Gout
Conditions
Keywords
Drug therapy
Brief summary
The purpose of this study is to evaluate the efficacy and safety of febuxostat 40 mg extended release (XR) and 80 mg XR in comparison with febuxostat 40 mg immediate release (IR) and 80 mg IR, respectively, in participants with gout.
Detailed description
The drug being tested in this study is called febuxostat. Febuxostat is being tested to decrease and maintain serum urate in people who have gout. This study will look at serum urate levels in people who take febuxostat extended release (XR) capsules compared to febuxostat immediate release (IR) capsules and placebo. The study will enroll approximately 1750 patients. Participants will be randomly assigned (by chance) to one of the five treatment groups-which will remain undisclosed to the patient and study doctor during the study (unless there is an urgent medical need): * Febuxostat 40 mg XR * Febuxostat 80 mg XR * Febuxostat 40 mg IR * Febuxostat 80 mg IR * Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient. All participants will be asked to take one capsule at the same time each day throughout the study, and will be asked to call an interactive voice response system any time they are having a gout flare up. In addition to study medication, participants will also take 0.6 mg of colchicine every day or every other day, or naproxen 250 mg twice a day and lansoprazole 15 mg once a day to prevent gout flare ups. This multi-centre trial will be conducted in the United States. The overall time to participate in this study is up to approximately 4 months and participants will make up to 7 visits to the clinic.
Interventions
DRUGFebuxostat IR
Febuxostat IR over-encapsulated tablets
DRUGFebuxostat XR
Febuxostat XR over-encapsulated capsules
Febuxostat placebo-matching capsules
DRUGColchicine
Colchicine tablets
DRUGNaproxen
Naproxen tablets
DRUGLansoprazole
Lansoprazole 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
1. In the opinion of the investigator, the participant is capable of understanding and complying with protocol requirements. 2. The participant or, when applicable, the participant's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedure. 3. Has a history or presence of gout defined as having one or more of the American Rheumatism Association (ARA) criteria for the diagnosis of gout: 1. A tophus proven to contain urate crystals by chemical or polarized light microscopic means, AND/OR; 2. Characteristic urate crystals in the joint fluid, AND/OR; 3. History of at least 6 of the following clinical, laboratory, and x-ray phenomena: i. more than one attack of acute arthritis, ii. maximum inflammation developed within 1 day, iii. monoarticular arthritis, iv. redness observed over joints, v. first metatarsophalangeal joint painful or swollen, vi. unilateral first metatarsophalangeal joint attack, vii. unilateral tarsal joint attack, viii. tophus (proven or suspected), ix. Hyperuricemia, x. asymmetric swelling within a joint on x-ray, xi. subcortical cysts without erosions on x-ray; xii. joint fluid culture negative for organisms during attack. 4. Is male or female at least 18 years of age, inclusive. 5. A female participant of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study. 6. Have a serum urate (sUA) level ≥8.0 mg/dL at the Day -4 Visit or at the retest visit. 7. Has an estimated Glomerular Filtration Rate (eGRF) ≥15 mL/min using the Modification of Diet in Renal Disease (MDRD) formula at the Screening visit (Day -21 for participants on urate lowering therapy (ULT) and Day -4 for participants not on ULT) or at the retest visit. 8. Has at least one gout flare within 12 months prior to Screening visit.
