Renal Impairment
Conditions
Keywords
Gout, physiology, Hyperuricemia, Uric Acid, Drug Therapy
Brief summary
The purpose of this study is to determine the effect of febuxostat, once daily (QD) or twice daily (BID), on renal function in gout patients with elevated serum urate levels and who have moderate to severe renal impairment.
Detailed description
Gout is caused by high levels of uric acid in the body, and is associated with a broad range of conditions including heart disease, chronic kidney disease and high blood pressure. Hyperuricemia, which is defined as an elevation in serum urate levels, develops into gout when urate crystals form in the body and settle in joints and other organs. Approximately 40-60% of patients with hyperuricemia and gout have some degree of renal impairment. Hyperuricemia has long been associated with renal disease, and chronic hyperuricemia as seen in gout can lead to deposition of urate crystals resulting in diminished renal function. This study will evaluate the effect of febuxostat on the renal function of patients with hyperuricemia and gout and moderate to severe renal impairment. All participants must have an average sitting blood pressure measurement less than 160 mmHg systolic and less than 95 mmHg diastolic. All participants must meet the American Rheumatism Association (ARA) diagnostic criteria for gout (subjects with tophi were excluded). Participants are expected to return to the site for approximately 10 visits.
Interventions
DRUGFebuxostat
Febuxostat capsules
DRUGPlacebo
Febuxostat 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
* Must have a serum urate greater than 7 mg/dL and a serum creatinine greater than or equal to 1.5 mg at Day -21 * Must have a history or presence of gout defined as having one or more of the American Rheumatism Association criteria for the diagnosis of gout (the criteria related to tophi have been excluded for the purpose of the study) * Must have an estimated Glomerular Filtration Rate (eGFR) of 15 or greater, or less than or equal to 50 mL/min, AND a serum creatinine greater than 1.5 mg/dL at Screening Visit Day -21
Exclusion criteria
* Has secondary hyperuricemia (eg, due to myeloproliferative disorder, or organ transplant) * Has tophaceous gout * Has a history of xanthinuria * Has received aspirin greater than 325 mg/day within 35 days prior to Day 1/Randomization Visit * Has known hypersensitivity or allergy to allopurinol or any component in its formulation * Has known hypersensitivity to febuxostat or colchicine or any components in their formulation * Has myocardial infarction or stroke within the 90 days prior to the Screening Visit * Has alanine aminotransferase and/or aspartate aminotransferase values greater than 2.0 times the upper limit of normal * Has end stage renal disease or is likely to be a candidate for dialysis over the 1 year study period * Has a serum creatinine less than or equal to 1.5 mg/dL, or an estimated Glomerular Filtration Rate at Day -21 Screening Visit less than 15 mL/min or greater than 50 mL/min as calculated by the central laboratory * Is required to take excluded medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Month 12 in Serum Creatinine | Baseline and Month 12 | Renal function was assessed by measuring the change from Baseline in serum creatinine. Analyses were conducted by the Central Laboratory. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Month 12 in Estimated Glomerular Filtration Rate (eGFR) | Baseline and Month 12 | Change from baseline to Month 12 in estimated Glomerular Filtration Rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula (as calculated by the central laboratory). |
| Percentage of Participants With Serum Urate (sUA) Less Than 6 mg/dL at Month 12 | Month 12 | Serum urate concentrations were determined using the enzymatic method as performed by the Central Laboratory. |
| Mean Clearance (CL/F) of Febuxostat at Steady State | The 2 pre-dose PK samples collected were collected at any 2 of the following visits: Months 3, 6, 9, and/or 12, at -0.25 to 0 hours. The 4 postdose PK samples were collected at Months 3, 6, and/or 9, at 0.25; 0.75 to 2.0; 2.5 to 4.0; and 5 to 12 hours. | Mean CL/F at steady state were estimated using a population pharmacokinetic (PK) approach, based on 2 PK samples collected prior to dosing, and 4 PK samples collected postdose. |
| Mean Area Under the Concentration-Time Curve During the Dosing Interval (AUC[0-τ]) of Febuxostat at Steady State | The 2 pre-dose PK samples collected were collected at any 2 of the following visits: Months 3, 6, 9, and/or 12, at -0.25 to 0 hours. The 4 postdose PK samples were collected at Months 3, 6, and/or 9, at 0.25; 0.75 to 2.0; 2.5 to 4.0; and 5 to 12 hours. | Mean AUC during the dosing interval at steady state was estimated using a population pharmacokinetic (PK) approach, based on 2 PK samples collected prior to dosing, and 4 PK samples collected postdose. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 46 investigative sites in the United States from 09 April 2010 to 31 May 2012.
