Gout
Conditions
Keywords
uric acid, xanthine oxidase, hyperuricemia, tophi, Drug Therapy
Brief summary
The purpose of this study is to determine the long-term safety of febuxostat, once daily (QD), compared to allopurinol in reducing serum urate levels in subjects with gout.
Detailed description
Uric acid is the end product of purine degradation in humans. Hyperuricemia, a urate concentration in serum exceeding the limit of urate solubility (approximately 7.0 mg/dL), is a common biochemical abnormality. Aberrations in any of the multiple mechanisms involved in the production and/or excretion of uric acid may increase serum urate concentrations, with persistent hyperuricemia as a marker for extracellular fluid monosodium urate supersaturation. As such, hyperuricemia is a necessary (but often insufficient) risk factor for monosodium urate crystal deposition in tissues and is the fundamental pathophysiological process underlying the clinical manifestations of gout, which is a chronic disease characterized by urate crystal formation and deposition in joints and bones. Gout may progress from episodic attacks of acute inflammatory arthritis to a disabling chronic disorder characterized by deforming arthropathy; destructive deposits of urate crystals (tophi) in bones, joints, and other organs; structural and functional renal impairment due to interstitial urate crystal deposition; and urinary tract stones composed entirely or partially of uric acid crystals. Management of gout requires chronic treatment aimed at lowering serum urate levels into a subsaturating range (usually \<6.0 mg/dL) in which crystal formation and deposition are prevented or reversed. Febuxostat (TMX-67) is a non-purine selective xanthine oxidase inhibitor being developed as an orally administered agent for the management of hyperuricemia in patients with gout. This study was originally designed and initiated having all subjects initially assigned to 80 mg febuxostat provided as an 80 mg tablet, to be administered orally. Subjects could be titrated to 120 mg, provided as one 40 and 80 mg tablet, between Months 2 and 6, if their serum uric acid rose \> 6.0 mg/dL; the dose could be down-titrated to 80 mg if the serum uric acid decreased to \< 3.0 mg/dL. The protocol was amended to add a comparator arm, and to have subjects randomized to 80 or 120 mg febuxostat or allopurinol (100 or 300 mg, dependent on renal function). The information below reflects the treatments following the implementation of the revised protocol.
Interventions
DRUGFebuxostat
Febuxostat 80 mg, tablets, orally, once daily.
DRUGAllopurinol
Allopurinol 100 mg or 300 mg, tablets, orally, once daily.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Is receiving thiazide diuretic therapy (only to subjects randomized to or receiving febuxostat). * Has a serum urate level less than 8.0 mg/dL and is not taking uric acid-lowering therapy (other than allopurinol or febuxostat). * Has participated in a clinical study in which febuxostat was administered. * Is completing Phase 3 Studies C02-009 or C02-010. * Must not have experienced any serious study drug-related adverse events in the previous study. * 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
* Has had any other significant medical condition as defined by the investigator that would interfere with the treatment, safety, or compliance with the protocol. * Is intolerant of allopurinol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 1. | Month 1 | Serum urate values were obtained at the Month 1 visit. The percentage of subjects whose serum urate was \<6.0 mg/dL at the Month 1 visit was summarized. |
| Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 12. | Month 12 | Serum urate values were obtained at the Month 12 visit. The percentage of subjects whose serum urate was \<6.0 mg/dL at the Month 12 visit was summarized. |
| Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 24. | Month 24 | Serum urate values were obtained at the Month 24 visit. The percentage of subjects whose serum urate was \<6.0 mg/dL at the Month 24 visit was summarized. |
| Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 36. | Month 36 | Serum urate values were obtained at the Month 36 visit. The percentage of subjects whose serum urate was \<6.0 mg/dL at the Month 36 visit was summarized. |
| Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Last Visit on Treatment. | Last Visit on treatment (up to 40 months). | The percentage of subjects whose serum urate was \<6.0 mg/dL at the last visit on treatment was summarized. The last visit on treatment was the last visit at which a serum urate value was collected prior to any changes in drug and/or dose from the initial treatment assignment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in the Total Number of Tophi for Subjects With Palpable Tophi at Final Visit. | Final Visit (up to 40 months). | The number of tophi were counted at baseline and final visits. The percent change from baseline in the number of tophi to the final visit was summarized. |
