Randomized controlled trial of febuxostat versus allopurinol or placebo in individuals with higher urinary uric acid excretion and calcium stones.
OBJECTIVE
Higher urinary uric acid excretion is a suspected risk factor for calcium oxalate stone formation. Febuxostat, a xanthine oxidoreductase inhibitor, is effective in lowering serum urate concentration and urinary uric acid excretion in healthy volunteers and people with gout. This work studied whether febuxostat, compared with allopurinol and placebo, would reduce 24-hour urinary uric acid excretion and prevent stone growth or new stone formation.


METHODS
In this 6-month, double-blind, multicenter, randomized controlled trial, hyperuricosuric participants with a recent history of calcium stones and one or more radio-opaque calcium stone ≥ 3 mm (as seen by multidetector computed tomography) received daily febuxostat at 80 mg, allopurinol at 300 mg, or placebo. The primary end point was percent change from baseline to month 6 in 24-hour urinary uric acid. Secondary end points included percent change from baseline to month 6 in size of index stone and change from baseline in the mean number of stones and 24-hour creatinine clearance.


RESULTS
Of 99 enrolled participants, 86 participants completed the study. Febuxostat led to significantly greater reduction in 24-hour urinary uric acid (-58.6%) than either allopurinol (-36.4%; P=0.003) or placebo (-12.7%; P<0.001). Percent change from baseline in the size of the largest calcium stone was not different with febuxostat compared with allopurinol or placebo. There was no change in stone size, stone number, or renal function. No new safety concerns were noted for either drug.


CONCLUSIONS
Febuxostat (80 mg) lowered 24-hour urinary uric acid significantly more than allopurinol (300 mg) in stone formers with higher urinary uric acid excretion after 6 months of treatment. There was no change in stone size or number over the 6-month period.
Nephrology Section, New York Harbor VA Medical Center, and Division of Nephrology, New York University Langone Medical Center, New York, New York;, †Global Medical Affairs, Takeda Pharmaceuticals International, Deerfield, Illinois;, ‡Clinical Science, and §Statistics, Takeda Global Research & Development Center, Inc., Deerfield, Illinois, ‖Experimental Medicine, Takeda California, San Diego, California.
David S
DS
Goldfarb
Patricia A
PA
MacDonald
Lhanoo
L
Gunawardhana
Solomon
S
Chefo
Lachy
L
McLean
D000328:Adult; D000493:Allopurinol / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000652:urine; D002129:Calcium Oxalate / Q000378:metabolism*; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000069465:Febuxostat; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D061330:Multidetector Computed Tomography; D013844:Thiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D014527:Uric Acid / Q000652:urine*; D014545:Urinary Calculi / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000652:urine; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors* / Q000378:metabolism
D015415:Biomarkers; D004791:Enzyme Inhibitors; D013844:Thiazoles; D000069465:Febuxostat; D002129:Calcium Oxalate; D014527:Uric Acid; D000493:Allopurinol; D014969:Xanthine Oxidase