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

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ClinicalTrials.gov Identifier: NCT01077284
Recruitment Status : Completed
First Posted : March 1, 2010
Results First Posted : February 15, 2013
Last Update Posted : February 15, 2013
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions Hyperuricosuria
Kidney Stones
Interventions Drug: Febuxostat
Drug: Allopurinol
Drug: Placebo
Enrollment 99
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.
Arm/Group Title Febuxostat Allopurinol Placebo
Hide Arm/Group Description Febuxostat 80 mg, capsules, orally, once daily for up to 6 months. Allopurinol 200mg or 300mg (determined by kidney function), capsules, orally, once daily for up to 6 months. Placebo-matching capsules, orally, once daily for up to 6 months.
Period Title: Overall Study
Started 33 33 33
Completed 28 28 30
Not Completed 5 5 3
Reason Not Completed
Adverse Event             2             0             1
Lost to Follow-up             1             2             0
Withdrawal by Subject             2             3             1
Other             0             0             1
Arm/Group Title Febuxostat Allopurinol Placebo Total
Hide Arm/Group Description Febuxostat 80 mg, capsules, orally, once daily for up to 6 months. Allopurinol 200mg or 300mg (determined by kidney function), capsules, orally, once daily for up to 6 months. Placebo-matching capsules, orally, once daily for up to 6 months. Total of all reporting groups
Overall Number of Baseline Participants 33 33 33 99
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 33 participants 33 participants 33 participants 99 participants
49.1  (9.69) 46.5  (9.95) 46.5  (11.54) 47.4  (10.39)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 33 participants 33 participants 33 participants 99 participants
Female
6
  18.2%
2
   6.1%
6
  18.2%
14
  14.1%
Male
27
  81.8%
31
  93.9%
27
  81.8%
85
  85.9%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 33 participants 33 participants 33 participants 99 participants
Hispanic or Latino 8 8 3 19
Non-Hispanic and Latino 25 25 30 80
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 33 participants 33 participants 33 participants 99 participants
Asian 2 0 2 4
Black or African American 3 1 1 5
Native Hawaiian or other Pacific Islander 1 0 1 2
White 26 31 29 86
Other 1 1 0 2
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 33 participants 33 participants 33 participants 99 participants
33 33 33 99
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 33 participants 33 participants 33 participants 99 participants
172.6  (12.67) 176.5  (7.71) 174.3  (9.31) 174.5  (10.14)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 33 participants 33 participants 33 participants 99 participants
98.0  (18.17) 100.9  (20.13) 100.8  (20.23) 99.9  (19.38)
Body mass index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 33 participants 33 participants 33 participants 99 participants
32.9  (5.71) 32.3  (5.82) 33.1  (6.29) 32.8  (5.89)
Body mass index categories  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 33 participants 33 participants 33 participants 99 participants
18.5 to <25 kg/m^2 2 1 2 5
25 to <30 kg/m^2 8 14 7 29
≥30 kg/m^2 23 18 24 65
Baseline Serum Urate  
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 33 participants 33 participants 33 participants 99 participants
6.2  (1.63) 6.3  (1.49) 6.3  (1.24) 6.3  (1.45)
Baseline Serum Urate categories  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 33 participants 33 participants 33 participants 99 participants
<9.0 mg/dL 31 31 32 94
9.0 to <10 mg/dL 2 0 1 3
≥10 mg/dL 0 2 0 2
Renal history   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 33 participants 33 participants 33 participants 99 participants
Moderately impaired 0 0 0 0
Mildly impaired 2 0 1 3
Normal 31 33 32 96
[1]
Measure Description: Moderately impaired = measured creatinine clearance (mCLcr) 30-59 mL/min, mildly impaired = mCLcr 60-89 mL/min, and normal = mCLcr ≥90 mL/min.
24-hour urine uric acid  
Mean (Standard Deviation)
Unit of measure:  Mg/24 hours
Number Analyzed 33 participants 33 participants 33 participants 99 participants
1000.6  (223.99) 948.1  (231.16) 909.4  (166.43) 952.7  (210.44)
24-hour urine uric acid categories   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 33 participants 33 participants 33 participants 99 participants
≤820 mg/24 hours (T1) 9 13 11 33
>820 to ≤987 mg/24 hours 9 9 14 32
>987 mg/24 hours (T2) 15 11 8 34
[1]
Measure Description: Categories are based on tertiles, T1: 33.3rd percentile and T2: 66.6th percentile.