Pre-assignment details
Participants meeting the American Rheumatism Association (ARA) diagnostic criteria for gout (subjects with tophi were excluded). were randomized to 1 of 3 arms in a 1:1:1 ratio to receive either febuxostat 40 mg/80 mg once daily (QD) or febuxostat 30 mg twice daily (BID) or placebo for up to 12 months.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo-matching capsules, orally, twice daily for up to 12 months. | 32 |
| Febuxostat 30 mg BID Febuxostat 30 mg, capsules, orally, twice daily (BID) for up to 12 months. | 32 |
| Febuxostat 40/80 mg QD Participants initially received 40 mg febuxostat once daily (QD) and remained on 40 mg QD for up to 12 months if their serum urate (sUA) was \<6.0 mg/dL at the Day 14 visit. Participants whose sUA was ≥6.0 mg/dL at the Day 14 visit received febuxostat 80 mg QD at the Month 1 visit, and for the remainder of the study. | 32 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 9 | 5 | 3 |
| Overall Study | Lost to Follow-up | 0 | 3 | 0 |
| Overall Study | Major protocol deviation | 3 | 3 | 0 |
| Overall Study | Other | 2 | 1 | 3 |
| Overall Study | Withdrawal by Subject | 3 | 3 | 2 |
Baseline characteristics
| Characteristic | Total | Febuxostat 30 mg BID | Placebo | Febuxostat 40/80 mg QD |
|---|---|---|---|---|
| Age Continuous | 65.7 years STANDARD_DEVIATION 10.57 | 67.3 years STANDARD_DEVIATION 11.11 | 66.3 years STANDARD_DEVIATION 12.05 | 63.6 years STANDARD_DEVIATION 8.15 |
| Body Mass Index (BMI) | 33.4 kg/m^2 STANDARD_DEVIATION 6.67 | 32.8 kg/m^2 STANDARD_DEVIATION 6.45 | 33.3 kg/m^2 STANDARD_DEVIATION 6.36 | 34.2 kg/m^2 STANDARD_DEVIATION 7.3 |
| Composition of most recent passed stone Calcium citrate | 1 participants | 0 participants | 0 participants | 1 participants |
| Composition of most recent passed stone Calcium Oxalate | 2 participants | 0 participants | 1 participants | 1 participants |
| Composition of most recent passed stone Mixed | 1 participants | 1 participants | 0 participants | 0 participants |
| Composition of most recent passed stone Uric acid | 2 participants | 0 participants | 1 participants | 1 participants |
| Gout flares in the past year 1-3 flares | 56 participnts | 16 participnts | 21 participnts | 19 participnts |
| Gout flares in the past year 4-6 flares | 15 participnts | 8 participnts | 4 participnts | 3 participnts |
| Gout flares in the past year More than 6 | 10 participnts | 3 participnts | 2 participnts | 5 participnts |
| Height | 173.1 cm STANDARD_DEVIATION 10.16 | 173.8 cm STANDARD_DEVIATION 9.6 | 172.6 cm STANDARD_DEVIATION 11.55 | 172.8 cm STANDARD_DEVIATION 9.48 |
| Kidney Stone Passage | 6 participants | 1 participants | 2 participants | 3 participants |
| Number of Lifetime Kidney Stone Episodes | 2.8 episodes STANDARD_DEVIATION 2.56 | 3.0 episodes STANDARD_DEVIATION 1.67 | 4.8 episodes STANDARD_DEVIATION 3.9 | 1.8 episodes STANDARD_DEVIATION 1.78 |
| Previous urate-lowering therapy Allopurinol | 62 participants | 22 participants | 19 participants | 21 participants |
| Previous urate-lowering therapy Febuxostat | 7 participants | 5 participants | 0 participants | 2 participants |
| Previous urate-lowering therapy None | 26 participants | 6 participants | 11 participants | 9 participants |
| Previous urate-lowering therapy Other | 7 participants | 2 participants | 3 participants | 2 participants |
| Previous urate-lowering therapy Probenecid | 1 participants | 0 participants | 0 participants | 1 participants |
| Prior Use of ARB or ACEi Angiotensin converting enzyme inhibitors (ACEi) | 39 participants | 13 participants | 13 participants | 13 participants |
