Gout
Conditions
Keywords
Uric Acid, xanthine oxidase, tophi, Drug Therapy
Brief summary
The purpose of this study is to determine the efficacy of febuxostat, once daily (QD), in reducing serum urate levels in subjects with gout.
Detailed description
Gout is a chronic urate crystal deposition disorder, which if left untreated may result in progressive disease characterized by joint and bone destruction from tophaceous deposits and renal impairment due to gouty nephropathy. Hyperuricemia, defined as a serum urate concentration of \>7.0 milligrams per deciliter (mg/dL), is the underlying metabolic aberration leading to urate crystal deposition in gout. Gout has several clinical presentations, including: recurrent acute attacks of inflammatory arthritis; deposition of monosodium urate monohydrate crystals in joints, bones and even parenchymal organs (tophaceous gout); renal impairment; and uric acid nephrolithiasis. As serum urate levels increase beyond \>7.0 mg/dL, the risks for gouty arthritis or for renal calculi increase. Currently allopurinol is the only xanthine oxidase inhibitor available. Allopurinol is the agent of choice for reduction of serum urate levels in patients with: uric acid overproduction; unresponsive or intolerant to uricosuric agents; impaired renal function; uric acid urolithiasis; or tophi. Febuxostat (TMX-67) is a non-purine selective xanthine oxidase inhibitor being developed as an orally administered agent for management of hyperuricemia in patients with gout.
Interventions
DRUGPlacebo
Febuxostat placebo-matching tablets, orally, once daily for up to 4 weeks.
DRUGFebuxostat
Febuxostat 40 mg, tablets, orally, once daily for up to 4 weeks.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Hyperuricemia (serum uric acid ≥8.0 mg/dL). * Must meet American College of Rheumatology criteria for gout. * Must have adequate renal function (serum creatinine \<1.5 mg/dL). * Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study.
Exclusion criteria
* History of xanthinuria * Alcohol consumption \>14/week * Has a history of significant concomitant illness. * Has active liver disease. * Has a body mass index greater than 50 kilogram per meter² (kg/m²) * Any other significant medical condition that would interfere with the treatment, safety or compliance with the protocol, as defined by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 Milligram Per Deciliter (mg/dL) at the Day 28 Visit. | Day 28. | Serum urate values were obtained at the Day 28 visit. The percentage of subjects whose serum urate decreased to \<6.0 mg/dL at the Day 28 visit was summarized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 14 Visit. | Day 14. | Serum urate values were obtained at the Day 14 visit. The percentage of subjects whose serum urate decreased to \<6.0 mg/dL at the Day 14 visit was summarized. |
| Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 21 Visit. | Day 21. | Serum urate values were obtained at the Day 21 visit. The percentage of subjects whose serum urate decreased to \<6.0 mg/dL at the Day 21 visit was summarized. |
| Percent Change in Serum Urate Levels From Baseline to the Day 7 Visit. | Baseline and Day 7. | Serum urate values were obtained at the Day 7 visit. The percent change in serum urate from baseline to the Day 7 visit was summarized. |
| Percent Change in Serum Urate Levels From Baseline to the Day 14 Visit. | Baseline and Day 14. | Serum urate values were obtained at the Day 14 visit. The percent change in serum urate from baseline to the Day 14 visit was summarized. |
| Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 7 Visit. | Day 7. | Serum urate values were obtained at the Day 7 visit. The percentage of subjects whose serum urate decreased to \<6.0 mg/dL at the Day 7 visit was summarized. |
| Percent Change in Serum Urate Levels From Baseline to the Day 28 Visit. | Baseline and Day 28. | Serum urate values were obtained at the Day 28 visit. The percent change in serum urate from baseline to the Day 28 visit was summarized. |
| Maximum Percent Change in Serum Urate Level From Baseline During the Entire Treatment Period. | Baseline and Any visit (Day 7, 14, 21,or 28) | Serum urate values were obtained at the Day 7, 14, 21,and 28 visits. The maximum percent change in serum urate levels obtained at any visit was summarized. |
| Percent Change in 24-hour Urine Uric Acid Level From Baseline to Day 28. | Baseline and Day 28. | 24-hour urine uric acid levels were obtained at the Day 28 visit. The percent change in 24-hour urine uric acid level from baseline to the Day 28 visit was summarized. |
| Percent Change in Serum Urate Levels From Baseline to the Day 21 Visit | Baseline and Day 21. | Serum urate values were obtained at the Day 21 visit. The percent change in serum urate from baseline to the Day 21 visit was summarized. |
Participant flow
Recruitment details
Subjects were enrolled at 24 investigative sites from 31 January 2001 to 9 July 2001
Pre-assignment details
Participants currently receiving urate-lowering therapy discontinued those urate-lowering therapies and initiated prophylactic medications before enrollemnt in once daily (QD) treatment groups. All other subjects also initiated prophylactic medications.