24-hour urinary calcium  
Mean (Standard Deviation)
Unit of measure:  Mg/24 hours
Number Analyzed 33 participants 33 participants 33 participants 99 participants
240.1  (84.08) 297.9  (77.60) 278.7  (99.62) 272.2  (90.00)
Lifetime kidney stone episodes  
Mean (Standard Deviation)
Unit of measure:  Kidney stone episodes
Number Analyzed 33 participants 33 participants 33 participants 99 participants
8.8  (10.18) 12.5  (19.72) 11.3  (14.97) 10.9  (15.38)
Kidney stone passage  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 33 participants 33 participants 33 participants 99 participants
No 6 0 4 10
Yes 27 33 29 89
Composition of most recent passed stone   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 33 participants 33 participants 33 participants 99 participants
Calcium Oxalate 8 14 13 35
Uric acid 1 0 0 1
Calcium citrate 0 0 1 1
Unknown 18 19 15 52
[1]
Measure Description: Includes participants with a kidney stone passage: 27, 33 and 29 participants for each treatment group, respectively.
Kidney stone procedures   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 33 participants 33 participants 33 participants 99 participants
None 13 13 18 44
Shock Wave Lithotripsy 17 20 14 51
Ureteroscopy 9 6 9 24
Nephrolithotomy/Nephrolithotripsy 3 2 0 5
Open surgery 2 2 2 6
Other procedure 2 4 2 8
Stone Procedure 20 20 15 55
[1]
Measure Description: Participants may have had more than one kidney stone procedure.
Use of kidney stone drug  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 33 participants 33 participants 33 participants 99 participants
None 28 30 30 88
Allopurinol 2 1 0 3
Other drug therapy 3 2 3 8
Baseline in-plane Diameter of the largest Calcium Oxalate Stone  
Mean (Standard Deviation)
Unit of measure:  Mm
Number Analyzed 33 participants 33 participants 33 participants 99 participants
12.24  (7.363) 9.34  (4.311) 8.22  (3.756) 9.91  (5.590)
1.Primary Outcome
Title Percent Change From Baseline to Month 6 in 24-hour Urine Uric Acid (uUA) Excretion
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Febuxostat Allopurinol Placebo
Hide Arm/Group Description:
Febuxostat 80 mg, capsules, orally, once daily for up to 6 months.
Allopurinol 200mg or 300mg (determined by kidney function), capsules, orally, once daily for up to 6 months.
Placebo-matching capsules, orally, once daily for up to 6 months.
Overall Number of Participants Analyzed 33 33 33
Mean (Standard Deviation)
Unit of Measure: percent change
-58.6  (28.56) -36.4  (36.97) -12.7  (28.81)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments Hochberg’s method for multiple comparisons was used to ensure that the overall 0.050 level of significance was maintained for comparisons of febuxostat to allopurinol and to placebo.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.003
Comments Hochberg's method for multiple comparisons was used to ensure that the overall 0.050 level of significance was maintained for comparisons of febuxostat to allopurinol and to placebo.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
2.Secondary Outcome
Title Percent Change From Baseline to Month 6 in the In-plane Diameter of the Largest Calcium Oxalate (CaOx) Stone
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Febuxostat Allopurinol Placebo
Hide Arm/Group Description:
Febuxostat 80 mg, capsules, orally, once daily for up to 6 months.
Allopurinol 200mg or 300mg (determined by kidney function), capsules, orally, once daily for up to 6 months.
Placebo-matching capsules, orally, once daily for up to 6 months.
Overall Number of Participants Analyzed 27 24 29
Mean (Standard Deviation)
Unit of Measure: percent change
-6.50  (28.357) 0.63  (12.605) 3.20  (23.697)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.130
Comments Hochberg's method for multiple comparisons was used to ensure that the overall 0.050 level of significance was maintained for comparisons of febuxostat to allopurinol and to placebo.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.348
Comments Hochberg's method for multiple comparisons was used to ensure that the overall 0.050 level of significance was maintained for comparisons of febuxostat to allopurinol and to placebo.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
3.Secondary Outcome
Title Change From Baseline to Month 6 in the Number of Calcium Oxalate Stones
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Febuxostat Allopurinol Placebo
Hide Arm/Group Description:
Febuxostat 80 mg, capsules, orally, once daily for up to 6 months.
Allopurinol 200mg or 300mg (determined by kidney function), capsules, orally, once daily for up to 6 months.
Placebo-matching capsules, orally, once daily for up to 6 months.
Overall Number of Participants Analyzed 28 24 30
Mean (Standard Deviation)
Unit of Measure: stones
Baseline (n=28, 24, 30) 4.84  (3.921) 6.60  (6.832) 5.57  (5.785)
Change from Baseline (n=26, 23, 26) -0.06  (1.602) 0.28  (1.953) 0.10  (1.817)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.403
Comments Hochberg's method for multiple comparisons was used to ensure that the overall 0.050 level of significance was maintained for comparisons of febuxostat to allopurinol and to placebo.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.413
Comments Hochberg's method for multiple comparisons was used to ensure that the overall 0.050 level of significance was maintained for comparisons of febuxostat to allopurinol and to placebo.