| Prior Use of ARB or ACEi Angiotensin receptor blocker (ARB) | 24 participants | 8 participants | 8 participants | 8 participants |
| Prior Use of ARB or ACEi None | 33 participants | 11 participants | 11 participants | 11 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 1 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 5 participants | 2 participants | 0 participants | 3 participants |
| Race/Ethnicity, Customized Black or African American | 16 participants | 5 participants | 4 participants | 7 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 8 participants | 2 participants | 3 participants | 3 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 3 participants | 0 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 88 participants | 30 participants | 29 participants | 29 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized White | 70 participants | 24 participants | 25 participants | 21 participants |
| Region of Enrollment United States | 96 participants | 32 participants | 32 participants | 32 participants |
| Renal History Based on Creatinine Clearance Moderately impaired | 60 participants | 23 participants | 15 participants | 22 participants |
| Renal History Based on Creatinine Clearance Severely impaired | 36 participants | 9 participants | 17 participants | 10 participants |
| Serum creatinine level 2.0 to <2.5 mg/dL | 29 participants | 13 participants | 7 participants | 9 participants |
| Serum creatinine level Greater than 2.5 mg/dL | 30 participants | 6 participants | 15 participants | 9 participants |
| Serum creatinine level Less than 2.0 mg/dL | 37 participants | 13 participants | 10 participants | 14 participants |
| Serum Urate | 10.5 mg/dL STANDARD_DEVIATION 1.7 | 10.4 mg/dL STANDARD_DEVIATION 1.43 | 10.8 mg/dL STANDARD_DEVIATION 1.96 | 10.4 mg/dL STANDARD_DEVIATION 1.7 |
| Serum Urate Categories ≥10 mg/dL | 58 participants | 21 participants | 19 participants | 18 participants |
| Serum Urate Categories <9.0 mg/dL | 16 participants | 5 participants | 7 participants | 4 participants |
| Serum Urate Categories 9.0 to <10.0 mg/dL | 22 participants | 6 participants | 6 participants | 10 participants |
| Sex: Female, Male Female | 19 Participants | 7 Participants | 6 Participants | 6 Participants |
| Sex: Female, Male Male | 77 Participants | 25 Participants | 26 Participants | 26 Participants |
| Time since last gout flare 1 to less than 4 months ago | 14 participants | 7 participants | 2 participants | 5 participants |
| Time since last gout flare 4 to less than 6 months ago | 10 participants | 4 participants | 4 participants | 2 participants |
| Time since last gout flare 6 to less than 12 months ago | 33 participants | 8 participants | 14 participants | 11 participants |
| Time since last gout flare Less than 1 month ago | 15 participants | 5 participants | 5 participants | 5 participants |
| Time since last gout flare more than 1 year ago | 24 participants | 8 participants | 7 participants | 9 participants |
| Weight | 100.7 kg STANDARD_DEVIATION 24.42 | 98.8 kg STANDARD_DEVIATION 19.84 | 100.7 kg STANDARD_DEVIATION 27.54 | 102.6 kg STANDARD_DEVIATION 25.85 |
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 | 20 / 32 | 21 / 32 | 23 / 32 |
| serious Total, serious adverse events | 7 / 32 | 5 / 32 | 8 / 32 |
Outcome results
Primary
Change From Baseline to Month 12 in Serum Creatinine
Renal function was assessed by measuring the change from Baseline in serum creatinine. Analyses were conducted by the Central Laboratory.
