Febuxostat Versus Allopurinol or Placebo in Patients With Hyperuricosuria and Calcium Oxalate Stones

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy of febuxostat, once daily (QD), compared to allopurinol or placebo in patients with excessive amounts of uric acid in their urine and who have recently had kidney stones.

Detailed Description
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Nephrolithiasis, also called kidney stone disease, occurs in patients with genetic susceptibility and who may have a broad spectrum of metabolic disorders and other comorbid conditions (for example obesity or diabetes). These renal stones develop as a result of supersaturation. Calcium oxalate (CaOx) is the most common type of stone. Reducing the urinary excretion of uric acid is an established approach for the treatment of CaOx kidney stones. The objective of this study is to evaluate treatment with febuxostat compared to allopurinol or placebo in the reduction of 24-hour urine uric acid (uUA) excretion levels in hyperuricosuric patients with a recent history of renal stones and the presence of at least one CaOx stone larger than or equal to 3 mm as seen on Multidetector Computed Tomographic Angiography (MDCT). Participants in this study will be required to make 4 office visits provide 3 urine samples and undergo 2 MDCT scans (a type of x-ray) of their kidneys.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo and Allopurinol Controlled, Phase 2 Study to Evaluate Febuxostat in the Medical Management of Subjects With Hyperuricosuria and Calcium Oxalate Stones

Conditions
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Hyperuricosuria, Kidney Stones

Intervention / Treatment
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* Drug: Febuxostat
* Drug: Allopurinol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has hyperuricosuria, defined as a daily urine uric acid excretion greater than 700 mg as measured by 24-hour urine collection prior to randomization. Has at least one calcium oxalate stone greater than or equal to 3 mm in its longest in-plane diameter, identified by Multiple Detector Computated Tomography prior to randomization. Has a recent (within the previous 5 years) history of renal stones prior to screening. Exclusion Criteria: Has gout, secondary hyperuricemia or has experienced a gout flare. Has a history of xanthinuria. Has received allopurinol or probenecid within 2 years prior to randomization. Has received febuxostat. Has alanine aminotransferase and/or aspartate aminotransferase values greater than 2.0 times the upper limit of normal at the Screening Visit. Has an abnormal serum calcium level at the Screening Visit. Has a significant medical condition and/or conditions that would interfere with the treatment, safety or compliance with the protocol according to the judgment of the Investigator. Has a history of drug abuse or a history of alcohol abuse within 5 years prior to the Screening Visit. Participant's measured creatinine clearance is less than 30 mL/min at the Screening Visit. Has hypercalciuria at Screening, while on a regular unrestricted diet, defined as urinary excretion of: greater than 250 mg of calcium/24-hour for females of body weight less than 62.5 kg; OR greater than 300 mg calcium/24-hour for males of body weight less than 75 kg; OR greater than 4 mg calcium/kg/24-hour for males of body weight greater than or equal 75 kg and females of body weight greater than or equal 62.5 kg. EXCLUDED MEDICATIONS: Febuxostat, allopurinol, probenecid. Salicylates (chronic use of aspirin ≤325 mg/day is allowed). Azathioprine. Mercaptopurine. Theophylline. Colchicine. Pyrazinamide. Sulfamethoxazole/trimethoprim. Losartan. The following restrictions also apply during the study: Long-term use (more than 4 continuous weeks) of prescription or over-the-counter nonsterioidal anti-inflammatory drugs or cyclooxygenase-2 inhibitors. If receiving diuretics, participant must have been on a stable dose for at least 30 days prior to screening. No changes in dosage are allowed during the study.

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 |
| --- | --- |
| Experimental: Febuxostat<br>Febuxostat 80 mg, capsules, orally, once daily for up to 6 months. | Drug: Febuxostat<br>* Febuxostat capsules<br>* Other names: TMX-67;|
| Active Comparator: Allopurinol<br>Allopurinol 200mg or 300mg (determined by kidney function), capsules, orally, once daily for up to 6 months. | Drug: Allopurinol<br>* Allopurinol capsules<br>* Other names: Zyloprim;|
| Placebo Comparator: Placebo<br>Placebo-matching capsules, orally, once daily for up to 6 months. | Drug: Placebo<br>* Placebo-matching capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Month 6 in 24-hour Urine Uric Acid (uUA) Excretion | The change from Baseline to Month 6 in 24-hour urine uric acid is expressed as a percentage of the Baseline uUA value. | Baseline and Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Month 6 in the In-plane Diameter of the Largest Calcium Oxalate (CaOx) Stone | Multidetector Computed Tomography (MDCT) was used to visualize and measure calcium oxalate kidney stones at Baseline and after 6 months of treatment. All MDCT images were analyzed independently by a Central Reader. The change from Baseline to month 6 is expressed as a percentage of the Baseline largest in-plane diameter. | Baseline and Month 6 | 
| Change From Baseline to Month 6 in the Number of Calcium Oxalate Stones | Multidetector Computed Tomography (MDCT) was used to visualize and count calcium oxalate kidney stones at Baseline and after 6 months of treatment. All MDCT images were analyzed independently by a Central Reader. | Baseline and Month 6 | 
| Change From Baseline to Month 6 in 24-hour Measured Creatinine Clearance | Creatinine clearance is a measure of how well the kidneys are filtering creatinine, a waste product produced by the muscles. Measured creatinine clearance was calculated according to the following: Urine 24 hour Creatinine/Serum Creatinine x (total Urine volume/elapsed time) x (1.73/body surface area). | Baseline and Month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney Calculi, Kidney Stones, Nephrolithiasis, Drug Therapy, Uric Acid