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
4.Secondary Outcome
Title Change From Baseline to Month 6 in 24-hour Measured Creatinine Clearance
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Febuxostat Allopurinol Placebo
Hide Arm/Group Description:
Febuxostat 80 mg, capsules, orally, once daily for up to 6 months.
Allopurinol 200mg or 300mg (determined by kidney function), capsules, orally, once daily for up to 6 months.
Placebo-matching capsules, orally, once daily for up to 6 months.
Overall Number of Participants Analyzed 33 33 33
Mean (Standard Deviation)
Unit of Measure: mL/min/1.73m²
Baseline (n=33, 33, 33) 146.9  (57.88) 146.0  (44.32) 147.1  (53.46)
Change from Baseline (n=30, 29, 30) -9.0  (60.82) -7.7  (83.28) -19.0  (45.72)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Febuxostat, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5535
Comments Hochberg's method for multiple comparisons was used to ensure that the overall 0.050 level of significance was maintained for comparisons of febuxostat to allopurinol and to placebo.
Method ANOVA
Comments P-values are from ANOVA with treatment as a fixed effect.
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Febuxostat, Allopurinol
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.9400
Comments Hochberg's method for multiple comparisons was used to ensure that the overall 0.050 level of significance was maintained for comparisons of febuxostat to allopurinol and to placebo.
Method ANOVA
Comments P-values are from ANOVA with treatment as a fixed effect.
Time Frame Treatment emergent AEs were defined as any AE, regardless of relationship to study drug, which occurred on or after the first double blind dose date and up to 30 days after the last dose date of the double-blind study drug (up to 7 months).
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
 
Arm/Group Title Febuxostat Allopurinol Placebo
Hide Arm/Group Description Febuxostat 80 mg, capsules, orally, once daily for up to 6 months. Allopurinol 200mg or 300mg (determined by kidney function), capsules, orally, once daily for up to 6 months. Placebo-matching capsules, orally, once daily for up to 6 months.
All-Cause Mortality
Febuxostat Allopurinol Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Febuxostat Allopurinol Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/33 (0.00%)   0/33 (0.00%)   1/33 (3.03%) 
Renal and urinary disorders       
Nephrolithiasis  1  0/33 (0.00%)  0/33 (0.00%)  1/33 (3.03%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Febuxostat Allopurinol Placebo
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   14/33 (42.42%)   13/33 (39.39%)   12/33 (36.36%) 
General disorders       
Oedema peripheral  1  1/33 (3.03%)  3/33 (9.09%)  1/33 (3.03%) 
Infections and infestations       
Upper respiratory tract infection  1  0/33 (0.00%)  2/33 (6.06%)  3/33 (9.09%) 
Investigations       
Blood creatine phosphokinase increased  1  2/33 (6.06%)  0/33 (0.00%)  0/33 (0.00%) 
Creatinine urine increased  1  2/33 (6.06%)  0/33 (0.00%)  0/33 (0.00%) 
Urine calcium increased  1  2/33 (6.06%)  1/33 (3.03%)  0/33 (0.00%) 
Musculoskeletal and connective tissue disorders       
Back pain  1  1/33 (3.03%)  3/33 (9.09%)  1/33 (3.03%) 
Flank pain  1  4/33 (12.12%)  0/33 (0.00%)  2/33 (6.06%) 
Muscle spasms  1  1/33 (3.03%)  2/33 (6.06%)  0/33 (0.00%) 
Nervous system disorders       
Headache  1  0/33 (0.00%)  3/33 (9.09%)  3/33 (9.09%) 
Renal and urinary disorders       
Nephrolithiasis  1  3/33 (9.09%)  1/33 (3.03%)  3/33 (9.09%) 
Haematuria  1  2/33 (6.06%)  0/33 (0.00%)  0/33 (0.00%) 
Skin and subcutaneous tissue disorders       
Rash  1  2/33 (6.06%)  0/33 (0.00%)  1/33 (3.03%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 14.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Results Point of Contact
Name/Title: Sr. VP, Clinical Science
Organization: Takeda Global Research and Development Center, Inc.
Phone: 800-778-2860
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT01077284     History of Changes
Other Study ID Numbers: TMX-67_201
U1111-1113-6322 ( Registry Identifier: WHO )
First Submitted: February 25, 2010
First Posted: March 1, 2010
Results First Submitted: October 15, 2012
Results First Posted: February 15, 2013
Last Update Posted: February 15, 2013