperuricemia, Uric Acid, Drug Therapy