Exclusion criteria
1. Has received any investigational compound within 30 days prior to Screening. 2. Is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress. 3. Is breastfeeding or pregnant. 4. Has secondary hyperuricemia (eg, due to myeloproliferative disorder). 5. Has a history of xanthinuria. 6. Has received ULT (ie, allopurinol, probenecid, etc.) within 20 days prior to Day 1/Randomization Visit. 7. Has a known hypersensitivity to febuxostat or any components of their formulation; has a known hypersensitivity to naproxen, any other nonsteroidal anti-inflammatory drug (NSAID), aspirin, lansoprazole, colchicine or any components in their formulation. 8. Has active peptic ulcer disease. 9. Has a history of cancer (other than basal cell carcinoma of the skin) within 5 years prior to the Screening Visit. 10. Has alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values \>2 x the upper limit of normal (ULN). 11. Has rheumatoid arthritis which requires treatment. 12. Has a significant medical condition and/or conditions that would interfere with the treatment, safety, or compliance with the protocol. 13. Has experienced a myocardial infarction (MI), stroke, hospitalized unstable angina, cardiac or cerebrovascular revascularization procedure or hospitalized transient ischemic attack (TIA) - except in participants who have severe renal impairment. 14. Participants with severe renal impairment had a MI or stroke within 90 days prior to initial screening visit or has a MI or stroke during the screening period prior to Day 1/Randomization Visit. 15. Participant consumes \>14 alcoholic beverages/week. Has a history of alcoholism or illicit drug abuse within 5 years. 16. Has participated in another investigational study within the 30 days prior to the Screening Visit. 17. Has a known history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus. 18. Is required to take excluded medications.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants With Serum Urate <5.0 mg/dL at Month 3 | Month 3 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least One Gout Flare Requiring Treatment | Baseline to Month 3 | A participant was considered to have a gout flare if the following criteria were met: Participant-reported acute particular pain typical of a gout attack that was deemed by participant and/or investigator to require treatment and was treated with colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids, Participant experienced at least 3 or more of: 1) Joint swelling, 2) Redness, 3) Tenderness, 4) Pain, Participant experienced at least one or more of: 1) Rapid onset of pain, 2) Decreased range of motion, 3) Joint warmth, 4) Other symptoms similar to a prior gout flare. |
| Percentage of Participants With Serum Urate <6.0 mg/dL at Month 3 | Month 3 | — |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 217 investigative sites in the United States from 18 April 2014 to 18 November 2015.
Pre-assignment details
Participants with a diagnosis of gout were enrolled equally in 1 of 5 treatment groups: once a day placebo, febuxostat 40 mg extended release (XR), febuxostat 80 mg XR, febuxostat 40 mg immediate release (IR) or febuxostat 80 mg IR.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Febuxostat placebo-matching capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject's eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. | 357 |
| Febuxostat IR 40 mg Febuxostat Immediate Release (IR) 40 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day (for participants with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min) or every other day (if eGFR ≥ 15 - ≤ 59 mL/min), or, alternatively, if colchicine is not tolerated and the subject's eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. | 357 |
| Febuxostat XR 40 mg Febuxostat Extended Release (XR) 40 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject's eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. | 355 |
| Febuxostat IR 80 mg Febuxostat IR 80 mg over-encapsulated tablet, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject's eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. | 357 |
| Febuxostat XR 80 mg Febuxostat XR 80 mg over-encapsulated capsule, orally, once daily, and colchicine 0.6 mg tablet, orally, every day or every other day, or, alternatively, if colchicine is not tolerated and the subject's eGFR is ≥ 50 mL/min, naproxen 250 mg tablets, orally, twice a day and lansoprazole 15 mg capsule, orally once daily, for 3 months. | 357 |
| Total | 1,783 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 1 | 2 | 1 | 2 |
