Tophaceous Gout
Conditions
Brief summary
This study will compare the serum uric acid lowering effects, clinical benefits, and safety of lesinurad in combination with febuxostat to febuxostat alone in patients with tophaceaous gout.
Detailed description
Febuxostat is an XO (Xanthine Oxidase) Inhibitor approved Urate Lowering Therapy (ULT) for patients with gout. Although febuxostat has been demonstrated to be superior to allopurinol in lowering serum urate (sUA) to \< 6mg/dL in 3 randomized, controlled clinical trials, proportions of subjects experiencing a reduction in tophus area and gout flares were not significantly different compared to allopurinol. Although this study will allow subjects who are naïve to ULT to enroll, it is anticipated that the majority of subjects will currently be taking or have previously experienced XO Inhibitor therapy. This trial will enroll a population of subjects with high uric acid body burden, as all must demonstrate the presence of tophi.
Interventions
Sponsors
Ardea Biosciences, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Subject is able to understand the study procedures, the risks involved and willing to provide written informed consent before the first study related activity. * Subject is willing to adhere to the visit/protocol schedules. * Subject meets the diagnosis of gout as per the American Rheumatism Association * Criteria for the Classification of Acute Arthritis of Primary Gout. * Subject meets one of the following criteria: * Subjects who are not currently taking an approved ULT must have an sUA value of ≥ 8 mg/dL (476 µmol/L). * Subjects entering the study on a medically appropriate dose of febuxostat or allopurinol must have an sUA value of ≥ 6.0 mg/dL (357 µmol/L). * Subject must be able to take gout flare prophylaxis with colchicine or non-steroidal anti-inflammatory drug (NSAID) (including Cox-2 selective NSAID) ± PPI. * Subject with at least 1 measurable tophus on the hands/wrists and/or feet/ankles ≥ 5 mm and ≤ 20 mm in the longest diameter. * Body mass index (BMI) \< 45 kg/m2
Exclusion criteria
* Subject with known hypersensitivity or allergy to febuxostat. * Subject who is taking any approved urate-lowering medication other than allopurinol or febuxostat that is indicated for the treatment of gout within 8 weeks of the Screening Visit. * Subject who previously received pegloticase. * Subject who consumes more than 14 drinks of alcohol per week (eg, 1 drink = 5 oz \[150 mL\] of wine, 12 oz \[360 mL\] of beer, or 1.5 oz \[45 mL\] of hard liquor). * Subject with a history or suspicion of drug abuse within the past 5 years. * Subject with a history of myositis/myopathy or rhabdomyolysis. * Subject that requires or may require systemic immunosuppressive or immunomodulatory treatment. * Subject with known or suspected human immunodeficiency virus (HIV) infection. * Subject with a positive test for active hepatitis B or hepatitis C infection. * Subject with a history of malignancy within the previous 5 years with the exception of non-melanoma skin cancer that has been treated with no evidence of recurrence, treated cervical dysplasia or treated in situ Grade 1 cervical cancer. * Subject within the last 12 months with: unstable angina, New York Heart Association thrombosis; or subjects currently receiving anticoagulants. * Subject with uncontrolled hypertension. * Subject with an estimated creatinine clearance \< 30 mL/min. * Subjects with a creatine kinase \> 2.5 x ULN at any time during the Screening Period. * Subject with active peptic ulcer disease requiring treatment. * Subject with a history of xanthinuria, active liver disease, or hepatic dysfunction. * Subject receiving chronic treatment with more than 325 mg of salicylates per day. * Subject taking valpromide, progabide, or valproic acid. * Subject who has received an investigational therapy within 8 weeks or 5 half-lives (whichever is longer) prior to the Screening Visit. * Subject with any other medical or psychological condition, which in the opinion of the Investigator and/or Medical Monitor, might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements, or to complete the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Subjects With a Serum Urate (sUA) Level That is < 5.0 mg/dL by Month 6 | 6 months, analysis after all subjects complete 12 months | Proportion of subjects with an sUA level that is \< 5.0 mg/dL by Month 6 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Resolution of at Least One Target Tophus | 12 Months | Proportion of subjects who experience complete resolution of at least 1 target tophus by Month 12 |
| Complete or Partial Response of at Least One Tophus | 12 Months | Proportion of subjects with a best tophus response on at least 1 target tophus of complete (disappearance of at least 1 target tophus) or partial (≥ 50% decrease in the area of at least 1 target tophus) resolution by Month 12 |
| Quality of Life | 12 Months | Proportion of subjects with an improvement from Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) of at least 0.25 at Month 12. The HAQ-DI assesses a patient's level of functional ability with items scores ranging from 0-3 with 0 being the least disability. |
Countries
Australia, Canada, New Zealand, Poland, Switzerland, United States
Participant flow
Pre-assignment details
330 participants were randomized and 324 participants were included in the Intent-to-Treat (ITT) population (ie, 6 subjects were randomized but not treated).
