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.

Study Overview

• Status: Completed
• Conditions: Kidney Stones; Hyperuricosuria
• Intervention / Treatment: Drug: Placebo; Drug: Febuxostat; Drug: Allopurinol

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 99
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States
  • Alaska
    • Anchorage, Alaska, United States
  • Arizona
    • Tucson, Arizona, United States
  • California
    • Costa Mesa, California, United States
    • Orange, California, United States
    • Palmdale, California, United States
    • Poway, California, United States
    • Rancho Cucamonga, California, United States
    • San Diego, California, United States
    • Santa Ana, California, United States
  • Colorado
    • Denver, Colorado, United States
  • Connecticut
    • New Britain, Connecticut, United States
  • Florida
    • Miami, Florida, United States
  • Georgia
    • Augusta, Georgia, United States
  • Hawaii
    • Honolulu, Hawaii, United States
  • Idaho
    • Boise, Idaho, United States
    • Meridian, Idaho, United States
  • Kentucky
    • Lexington, Kentucky, United States
  • Michigan
    • Kalamazoo, Michigan, United States
  • Mississippi
    • Jackson, Mississippi, United States
  • New Mexico
    • Albuquerque, New Mexico, United States
  • New York
    • New Windsor, New York, United States
  • North Carolina
    • Shelby, North Carolina, United States
    • Wilmington, North Carolina, United States
  • Rhode Island
    • East Providence, Rhode Island, United States
  • Texas
    • Dallas, Texas, United States
    • Houston, Texas, United States
    • Sugar Land, Texas, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Febuxostat; Febuxostat 80 mg, capsules, orally, once daily for up to 6 months.	Drug: Febuxostat; Febuxostat capsules; Other Names: Uloric; TMX-67
Active Comparator: Allopurinol; Allopurinol 200mg or 300mg (determined by kidney function), capsules, orally, once daily for up to 6 months.	Drug: Allopurinol; Allopurinol capsules; Other Names: Zyloprim
Placebo Comparator: Placebo; Placebo-matching capsules, orally, once daily for up to 6 months.	Drug: Placebo; Placebo-matching capsules

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Takeda

Publications and helpful links

General Publications

• Goldfarb DS, MacDonald PA, Gunawardhana L, Chefo S, McLean L. Randomized controlled trial of febuxostat versus allopurinol or placebo in individuals with higher urinary uric acid excretion and calcium stones. Clin J Am Soc Nephrol. 2013 Nov;8(11):1960-7. doi: 10.2215/CJN.01760213. Epub 2013 Aug 8.

Helpful Links

• Uloric Package Insert

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (Actual): November 1, 2011
• Study Completion (Actual): November 1, 2011

Study Registration Dates

• First Submitted: February 25, 2010
• First Submitted That Met QC Criteria: February 26, 2010
• First Posted (Estimate): March 1, 2010

Study Record Updates

• Last Update Posted (Estimate): February 15, 2013
• Last Update Submitted That Met QC Criteria: January 14, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: Drug Therapy; Uric Acid; Nephrolithiasis; Kidney Stones; Kidney Calculi
• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Pathological Conditions, Anatomical; Urolithiasis; Urinary Calculi; Calculi; Kidney Calculi; Nephrolithiasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Antioxidants; Free Radical Scavengers; Gout Suppressants; Allopurinol; Febuxostat
• Other Study ID Numbers: TMX-67_201; U1111-1113-6322 (Registry Identifier: WHO)