| Overall Study | Lost to Follow-up | 13 | 16 | 16 | 18 | 13 |
| Overall Study | Major Protocol Deviation | 9 | 10 | 16 | 12 | 6 |
| Overall Study | Other Miscellaneous Reasons | 10 | 9 | 4 | 9 | 12 |
| Overall Study | Pretreatment Event/Adverse Event | 9 | 9 | 10 | 13 | 7 |
| Overall Study | Voluntary Withdrawal | 20 | 8 | 10 | 15 | 16 |
| Overall Study | Withdrawal due to a Gout Flare | 1 | 1 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Febuxostat IR 40 mg | Placebo | Total | Febuxostat XR 80 mg | Febuxostat IR 80 mg | Febuxostat XR 40 mg |
|---|---|---|---|---|---|---|
| Age, Continuous | 55.5 years STANDARD_DEVIATION 11.07 | 54.4 years STANDARD_DEVIATION 11.55 | 55.1 years STANDARD_DEVIATION 11.71 | 55.4 years STANDARD_DEVIATION 11.93 | 54.9 years STANDARD_DEVIATION 11.32 | 55.1 years STANDARD_DEVIATION 12.68 |
| Age, Customized 18 to < 65 years | 283 participants | 294 participants | 1414 participants | 283 participants | 287 participants | 267 participants |
| Age, Customized 45 to < 65 years | 225 participants | 223 participants | 1082 participants | 222 participants | 219 participants | 193 participants |
| Age, Customized < 45 years | 58 participants | 71 participants | 332 participants | 61 participants | 68 participants | 74 participants |
| Age, Customized 65 to < 85 years | 73 participants | 60 participants | 361 participants | 73 participants | 69 participants | 86 participants |
| Age, Customized >= 65 years | 74 participants | 63 participants | 369 participants | 74 participants | 70 participants | 88 participants |
| Age, Customized >= 85 years | 1 participants | 3 participants | 8 participants | 1 participants | 1 participants | 2 participants |
| Alcohol Classification Current Drinker | 204 participants | 234 participants | 1122 participants | 232 participants | 234 participants | 218 participants |
| Alcohol Classification Ex-Drinker | 61 participants | 42 participants | 261 participants | 51 participants | 55 participants | 52 participants |
| Alcohol Classification Never Drank | 92 participants | 81 participants | 400 participants | 74 participants | 68 participants | 85 participants |
| Body Mass Index (BMI) | 34.32 kg/m^2 STANDARD_DEVIATION 8.014 | 34.88 kg/m^2 STANDARD_DEVIATION 8.276 | 34.25 kg/m^2 STANDARD_DEVIATION 7.834 | 34.08 kg/m^2 STANDARD_DEVIATION 7.205 | 33.68 kg/m^2 STANDARD_DEVIATION 7.477 | 34.29 kg/m^2 STANDARD_DEVIATION 8.141 |
| Height | 174.8 cm STANDARD_DEVIATION 10.46 | 175.2 cm STANDARD_DEVIATION 9.95 | 174.8 cm STANDARD_DEVIATION 9.96 | 175.3 cm STANDARD_DEVIATION 9.5 | 174.3 cm STANDARD_DEVIATION 9.42 | 174.4 cm STANDARD_DEVIATION 10.45 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 participants | 1 participants | 7 participants | 3 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 19 participants | 23 participants | 112 participants | 25 participants | 23 participants | 22 participants |
| Race/Ethnicity, Customized Black or African American | 89 participants | 94 participants | 474 participants | 93 participants | 98 participants | 100 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 51 participants | 53 participants | 266 participants | 52 participants | 49 participants | 61 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 5 participants | 3 participants | 20 participants | 5 participants | 3 participants | 4 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 306 participants | 304 participants | 1517 participants | 305 participants | 308 participants | 294 participants |
| Race/Ethnicity, Customized Other: Multi-Racial | 7 participants | 5 participants | 23 participants | 6 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized White | 235 participants | 231 participants | 1147 participants | 225 participants | 230 participants | 226 participants |
| Region of Enrollment United States | 357 participants | 357 participants | 1783 participants | 357 participants | 357 participants | 355 participants |
| Sex: Female, Male Female | 46 Participants | 41 Participants | 206 Participants | 34 Participants | 42 Participants | 43 Participants |
| Sex: Female, Male Male | 311 Participants | 316 Participants | 1577 Participants | 323 Participants | 315 Participants | 312 Participants |
| Smoking History Current Smoker | 56 participants | 58 participants | 286 participants | 47 participants | 65 participants | 60 participants |
| Smoking History Ex-Smoker | 111 participants | 108 participants | 536 participants | 105 participants | 102 participants | 110 participants |
