Hyperuricosuria, Kidney Stones
Conditions
Keywords
Kidney Calculi, Kidney Stones, Nephrolithiasis, Drug Therapy, Uric Acid
Brief summary
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
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.
Interventions
DRUGFebuxostat
Febuxostat capsules
DRUGAllopurinol
Allopurinol capsules
DRUGPlacebo
Placebo-matching capsules
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Month 6 in 24-hour Urine Uric Acid (uUA) Excretion | Baseline and Month 6 | The change from Baseline to Month 6 in 24-hour urine uric acid is expressed as a percentage of the Baseline uUA value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Month 6 in the In-plane Diameter of the Largest Calcium Oxalate (CaOx) Stone | Baseline and Month 6 | 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. |
| Change From Baseline to Month 6 in the Number of Calcium Oxalate Stones | Baseline and Month 6 | 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. |
| Change From Baseline to Month 6 in 24-hour Measured Creatinine Clearance | Baseline and Month 6 | 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). |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 24 investigative sites in the United States from 12 February 2010 to 21 November 2011.
Pre-assignment details
Participants with hyperuricosuria and calcium oxalate stones were randomized to 1 of 3 treatment groups in a 1:1:1 ratio to receive placebo, allopurinol or febuxostat.
Participants by arm
| Arm | Count |
|---|---|
| Febuxostat Febuxostat 80 mg, capsules, orally, once daily for up to 6 months. | 33 |
| Allopurinol Allopurinol 200mg or 300mg (determined by kidney function), capsules, orally, once daily for up to 6 months. | 33 |
| Placebo Placebo-matching capsules, orally, once daily for up to 6 months. | 33 |
| Total | 99 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 2 | 0 |
| Overall Study | Other | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 3 | 1 |
Baseline characteristics
| Characteristic | Total | Febuxostat | Allopurinol | Placebo |
|---|---|---|---|---|
| 24-hour urinary calcium | 272.2 mg/24 hours STANDARD_DEVIATION 90 | 240.1 mg/24 hours STANDARD_DEVIATION 84.08 | 297.9 mg/24 hours STANDARD_DEVIATION 77.6 | 278.7 mg/24 hours STANDARD_DEVIATION 99.62 |
| 24-hour urine uric acid | 952.7 mg/24 hours STANDARD_DEVIATION 210.44 | 1000.6 mg/24 hours STANDARD_DEVIATION 223.99 | 948.1 mg/24 hours STANDARD_DEVIATION 231.16 | 909.4 mg/24 hours STANDARD_DEVIATION 166.43 |
| 24-hour urine uric acid categories ≤820 mg/24 hours (T1) | 33 participants | 9 participants | 13 participants | 11 participants |
| 24-hour urine uric acid categories >820 to ≤987 mg/24 hours | 32 participants | 9 participants | 9 participants | 14 participants |
| 24-hour urine uric acid categories >987 mg/24 hours (T2) | 34 participants | 15 participants | 11 participants | 8 participants |
| Age Continuous | 47.4 years STANDARD_DEVIATION 10.39 | 49.1 years STANDARD_DEVIATION 9.69 | 46.5 years STANDARD_DEVIATION 9.95 | 46.5 years STANDARD_DEVIATION 11.54 |
| Baseline in-plane Diameter of the largest Calcium Oxalate Stone | 9.91 mm STANDARD_DEVIATION 5.59 | 12.24 mm STANDARD_DEVIATION 7.363 | 9.34 mm STANDARD_DEVIATION 4.311 | 8.22 mm STANDARD_DEVIATION 3.756 |
| Baseline Serum Urate | 6.3 mg/dL STANDARD_DEVIATION 1.45 | 6.2 mg/dL STANDARD_DEVIATION 1.63 | 6.3 mg/dL STANDARD_DEVIATION 1.49 | 6.3 mg/dL STANDARD_DEVIATION 1.24 |
| Baseline Serum Urate categories ≥10 mg/dL | 2 participants | 0 participants | 2 participants | 0 participants |
| Baseline Serum Urate categories <9.0 mg/dL | 94 participants | 31 participants | 31 participants | 32 participants |
| Baseline Serum Urate categories 9.0 to <10 mg/dL | 3 participants | 2 participants | 0 participants | 1 participants |
| Body mass index (BMI) | 32.8 kg/m^2 STANDARD_DEVIATION 5.89 | 32.9 kg/m^2 STANDARD_DEVIATION 5.71 | 32.3 kg/m^2 STANDARD_DEVIATION 5.82 | 33.1 kg/m^2 STANDARD_DEVIATION 6.29 |
| Body mass index categories 18.5 to <25 kg/m^2 | 5 participants | 2 participants | 1 participants | 2 participants |