Time frame: Baseline and Month 12
Population: Full analysis set, including all patients who were randomized and received at least 1 dose of double-blind study medication. Only patients with both a baseline value and at least 1 value during the double-blind treatment period are included in the analysis. Missing data were imputed as carrying forward the last observed post-baseline value.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to Month 12 in Serum Creatinine | Baseline | 2.52 mg/dL | Standard Error 0.126 |
| Placebo | Change From Baseline to Month 12 in Serum Creatinine | Change from Baseline at Month 12 | 0.19 mg/dL | Standard Error 0.094 |
| Febuxostat 30 mg BID | Change From Baseline to Month 12 in Serum Creatinine | Baseline | 2.10 mg/dL | Standard Error 0.126 |
| Febuxostat 30 mg BID | Change From Baseline to Month 12 in Serum Creatinine | Change from Baseline at Month 12 | 0.09 mg/dL | Standard Error 0.093 |
| Febuxostat 40/80 mg QD | Change From Baseline to Month 12 in Serum Creatinine | Baseline | 2.22 mg/dL | Standard Error 0.128 |
| Febuxostat 40/80 mg QD | Change From Baseline to Month 12 in Serum Creatinine | Change from Baseline at Month 12 | 0.23 mg/dL | Standard Error 0.094 |
Comparison: All statistical tests were two sided and conducted at the 0.05 significance level.p-value: 0.45995% CI: [-0.37, 0.17]ANCOVA
Comparison: All statistical tests were two sided and conducted at the 0.05 significance level.p-value: 0.78995% CI: [-0.23, 0.3]ANCOVA
Secondary
Change From Baseline to Month 12 in Estimated Glomerular Filtration Rate (eGFR)
Change from baseline to Month 12 in estimated Glomerular Filtration Rate (eGFR) using the Modification of Diet in Renal Disease (MDRD) formula (as calculated by the central laboratory).
Time frame: Baseline and Month 12
Population: Full analysis set with available data at Baseline. and at least 1 post-baseline value. Missing data was imputed as carrying forward the last post-baseline value.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline to Month 12 in Estimated Glomerular Filtration Rate (eGFR) | Baseline | 29.31 mL/min/1.73m² | Standard Error 1.461 |
| Placebo | Change From Baseline to Month 12 in Estimated Glomerular Filtration Rate (eGFR) | Change from Baseline at Month 12 | -2.05 mL/min/1.73m² | Standard Error 1.198 |
| Febuxostat 30 mg BID | Change From Baseline to Month 12 in Estimated Glomerular Filtration Rate (eGFR) | Baseline | 34.14 mL/min/1.73m² | Standard Error 1.461 |
| Febuxostat 30 mg BID | Change From Baseline to Month 12 in Estimated Glomerular Filtration Rate (eGFR) | Change from Baseline at Month 12 | 0.33 mL/min/1.73m² | Standard Error 1.172 |
| Febuxostat 40/80 mg QD | Change From Baseline to Month 12 in Estimated Glomerular Filtration Rate (eGFR) | Baseline | 34.08 mL/min/1.73m² | Standard Error 1.484 |
| Febuxostat 40/80 mg QD | Change From Baseline to Month 12 in Estimated Glomerular Filtration Rate (eGFR) | Change from Baseline at Month 12 | -0.86 mL/min/1.73m² | Standard Error 0.19 |
p-value: 0.16295% CI: [-0.97, 5.73]ANCOVA
p-value: 0.48595% CI: [-2.18, 4.57]ANCOVA
Secondary
Mean Area Under the Concentration-Time Curve During the Dosing Interval (AUC[0-τ]) of Febuxostat at Steady State
Mean AUC during the dosing interval at steady state was estimated using a population pharmacokinetic (PK) approach, based on 2 PK samples collected prior to dosing, and 4 PK samples collected postdose.