| Percent Change in Serum Urate Levels From Baseline to the Last Visit on Treatment. | Last Visit on treatment (up to 40 months). | The percent change in serum urate from baseline to the last visit on treatment was summarized. The last visit on treatment was the last visit at which a serum urate value was collected prior to any changes in drug and/or dose from the initial treatment assignment. |
| Percentage of Subjects Requiring Treatment for Gout Flare After Month 12. | After Month 12 to Final Visit | The percentage of subjects requiring treatment for gout flare after the first 12 months of final stable treatment was summarized. |
| Percentage of Subjects Requiring Treatment for Gout Flare up to Month 12. | Month 12 | The percentage of subjects requiring treatment for gout flare during the first twelve months of final stable treatment was summarized. |
| Percent Change From Baseline in Primary Tophus Size at Month 12 for Subjects With Palpable Tophi Measured at Baseline. | Month 12 | The area of the primary tophus was calculated based on the length and width of the tophus measured at the Month 12 visit. The percent change from baseline in primary tophus size to the Month 12 visit was summarized. |
| Percent Change From Baseline in Primary Tophus Size at Month 24 for Subjects With Palpable Tophi Measured at Baseline. | Month 24 | The area of the primary tophus was calculated based on the length and width of the tophus measured at baseline and Month 24 visit. The percent change from baseline in primary tophus size to the Month 24 visit was summarized. |
| Percent Change From Baseline in Primary Tophus Size at Month 36 for Subjects With Palpable Tophi Measured at Baseline. | Month 36 | The area of the primary tophus was calculated based on the length and width of the tophus measured at baseline and Month 36 visit. The percent change from baseline in primary tophus size to the Month 36 visit was summarized. |
| Percent Change From Baseline in Primary Tophus Size at Final Visit for Subjects With Palpable Tophi Measured at Baseline. | Final Visit (up to 40 months). | The area of the primary tophus was calculated based on the length and width of the tophus measured at baseline and final visit. The percent change from baseline in primary tophus size to the final visit was summarized. |
Participant flow
Recruitment details
Subjects were enrolled at 174 investigative sites, including 168 in the United States and 6 in Canada, from 28 July 2003 to 26 February 2007.
Pre-assignment details
Subjects were to have completed either 28 weeks or 52 weeks of double-blind dosing in Study C02-009 (NCT00174915) or C02-010 (NCT00102440), respectively before enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Febuxostat 80 mg QD Febuxostat 80 mg, taken orally, once daily. | 606 |
| Febuxostat 120 mg QD Febuxostat 120 mg, taken orally, once daily | 388 |
| Allopurinol QD Allopurinol 100 mg or 300 mg, tablets, orally, once daily. | 92 |
| Total | 1,086 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 54 | 22 | 2 |
| Overall Study | Did not continue under Amendment 4 | 1 | 1 | 2 |
| Overall Study | Gout Flare | 2 | 3 | 0 |
| Overall Study | Lost to Follow-up | 42 | 39 | 9 |
| Overall Study | Personal Reason(s) | 39 | 31 | 8 |
| Overall Study | Protocol Violation | 6 | 3 | 3 |
| Overall Study | Reason Not Specified | 40 | 34 | 11 |
| Overall Study | Therapeutic Failure | 10 | 38 | 22 |
Baseline characteristics
| Characteristic | Febuxostat 80 mg QD | Febuxostat 120 mg QD | Allopurinol QD | Total |
|---|---|---|---|---|
| Age Continuous | 53.0 years STANDARD_DEVIATION 11.74 | 48.4 years STANDARD_DEVIATION 11.02 | 51.3 years STANDARD_DEVIATION 12.72 | 51.2 years STANDARD_DEVIATION 11.76 |
| Body Mass Index (BMI) | 31.9 kg/m² STANDARD_DEVIATION 5.49 | 34.1 kg/m² STANDARD_DEVIATION 6.71 | 32.4 kg/m² STANDARD_DEVIATION 5.58 | 31.9 kg/m² STANDARD_DEVIATION 5.49 |
| Presence of Tophus Absent | 490 participants | 305 participants | 77 participants | 872 participants |
| Presence of Tophus Present | 116 participants | 83 participants | 15 participants | 214 participants |
| Race/Ethnicity Asian | 15 participants | 9 participants | 4 participants | 28 participants |
| Race/Ethnicity Black or African American | 47 participants | 33 participants | 16 participants | 96 participants |
| Race/Ethnicity Hispanic | 30 participants | 29 participants | 7 participants | 66 participants |
| Race/Ethnicity Other | 15 participants | 18 participants | 1 participants | 34 participants |