Participants by arm
| Arm | Count |
|---|---|
| Febuxostat 40 mg QD Febuxostat 40 mg, orally, once daily. | 37 |
| Febuxostat 80 mg QD Febuxostat 80 mg, orally, once daily. | 40 |
| Febuxostat 120 mg QD Febuxostat 120 mg, orally, once daily. | 38 |
| Placebo QD Placebo, orally, once daily | 38 |
| Total | 153 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 | 2 | 1 |
| Overall Study | Gout Flare | 0 | 0 | 0 | 1 |
| Overall Study | Other | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Febuxostat 40 mg QD | Febuxostat 80 mg QD | Febuxostat 120 mg QD | Placebo QD | Total |
|---|---|---|---|---|---|
| Age Continuous | 52.2 years STANDARD_DEVIATION 14.04 | 55.2 years STANDARD_DEVIATION 13.09 | 56.2 years STANDARD_DEVIATION 10.83 | 52.4 years STANDARD_DEVIATION 12.63 | 54.0 years STANDARD_DEVIATION 12.69 |
| Age, Customized <45 years | 8 participants | 10 participants | 7 participants | 12 participants | 37 participants |
| Age, Customized 45 years to <65 years | 21 participants | 19 participants | 23 participants | 17 participants | 80 participants |
| Age, Customized ≥65 years | 8 participants | 11 participants | 8 participants | 9 participants | 36 participants |
| Body Mass Index >25 kg/m² to 30 kg/m² | 12 participants | 12 participants | 14 participants | 13 participants | 51 participants |
| Body Mass Index ≤25 kilogram per meter² (kg/m²) | 2 participants | 3 participants | 3 participants | 0 participants | 8 participants |
| Body Mass Index >30 kg/m² to 35 kg/m² | 16 participants | 12 participants | 12 participants | 16 participants | 56 participants |
| Body Mass Index >35 kg/m² to 40 kg/m² | 4 participants | 7 participants | 5 participants | 6 participants | 22 participants |
| Body Mass Index >40 kg/m² | 3 participants | 6 participants | 3 participants | 3 participants | 15 participants |
| Body Mass Index missing | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 1 participants | 1 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 3 participants | 3 participants | 2 participants | 3 participants | 11 participants |
| Race/Ethnicity, Customized Hispanic | 1 participants | 1 participants | 1 participants | 1 participants | 4 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 0 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized White | 32 participants | 35 participants | 34 participants | 32 participants | 133 participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 5 Participants | 6 Participants | 17 Participants |
| Sex: Female, Male Male | 33 Participants | 38 Participants | 33 Participants | 32 Participants | 136 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 37 | 19 / 40 | 16 / 38 | 17 / 38 |
| serious Total, serious adverse events | 0 / 37 | 1 / 40 | 2 / 38 | 0 / 38 |
Outcome results
Primary
Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 Milligram Per Deciliter (mg/dL) at the Day 28 Visit.
Serum urate values were obtained at the Day 28 visit. The percentage of subjects whose serum urate decreased to \<6.0 mg/dL at the Day 28 visit was summarized.
Time frame: Day 28.
Population: Analysis performed on intent-to-treat (ITT) subjects, defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥8.0 mg/dL. The last observation carried forward (LOCF) method was used to impute missing data. The baseline value was carried forward if no postbaseline visits were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat 40 mg QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 Milligram Per Deciliter (mg/dL) at the Day 28 Visit. | 56 percentage of subjects |
| Febuxostat 80 mg QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 Milligram Per Deciliter (mg/dL) at the Day 28 Visit. | 76 percentage of subjects |
| Febuxostat 120 mg QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 Milligram Per Deciliter (mg/dL) at the Day 28 Visit. | 94 percentage of subjects |
| Placebo QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 Milligram Per Deciliter (mg/dL) at the Day 28 Visit. | 0 percentage of subjects |
p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact
Secondary
Maximum Percent Change in Serum Urate Level From Baseline During the Entire Treatment Period.
Serum urate values were obtained at the Day 7, 14, 21,and 28 visits. The maximum percent change in serum urate levels obtained at any visit was summarized.