| Body mass index categories 25 to <30 kg/m^2 | 29 participants | 8 participants | 14 participants | 7 participants |
| Body mass index categories ≥30 kg/m^2 | 65 participants | 23 participants | 18 participants | 24 participants |
| Composition of most recent passed stone Calcium citrate | 1 participants | 0 participants | 0 participants | 1 participants |
| Composition of most recent passed stone Calcium Oxalate | 35 participants | 8 participants | 14 participants | 13 participants |
| Composition of most recent passed stone Unknown | 52 participants | 18 participants | 19 participants | 15 participants |
| Composition of most recent passed stone Uric acid | 1 participants | 1 participants | 0 participants | 0 participants |
| Height | 174.5 cm STANDARD_DEVIATION 10.14 | 172.6 cm STANDARD_DEVIATION 12.67 | 176.5 cm STANDARD_DEVIATION 7.71 | 174.3 cm STANDARD_DEVIATION 9.31 |
| Kidney stone passage No | 10 participants | 6 participants | 0 participants | 4 participants |
| Kidney stone passage Yes | 89 participants | 27 participants | 33 participants | 29 participants |
| Kidney stone procedures Nephrolithotomy/Nephrolithotripsy | 5 participants | 3 participants | 2 participants | 0 participants |
| Kidney stone procedures None | 44 participants | 13 participants | 13 participants | 18 participants |
| Kidney stone procedures Open surgery | 6 participants | 2 participants | 2 participants | 2 participants |
| Kidney stone procedures Other procedure | 8 participants | 2 participants | 4 participants | 2 participants |
| Kidney stone procedures Shock Wave Lithotripsy | 51 participants | 17 participants | 20 participants | 14 participants |
| Kidney stone procedures Stone Procedure | 55 participants | 20 participants | 20 participants | 15 participants |
| Kidney stone procedures Ureteroscopy | 24 participants | 9 participants | 6 participants | 9 participants |
| Lifetime kidney stone episodes | 10.9 kidney stone episodes STANDARD_DEVIATION 15.38 | 8.8 kidney stone episodes STANDARD_DEVIATION 10.18 | 12.5 kidney stone episodes STANDARD_DEVIATION 19.72 | 11.3 kidney stone episodes STANDARD_DEVIATION 14.97 |
| Race/Ethnicity, Customized Asian | 4 participants | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 5 participants | 3 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 19 participants | 8 participants | 8 participants | 3 participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 2 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Non-Hispanic and Latino | 80 participants | 25 participants | 25 participants | 30 participants |
| Race/Ethnicity, Customized Other | 2 participants | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized White | 86 participants | 26 participants | 31 participants | 29 participants |
| Region of Enrollment United States | 99 participants | 33 participants | 33 participants | 33 participants |
| Renal history Mildly impaired | 3 participants | 2 participants | 0 participants | 1 participants |
| Renal history Moderately impaired | 0 participants | 0 participants | 0 participants | 0 participants |
| Renal history Normal | 96 participants | 31 participants | 33 participants | 32 participants |
| Sex: Female, Male Female | 14 Participants | 6 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 85 Participants | 27 Participants | 31 Participants | 27 Participants |
| Use of kidney stone drug Allopurinol | 3 participants | 2 participants | 1 participants | 0 participants |
| Use of kidney stone drug None | 88 participants | 28 participants | 30 participants | 30 participants |
| Use of kidney stone drug Other drug therapy | 8 participants | 3 participants | 2 participants | 3 participants |
| Weight | 99.9 kg STANDARD_DEVIATION 19.38 | 98.0 kg STANDARD_DEVIATION 18.17 | 100.9 kg STANDARD_DEVIATION 20.13 | 100.8 kg STANDARD_DEVIATION 20.23 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 33 | 13 / 33 | 12 / 33 |
| serious Total, serious adverse events | 0 / 33 | 0 / 33 | 1 / 33 |
Outcome results
Primary
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.