| Race/Ethnicity White | 499 participants | 299 participants | 64 participants | 862 participants |
| Renal Function Impaired | 13 participants | 7 participants | 0 participants | 20 participants |
| Renal Function Normal | 593 participants | 381 participants | 92 participants | 1066 participants |
| Serum Urate | 9.65 mg/dL STANDARD_DEVIATION 1.2 | 10.05 mg/dL STANDARD_DEVIATION 1.29 | 9.83 mg/dL STANDARD_DEVIATION 1.27 | 9.81 mg/dL STANDARD_DEVIATION 1.25 |
| Sex: Female, Male Female | 25 Participants | 17 Participants | 2 Participants | 44 Participants |
| Sex: Female, Male Male | 581 Participants | 371 Participants | 90 Participants | 1042 Participants |
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 | 444 / 801 | 257 / 487 | 66 / 178 |
| serious Total, serious adverse events | 98 / 801 | 50 / 487 | 16 / 178 |
Outcome results
Primary
Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Last Visit on Treatment.
The percentage of subjects whose serum urate was \<6.0 mg/dL at the last visit on treatment was summarized. The last visit on treatment was the last visit at which a serum urate value was collected prior to any changes in drug and/or dose from the initial treatment assignment.
Time frame: Last Visit on treatment (up to 40 months).
Population: Results were summarized by the initial treatment the subject was assigned to before any changes in drug and/or dose. All subjects with a post-baseline serum urate level measurement while receiving their initial treatment were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat 80 mg QD | Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Last Visit on Treatment. | 70.8 percentage of subjects |
| Febuxostat 120 mg QD | Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Last Visit on Treatment. | 82.0 percentage of subjects |
| Allopurinol QD | Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Last Visit on Treatment. | 32.6 percentage of subjects |
Primary
Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 1.
Serum urate values were obtained at the Month 1 visit. The percentage of subjects whose serum urate was \<6.0 mg/dL at the Month 1 visit was summarized.
Time frame: Month 1
Population: Results were summarized by the initial treatment the subject was assigned to before any changes in drug and/or dose. Subjects with a serum urate value at the Month 1 visit and who had not changed from their initial treatment were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat 80 mg QD | Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 1. | 80.8 percentage of subjects |
| Febuxostat 120 mg QD | Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 1. | 87.0 percentage of subjects |
| Allopurinol QD | Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 1. | 46.0 percentage of subjects |
Primary
Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 12.
Serum urate values were obtained at the Month 12 visit. The percentage of subjects whose serum urate was \<6.0 mg/dL at the Month 12 visit was summarized.
Time frame: Month 12
Population: Results were summarized by the initial treatment the subject was assigned to before any changes in drug and/or dose. Subjects with a serum urate value at the Month 12 visit and who had not changed from their initial treatment were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat 80 mg QD | Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 12. | 88.9 percentage of subjects |
| Febuxostat 120 mg QD | Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 12. | 86.3 percentage of subjects |
| Allopurinol QD | Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 12. | 82.2 percentage of subjects |
Primary
Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 24.
Serum urate values were obtained at the Month 24 visit. The percentage of subjects whose serum urate was \<6.0 mg/dL at the Month 24 visit was summarized.
Time frame: Month 24
Population: Results were summarized by the initial treatment the subject was assigned to before any changes in drug and/or dose. Subjects with a serum urate value at the Month 24 visit and who had not changed from their initial treatment were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat 80 mg QD | Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 24. | 89.3 percentage of subjects |
| Febuxostat 120 mg QD | Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 24. | 87.2 percentage of subjects |
| Allopurinol QD | Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 24. | 78.6 percentage of subjects |
Primary
Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 36.
Serum urate values were obtained at the Month 36 visit. The percentage of subjects whose serum urate was \<6.0 mg/dL at the Month 36 visit was summarized.