Time frame: The 2 pre-dose PK samples collected were collected at any 2 of the following visits: Months 3, 6, 9, and/or 12, at -0.25 to 0 hours. The 4 postdose PK samples were collected at Months 3, 6, and/or 9, at 0.25; 0.75 to 2.0; 2.5 to 4.0; and 5 to 12 hours.
Population: Participants who received febuxostat and had available data for PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Area Under the Concentration-Time Curve During the Dosing Interval (AUC[0-τ]) of Febuxostat at Steady State | 3.98 hr*µg/mL | Standard Deviation 1.21 |
| Febuxostat 30 mg BID | Mean Area Under the Concentration-Time Curve During the Dosing Interval (AUC[0-τ]) of Febuxostat at Steady State | 4.91 hr*µg/mL | Standard Deviation 1.29 |
| Febuxostat 40/80 mg QD | Mean Area Under the Concentration-Time Curve During the Dosing Interval (AUC[0-τ]) of Febuxostat at Steady State | 8.21 hr*µg/mL | Standard Deviation 2.3 |
Secondary
Mean Clearance (CL/F) of Febuxostat at Steady State
Mean CL/F at steady state were estimated using a population pharmacokinetic (PK) approach, based on 2 PK samples collected prior to dosing, and 4 PK samples collected postdose.
Time frame: The 2 pre-dose PK samples collected were collected at any 2 of the following visits: Months 3, 6, 9, and/or 12, at -0.25 to 0 hours. The 4 postdose PK samples were collected at Months 3, 6, and/or 9, at 0.25; 0.75 to 2.0; 2.5 to 4.0; and 5 to 12 hours.
Population: Participants who received febuxostat and had available data for PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Mean Clearance (CL/F) of Febuxostat at Steady State | 8.16 liters/hour | Standard Deviation 2.31 |
| Febuxostat 30 mg BID | Mean Clearance (CL/F) of Febuxostat at Steady State | 8.71 liters/hour | Standard Deviation 2.21 |
| Febuxostat 40/80 mg QD | Mean Clearance (CL/F) of Febuxostat at Steady State | 10.9 liters/hour | Standard Deviation 4.7 |
Secondary
Percentage of Participants With Serum Urate (sUA) Less Than 6 mg/dL at Month 12
Serum urate concentrations were determined using the enzymatic method as performed by the Central Laboratory.
Time frame: Month 12
Population: Full analysis set, including all patients who were randomized and received at least 1 dose of double-blind study medication. A patient was included in the analysis only when there was at least 1 value during the double-blind treatment period. Missing data were imputed as carrying forward the last observed post-baseline value.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Serum Urate (sUA) Less Than 6 mg/dL at Month 12 | 0 percentage of participants |
| Febuxostat 30 mg BID | Percentage of Participants With Serum Urate (sUA) Less Than 6 mg/dL at Month 12 | 68.8 percentage of participants |
| Febuxostat 40/80 mg QD | Percentage of Participants With Serum Urate (sUA) Less Than 6 mg/dL at Month 12 | 45.2 percentage of participants |
p-value: <0.001Cochran-Mantel-Haenszel
p-value: <0.001Cochran-Mantel-Haenszel
p-value: 0.062Cochran-Mantel-Haenszel