Time frame: Baseline and Month 6
Population: The full analysis set (patients who took at least 1 dose of double-blind study drug and had a baseline 24-hour uUA \>700 mg and at least 1 kidney CaOx stone ≥3 mm in its longest inplane diameter). Missing Month 6 values were imputed with baseline values if patient discontinued due to an AE; or otherwise with the last available post-baseline value.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Febuxostat | Percent Change From Baseline to Month 6 in 24-hour Urine Uric Acid (uUA) Excretion | -58.6 percent change | Standard Deviation 28.56 |
| Allopurinol | Percent Change From Baseline to Month 6 in 24-hour Urine Uric Acid (uUA) Excretion | -36.4 percent change | Standard Deviation 36.97 |
| Placebo | Percent Change From Baseline to Month 6 in 24-hour Urine Uric Acid (uUA) Excretion | -12.7 percent change | Standard Deviation 28.81 |
p-value: <0.001Wilcoxon (Mann-Whitney)
p-value: 0.003Wilcoxon (Mann-Whitney)
Secondary
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).
Time frame: Baseline and Month 6
Population: Full analysis set. Missing Month 6 Visit 24-hour mCLcr values are imputed by Month 3 values if the Month 3 value was available otherwise the patient was excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Febuxostat | Change From Baseline to Month 6 in 24-hour Measured Creatinine Clearance | Baseline (n=33, 33, 33) | 146.9 mL/min/1.73m² | Standard Deviation 57.88 |
| Febuxostat | Change From Baseline to Month 6 in 24-hour Measured Creatinine Clearance | Change from Baseline (n=30, 29, 30) | -9.0 mL/min/1.73m² | Standard Deviation 60.82 |
| Allopurinol | Change From Baseline to Month 6 in 24-hour Measured Creatinine Clearance | Baseline (n=33, 33, 33) | 146.0 mL/min/1.73m² | Standard Deviation 44.32 |
| Allopurinol | Change From Baseline to Month 6 in 24-hour Measured Creatinine Clearance | Change from Baseline (n=30, 29, 30) | -7.7 mL/min/1.73m² | Standard Deviation 83.28 |
| Placebo | Change From Baseline to Month 6 in 24-hour Measured Creatinine Clearance | Change from Baseline (n=30, 29, 30) | -19.0 mL/min/1.73m² | Standard Deviation 45.72 |
| Placebo | Change From Baseline to Month 6 in 24-hour Measured Creatinine Clearance | Baseline (n=33, 33, 33) | 147.1 mL/min/1.73m² | Standard Deviation 53.46 |
p-value: 0.5535ANOVA
p-value: 0.94ANOVA
Secondary
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.
Time frame: Baseline and Month 6
Population: Full analysis set for whom both Baseline and Month 6 MDCT data were available. Measurements more than 1 day after a patient's last dose of study drug were not included.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Febuxostat | Change From Baseline to Month 6 in the Number of Calcium Oxalate Stones | Baseline (n=28, 24, 30) | 4.84 stones | Standard Deviation 3.921 |
| Febuxostat | Change From Baseline to Month 6 in the Number of Calcium Oxalate Stones | Change from Baseline (n=26, 23, 26) | -0.06 stones | Standard Deviation 1.602 |
| Allopurinol | Change From Baseline to Month 6 in the Number of Calcium Oxalate Stones | Baseline (n=28, 24, 30) | 6.60 stones | Standard Deviation 6.832 |
| Allopurinol | Change From Baseline to Month 6 in the Number of Calcium Oxalate Stones | Change from Baseline (n=26, 23, 26) | 0.28 stones | Standard Deviation 1.953 |
| Placebo | Change From Baseline to Month 6 in the Number of Calcium Oxalate Stones | Baseline (n=28, 24, 30) | 5.57 stones | Standard Deviation 5.785 |
| Placebo | Change From Baseline to Month 6 in the Number of Calcium Oxalate Stones | Change from Baseline (n=26, 23, 26) | 0.10 stones | Standard Deviation 1.817 |
p-value: 0.403Wilcoxon (Mann-Whitney)
p-value: 0.413Wilcoxon (Mann-Whitney)
Secondary
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.
Time frame: Baseline and Month 6
Population: Full analysis set, for whom Baseline and Month 6 MDCT data were available. Measurements more than 1-day after a patient's last dose of study drug were not included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Febuxostat | Percent Change From Baseline to Month 6 in the In-plane Diameter of the Largest Calcium Oxalate (CaOx) Stone | -6.50 percent change | Standard Deviation 28.357 |
| Allopurinol | Percent Change From Baseline to Month 6 in the In-plane Diameter of the Largest Calcium Oxalate (CaOx) Stone | 0.63 percent change | Standard Deviation 12.605 |
| Placebo | Percent Change From Baseline to Month 6 in the In-plane Diameter of the Largest Calcium Oxalate (CaOx) Stone | 3.20 percent change | Standard Deviation 23.697 |
p-value: 0.13Wilcoxon (Mann-Whitney)
p-value: 0.348Wilcoxon (Mann-Whitney)