Time frame: Baseline and Any visit (Day 7, 14, 21,or 28)
Population: The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Febuxostat 40 mg QD | Maximum Percent Change in Serum Urate Level From Baseline During the Entire Treatment Period. | 42.5 percent change from baseline | Standard Deviation 10.04 |
| Febuxostat 80 mg QD | Maximum Percent Change in Serum Urate Level From Baseline During the Entire Treatment Period. | 49.2 percent change from baseline | Standard Deviation 13.24 |
| Febuxostat 120 mg QD | Maximum Percent Change in Serum Urate Level From Baseline During the Entire Treatment Period. | 62.8 percent change from baseline | Standard Deviation 7.05 |
| Placebo QD | Maximum Percent Change in Serum Urate Level From Baseline During the Entire Treatment Period. | 10.0 percent change from baseline | Standard Deviation 11.12 |
p-value: <0.001t-test, 2 sided
p-value: <0.001t-test, 2 sided
p-value: <0.001t-test, 2 sided
Secondary
Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 14 Visit.
Serum urate values were obtained at the Day 14 visit. The percentage of subjects whose serum urate decreased to \<6.0 mg/dL at the Day 14 visit was summarized.
Time frame: Day 14.
Population: The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. The LOCF method was used to impute missing data. The baseline value was carried forward if no post-baseline visits were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat 40 mg QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 14 Visit. | 56 percentage of subjects |
| Febuxostat 80 mg QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 14 Visit. | 68 percentage of subjects |
| Febuxostat 120 mg QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 14 Visit. | 94 percentage of subjects |
| Placebo QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 14 Visit. | 0 percentage of subjects |
p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact
Secondary
Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 21 Visit.
Serum urate values were obtained at the Day 21 visit. The percentage of subjects whose serum urate decreased to \<6.0 mg/dL at the Day 21 visit was summarized.
Time frame: Day 21.
Population: The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. The LOCF method was used to impute missing data. The baseline value was carried forward if no post-baseline visits were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat 40 mg QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 21 Visit. | 59 percentage of subjects |
| Febuxostat 80 mg QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 21 Visit. | 76 percentage of subjects |
| Febuxostat 120 mg QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 21 Visit. | 97 percentage of subjects |
| Placebo QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 21 Visit. | 0 percentage of subjects |
p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact
Secondary
Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 7 Visit.
Serum urate values were obtained at the Day 7 visit. The percentage of subjects whose serum urate decreased to \<6.0 mg/dL at the Day 7 visit was summarized.
Time frame: Day 7.
Population: The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. The LOCF method was used to impute missing data. The baseline value was carried forward if no post-baseline visits were available.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat 40 mg QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 7 Visit. | 50 percentage of subjects |
| Febuxostat 80 mg QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 7 Visit. | 59 percentage of subjects |
| Febuxostat 120 mg QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 7 Visit. | 91 percentage of subjects |
| Placebo QD | Percentage of Subjects Whose Serum Urate Level Decreased to <6.0 mg/dL at the Day 7 Visit. | 3 percentage of subjects |
p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact
p-value: <0.001Fisher Exact
Secondary
Percent Change in 24-hour Urine Uric Acid Level From Baseline to Day 28.
24-hour urine uric acid levels were obtained at the Day 28 visit. The percent change in 24-hour urine uric acid level from baseline to the Day 28 visit was summarized.
Time frame: Baseline and Day 28.
Population: The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. Missing data was not imputed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Febuxostat 40 mg QD | Percent Change in 24-hour Urine Uric Acid Level From Baseline to Day 28. | -43.6 percent change from baseline | Standard Deviation 28.9 |
| Febuxostat 80 mg QD | Percent Change in 24-hour Urine Uric Acid Level From Baseline to Day 28. | -46.5 percent change from baseline | Standard Deviation 27 |
| Febuxostat 120 mg QD | Percent Change in 24-hour Urine Uric Acid Level From Baseline to Day 28. | -45.7 percent change from baseline | Standard Deviation 30.1 |
| Placebo QD | Percent Change in 24-hour Urine Uric Acid Level From Baseline to Day 28. | 5.9 percent change from baseline | Standard Deviation 37.1 |
p-value: <0.001t-test, 2 sided
p-value: <0.001t-test, 2 sided
p-value: <0.001t-test, 2 sided
Secondary
Percent Change in Serum Urate Levels From Baseline to the Day 14 Visit.
Serum urate values were obtained at the Day 14 visit. The percent change in serum urate from baseline to the Day 14 visit was summarized.
Time frame: Baseline and Day 14.
