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

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

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.

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.

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.