Time frame: Month 36
Population: Results were summarized by the initial treatment the subject was assigned to before any changes in drug and/or dose. Subjects with a serum urate value at the Month 36 visit and who had not changed from their initial treatment were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat 80 mg QD | Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 36. | 90.8 percentage of subjects |
| Febuxostat 120 mg QD | Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 36. | 91.5 percentage of subjects |
| Allopurinol QD | Percentage of Subjects Whose Serum Urate Level Decreases to < 6.0 mg/dL at Month 36. | 90.0 percentage of subjects |
Secondary
Percentage of Subjects Requiring Treatment for Gout Flare After Month 12.
The percentage of subjects requiring treatment for gout flare after the first 12 months of final stable treatment was summarized.
Time frame: After Month 12 to Final Visit
Population: Results were summarized by final stable treatment which was the treatment a subject was receiving after drug and/or dose changes were no longer allowed. A subject who reported more than one gout flare during the time interval was counted only once.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat 80 mg QD | Percentage of Subjects Requiring Treatment for Gout Flare After Month 12. | 15.3 percentage of subjects |
| Febuxostat 120 mg QD | Percentage of Subjects Requiring Treatment for Gout Flare After Month 12. | 19.8 percentage of subjects |
| Allopurinol QD | Percentage of Subjects Requiring Treatment for Gout Flare After Month 12. | 23.2 percentage of subjects |
Secondary
Percentage of Subjects Requiring Treatment for Gout Flare up to Month 12.
The percentage of subjects requiring treatment for gout flare during the first twelve months of final stable treatment was summarized.
Time frame: Month 12
Population: Results were summarized by final stable treatment which was the treatment a subject was receiving after drug and/or dose changes were no longer allowed. A subject who reported more than one gout flare during the time interval was counted only once.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Febuxostat 80 mg QD | Percentage of Subjects Requiring Treatment for Gout Flare up to Month 12. | 29.4 percentage of subjects |
| Febuxostat 120 mg QD | Percentage of Subjects Requiring Treatment for Gout Flare up to Month 12. | 42.5 percentage of subjects |
| Allopurinol QD | Percentage of Subjects Requiring Treatment for Gout Flare up to Month 12. | 28.3 percentage of subjects |
Secondary
Percent Change From Baseline in Primary Tophus Size at Final Visit for Subjects With Palpable Tophi Measured at Baseline.
The area of the primary tophus was calculated based on the length and width of the tophus measured at baseline and final visit. The percent change from baseline in primary tophus size to the final visit was summarized.
Time frame: Final Visit (up to 40 months).
Population: Results were summarized by final stable treatment which was the treatment a subject was receiving after drug and/or dose changes were no longer allowed. Subjects with a primary tophus at baseline which was also measured while receiving their final stable treatment were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Febuxostat 80 mg QD | Percent Change From Baseline in Primary Tophus Size at Final Visit for Subjects With Palpable Tophi Measured at Baseline. | -96 percent change from baseline |
| Febuxostat 120 mg QD | Percent Change From Baseline in Primary Tophus Size at Final Visit for Subjects With Palpable Tophi Measured at Baseline. | -84 percent change from baseline |
| Allopurinol QD | Percent Change From Baseline in Primary Tophus Size at Final Visit for Subjects With Palpable Tophi Measured at Baseline. | -67 percent change from baseline |
Secondary
Percent Change From Baseline in Primary Tophus Size at Month 12 for Subjects With Palpable Tophi Measured at Baseline.
The area of the primary tophus was calculated based on the length and width of the tophus measured at the Month 12 visit. The percent change from baseline in primary tophus size to the Month 12 visit was summarized.
Time frame: Month 12
Population: Results were summarized by final stable treatment which was the treatment a subject was receiving after drug and/or dose changes were no longer allowed. Subjects with a primary tophus at baseline which was also measured at the Month 12 visit were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Febuxostat 80 mg QD | Percent Change From Baseline in Primary Tophus Size at Month 12 for Subjects With Palpable Tophi Measured at Baseline. | -82 percent change from baseline |
| Febuxostat 120 mg QD | Percent Change From Baseline in Primary Tophus Size at Month 12 for Subjects With Palpable Tophi Measured at Baseline. | -79 percent change from baseline |
| Allopurinol QD | Percent Change From Baseline in Primary Tophus Size at Month 12 for Subjects With Palpable Tophi Measured at Baseline. | -56 percent change from baseline |
Secondary
Percent Change From Baseline in Primary Tophus Size at Month 24 for Subjects With Palpable Tophi Measured at Baseline.