Population: The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. The LOCF method was used to impute missing data. The baseline value was carried forward if no post-baseline visits were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Febuxostat 40 mg QD | Percent Change in Serum Urate Levels From Baseline to the Day 14 Visit. | -37.1 percent change from baseline | Standard Deviation 11.7 |
| Febuxostat 80 mg QD | Percent Change in Serum Urate Levels From Baseline to the Day 14 Visit. | -41.8 percent change from baseline | Standard Deviation 14.63 |
| Febuxostat 120 mg QD | Percent Change in Serum Urate Levels From Baseline to the Day 14 Visit. | -56.9 percent change from baseline | Standard Deviation 8.36 |
| Placebo QD | Percent Change in Serum Urate Levels From Baseline to the Day 14 Visit. | 1.62 percent change from baseline | Standard Deviation 10.21 |
p-value: <0.001t-test, 2 sided
p-value: <0.001t-test, 2 sided
p-value: <0.001t-test, 2 sided
Secondary
Percent Change in Serum Urate Levels From Baseline to the Day 21 Visit
Serum urate values were obtained at the Day 21 visit. The percent change in serum urate from baseline to the Day 21 visit was summarized.
Time frame: Baseline and Day 21.
Population: The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. The last observation carried forward (LOCF) method was used to impute missing data. The baseline value was carried forward if no post-baseline visits were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Febuxostat 40 mg QD | Percent Change in Serum Urate Levels From Baseline to the Day 21 Visit | -37.3 percent change from baseline | Standard Deviation 11.3 |
| Febuxostat 80 mg QD | Percent Change in Serum Urate Levels From Baseline to the Day 21 Visit | -43.9 percent change from baseline | Standard Deviation 16.3 |
| Febuxostat 120 mg QD | Percent Change in Serum Urate Levels From Baseline to the Day 21 Visit | -59.4 percent change from baseline | Standard Deviation 7.58 |
| Placebo QD | Percent Change in Serum Urate Levels From Baseline to the Day 21 Visit | -0.57 percent change from baseline | Standard Deviation 10.63 |
p-value: <0.001t-test, 2 sided
p-value: <0.001t-test, 2 sided
p-value: <0.001t-test, 2 sided
Secondary
Percent Change in Serum Urate Levels From Baseline to the Day 28 Visit.
Serum urate values were obtained at the Day 28 visit. The percent change in serum urate from baseline to the Day 28 visit was summarized.
Time frame: Baseline and Day 28.
Population: The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. The LOCF method was used to impute missing data. The baseline value was carried forward if no post-baseline visits were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Febuxostat 40 mg QD | Percent Change in Serum Urate Levels From Baseline to the Day 28 Visit. | -36.6 percent change from baseline | Standard Deviation 12.07 |
| Febuxostat 80 mg QD | Percent Change in Serum Urate Levels From Baseline to the Day 28 Visit. | -44.3 percent change from baseline | Standard Deviation 17.53 |
| Febuxostat 120 mg QD | Percent Change in Serum Urate Levels From Baseline to the Day 28 Visit. | -59.1 percent change from baseline | Standard Deviation 9.92 |
| Placebo QD | Percent Change in Serum Urate Levels From Baseline to the Day 28 Visit. | -2.2 percent change from baseline | Standard Deviation 12.5 |
p-value: <0.001t-test, 2 sided
p-value: <0.001t-test, 2 sided
p-value: <0.001t-test, 2 sided
Secondary
Percent Change in Serum Urate Levels From Baseline to the Day 7 Visit.
Serum urate values were obtained at the Day 7 visit. The percent change in serum urate from baseline to the Day 7 visit was summarized.
Time frame: Baseline and Day 7.
Population: The analysis was performed on ITT subjects, which were defined as all randomized subjects who took at least 1 dose of study drug and who had baseline serum urate ≥ 8.0 mg/dL. The LOCF method was used to impute missing data. The baseline value was carried forward if no post-baseline visits were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Febuxostat 40 mg QD | Percent Change in Serum Urate Levels From Baseline to the Day 7 Visit. | -35.0 percent change from baseline | Standard Deviation 9.67 |
| Febuxostat 80 mg QD | Percent Change in Serum Urate Levels From Baseline to the Day 7 Visit. | -39.2 percent change from baseline | Standard Deviation 15.9 |
| Febuxostat 120 mg QD | Percent Change in Serum Urate Levels From Baseline to the Day 7 Visit. | -53.44 percent change from baseline | Standard Deviation 12.3 |
| Placebo QD | Percent Change in Serum Urate Levels From Baseline to the Day 7 Visit. | 0.71 percent change from baseline | Standard Deviation 12.6 |
p-value: <0.001t-test, 2 sided
p-value: <0.001t-test, 2 sided
p-value: <0.001t-test, 2 sided