| Smoking History Never Smoked | 190 participants | 191 participants | 961 participants | 205 participants | 190 participants | 185 participants |
| Weight | 104.65 kg STANDARD_DEVIATION 24.157 | 106.83 kg STANDARD_DEVIATION 25.285 | 104.60 kg STANDARD_DEVIATION 24.745 | 104.64 kg STANDARD_DEVIATION 23.033 | 102.16 kg STANDARD_DEVIATION 22.832 | 104.71 kg STANDARD_DEVIATION 27.995 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 53 / 356 | 53 / 358 | 45 / 355 | 55 / 357 | 38 / 357 |
| serious Total, serious adverse events | 8 / 356 | 12 / 358 | 6 / 355 | 8 / 357 | 8 / 357 |
Outcome results
Primary
Percentage of Participants With Serum Urate <5.0 mg/dL at Month 3
Time frame: Month 3
Population: Full Analysis Set (FAS) included all participants who were randomized and received at least 1 dose of double-blind study medication. Participants who discontinued double-blind study drug prior to the Month 3 visit were considered treatment failures, i.e. to have serum urate ≥ 5.0 mg/dL.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Serum Urate <5.0 mg/dL at Month 3 | 0.3 percentage of participants |
| Febuxostat IR 40 mg | Percentage of Participants With Serum Urate <5.0 mg/dL at Month 3 | 15.7 percentage of participants |
| Febuxostat XR 40 mg | Percentage of Participants With Serum Urate <5.0 mg/dL at Month 3 | 25.9 percentage of participants |
| Febuxostat IR 80 mg | Percentage of Participants With Serum Urate <5.0 mg/dL at Month 3 | 42.6 percentage of participants |
| Febuxostat XR 80 mg | Percentage of Participants With Serum Urate <5.0 mg/dL at Month 3 | 50.1 percentage of participants |
p-value: <0.00195% CI: [20.4, 30.9]Z-test
p-value: <0.00195% CI: [43.9, 55.8]Z-test
p-value: 0.00195% CI: [3.5, 17]Z-test
p-value: 0.04395% CI: [-0.8, 15.9]Z-test
Secondary
Percentage of Participants With at Least One Gout Flare Requiring Treatment
A participant was considered to have a gout flare if the following criteria were met: Participant-reported acute particular pain typical of a gout attack that was deemed by participant and/or investigator to require treatment and was treated with colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs) or steroids, Participant experienced at least 3 or more of: 1) Joint swelling, 2) Redness, 3) Tenderness, 4) Pain, Participant experienced at least one or more of: 1) Rapid onset of pain, 2) Decreased range of motion, 3) Joint warmth, 4) Other symptoms similar to a prior gout flare.
Time frame: Baseline to Month 3
Population: FAS included all participants who were randomized and received at least 1 dose of double-blind study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With at Least One Gout Flare Requiring Treatment | 20.7 percentage of participants |
| Febuxostat IR 40 mg | Percentage of Participants With at Least One Gout Flare Requiring Treatment | 21.0 percentage of participants |
| Febuxostat XR 40 mg | Percentage of Participants With at Least One Gout Flare Requiring Treatment | 22.8 percentage of participants |
| Febuxostat IR 80 mg | Percentage of Participants With at Least One Gout Flare Requiring Treatment | 27.2 percentage of participants |
| Febuxostat XR 80 mg | Percentage of Participants With at Least One Gout Flare Requiring Treatment | 26.6 percentage of participants |
p-value: 0.50395% CI: [-4.9, 9]Z-test
p-value: 0.06495% CI: [-1.2, 13]Z-test
p-value: 0.56195% CI: [-5.1, 8.7]Z-test
p-value: 0.86995% CI: [-8, 6.9]Z-test
Secondary
Percentage of Participants With Serum Urate <6.0 mg/dL at Month 3
Time frame: Month 3
Population: FAS included all participants who were randomized and received at least 1 dose of double-blind study medication. Participants who discontinued double-blind study drug prior to the Month 3 visit were considered treatment failures, i.e. to have serum urate ≥ 5.0 mg/dL.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Serum Urate <6.0 mg/dL at Month 3 | 0.6 percentage of participants |
| Febuxostat IR 40 mg | Percentage of Participants With Serum Urate <6.0 mg/dL at Month 3 | 40.3 percentage of participants |
| Febuxostat XR 40 mg | Percentage of Participants With Serum Urate <6.0 mg/dL at Month 3 | 48.2 percentage of participants |
| Febuxostat IR 80 mg | Percentage of Participants With Serum Urate <6.0 mg/dL at Month 3 | 57.7 percentage of participants |
| Febuxostat XR 80 mg | Percentage of Participants With Serum Urate <6.0 mg/dL at Month 3 | 61.1 percentage of participants |
p-value: <0.00195% CI: [41.6, 53.6]Z-test
p-value: <0.00195% CI: [54.6, 66.3]Z-test
p-value: 0.03695% CI: [-0.5, 16.1]Z-test
p-value: 0.36495% CI: [-4.9, 11.6]Z-test