The area of the primary tophus was calculated based on the length and width of the tophus measured at baseline and Month 24 visit. The percent change from baseline in primary tophus size to the Month 24 visit was summarized.
Time frame: Month 24
Population: Results were summarized by final stable treatment which was the treatment a subject was receiving after drug and/or dose changes were no longer allowed. Subjects with a primary tophus at baseline which was also measured at the Month 24 visit were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Febuxostat 80 mg QD | Percent Change From Baseline in Primary Tophus Size at Month 24 for Subjects With Palpable Tophi Measured at Baseline. | -100 percent change from baseline |
| Febuxostat 120 mg QD | Percent Change From Baseline in Primary Tophus Size at Month 24 for Subjects With Palpable Tophi Measured at Baseline. | -96 percent change from baseline |
| Allopurinol QD | Percent Change From Baseline in Primary Tophus Size at Month 24 for Subjects With Palpable Tophi Measured at Baseline. | -87 percent change from baseline |
Secondary
Percent Change From Baseline in Primary Tophus Size at Month 36 for Subjects With Palpable Tophi Measured at Baseline.
The area of the primary tophus was calculated based on the length and width of the tophus measured at baseline and Month 36 visit. The percent change from baseline in primary tophus size to the Month 36 visit was summarized.
Time frame: Month 36
Population: Results were summarized by final stable treatment which was the treatment a subject was receiving after drug and/or dose changes were no longer allowed. Subjects with a primary tophus at baseline which was also measured at the Month 36 visit were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Febuxostat 80 mg QD | Percent Change From Baseline in Primary Tophus Size at Month 36 for Subjects With Palpable Tophi Measured at Baseline. | -83 percent change from baseline |
Secondary
Percent Change From Baseline in the Total Number of Tophi for Subjects With Palpable Tophi at Final Visit.
The number of tophi were counted at baseline and final visits. The percent change from baseline in the number of tophi to the final visit was summarized.
Time frame: Final Visit (up to 40 months).
Population: Results were summarized by final stable treatment which was the treatment a subject was receiving after drug and/or dose changes were no longer allowed. Subjects with a primary tophus at baseline who also had their tophi counted while receiving their final stable treatment were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Febuxostat 80 mg QD | Percent Change From Baseline in the Total Number of Tophi for Subjects With Palpable Tophi at Final Visit. | -59.9 percent change from baseline | Standard Deviation 45.9 |
| Febuxostat 120 mg QD | Percent Change From Baseline in the Total Number of Tophi for Subjects With Palpable Tophi at Final Visit. | -58.3 percent change from baseline | Standard Deviation 42.5 |
| Allopurinol QD | Percent Change From Baseline in the Total Number of Tophi for Subjects With Palpable Tophi at Final Visit. | -48.7 percent change from baseline | Standard Deviation 42.5 |
Secondary
Percent Change in Serum Urate Levels From Baseline to the Last Visit on Treatment.
The percent change in serum urate from baseline to the last visit on treatment was summarized. The last visit on treatment was the last visit at which a serum urate value was collected prior to any changes in drug and/or dose from the initial treatment assignment.
Time frame: Last Visit on treatment (up to 40 months).
Population: Results were summarized by the initial treatment the subject was assigned to before any changes in drug and/or dose. All subjects with a post-baseline serum urate level measurement while receiving their initial treatment were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Febuxostat 80 mg QD | Percent Change in Serum Urate Levels From Baseline to the Last Visit on Treatment. | -46.69 percent change from baseline | Standard Deviation 17.43 |
| Febuxostat 120 mg QD | Percent Change in Serum Urate Levels From Baseline to the Last Visit on Treatment. | -52.99 percent change from baseline | Standard Deviation 19.12 |
| Allopurinol QD | Percent Change in Serum Urate Levels From Baseline to the Last Visit on Treatment. | -32.17 percent change from baseline | Standard Deviation 17.71 |