Participants by arm
| Arm | Count |
|---|---|
| Lesinurad 200 mg + Febuxostat | 106 |
| Lesinurad 400 mg + Febuxostat | 109 |
| Placebo + Febuxostat | 109 |
| Total | 324 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 6 | 4 |
| Overall Study | Death | 1 | 1 | 0 |
| Overall Study | Gout Flare | 0 | 3 | 1 |
| Overall Study | Lost to Follow-up | 5 | 1 | 5 |
| Overall Study | Protocol Violation | 11 | 10 | 9 |
| Overall Study | Withdrawal by Subject | 3 | 4 | 3 |
Baseline characteristics
| Characteristic | Lesinurad 200 mg + Febuxostat | Lesinurad 400 mg + Febuxostat | Placebo + Febuxostat | Total |
|---|---|---|---|---|
| Age, Continuous | 54.2 years STANDARD_DEVIATION 11 | 53.3 years STANDARD_DEVIATION 11.2 | 54.6 years STANDARD_DEVIATION 10.9 | 54.1 years STANDARD_DEVIATION 11 |
| Age, Customized <65 Years | 89 Participants | 90 Participants | 89 Participants | 268 Participants |
| Age, Customized >=65 Years | 17 Participants | 19 Participants | 20 Participants | 56 Participants |
| Region of Enrollment Australia | 6 Participants | 6 Participants | 4 Participants | 16 Participants |
| Region of Enrollment Canada | 9 Participants | 2 Participants | 6 Participants | 17 Participants |
| Region of Enrollment New Zealand | 2 Participants | 6 Participants | 5 Participants | 13 Participants |
| Region of Enrollment Poland | 8 Participants | 10 Participants | 14 Participants | 32 Participants |
| Region of Enrollment Switzerland | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment United States | 81 Participants | 84 Participants | 79 Participants | 244 Participants |
| Sex: Female, Male Female | 6 Participants | 7 Participants | 2 Participants | 15 Participants |
| Sex: Female, Male Male | 100 Participants | 102 Participants | 107 Participants | 309 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 | 50 / 106 | 59 / 109 | 34 / 109 |
| serious Total, serious adverse events | 6 / 106 | 9 / 109 | 10 / 109 |
Outcome results
Primary
Subjects With a Serum Urate (sUA) Level That is < 5.0 mg/dL by Month 6
Proportion of subjects with an sUA level that is \< 5.0 mg/dL by Month 6
Time frame: 6 months, analysis after all subjects complete 12 months
Population: Intent-to-Treat Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lesinurad 200 mg + Febuxostat 80 mg | Subjects With a Serum Urate (sUA) Level That is < 5.0 mg/dL by Month 6 | 0.566 Proportion of Subjects |
| Lesinurad 400 mg + Febuxostat 80 mg | Subjects With a Serum Urate (sUA) Level That is < 5.0 mg/dL by Month 6 | 0.761 Proportion of Subjects |
| Placebo + Febuxostat 80 mg | Subjects With a Serum Urate (sUA) Level That is < 5.0 mg/dL by Month 6 | 0.468 Proportion of Subjects |
p-value: 0.129895% CI: [-0.03, 0.23]Cochran-Mantel-Haenszel
p-value: <0.000195% CI: [0.17, 0.42]Cochran-Mantel-Haenszel
Secondary
Complete or Partial Response of at Least One Tophus
Proportion of subjects with a best tophus response on at least 1 target tophus of complete (disappearance of at least 1 target tophus) or partial (≥ 50% decrease in the area of at least 1 target tophus) resolution by Month 12
Time frame: 12 Months
Population: Intent-to-Treat Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lesinurad 200 mg + Febuxostat 80 mg | Complete or Partial Response of at Least One Tophus | 0.566 Proportion of Subjects |
| Lesinurad 400 mg + Febuxostat 80 mg | Complete or Partial Response of at Least One Tophus | 0.587 Proportion of Subjects |
| Placebo + Febuxostat 80 mg | Complete or Partial Response of at Least One Tophus | 0.505 Proportion of Subjects |
p-value: 0.64595% CI: [-0.1, 0.17]Cochran-Mantel-Haenszel
p-value: 0.411895% CI: [-0.08, 0.19]Cochran-Mantel-Haenszel
Secondary
Complete Resolution of at Least One Target Tophus
Proportion of subjects who experience complete resolution of at least 1 target tophus by Month 12
Time frame: 12 Months
Population: Intent-to-Treat Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lesinurad 200 mg + Febuxostat 80 mg | Complete Resolution of at Least One Target Tophus | 0.255 Proportion of Subjects |
| Lesinurad 400 mg + Febuxostat 80 mg | Complete Resolution of at Least One Target Tophus | 0.303 Proportion of Subjects |
| Placebo + Febuxostat 80 mg | Complete Resolution of at Least One Target Tophus | 0.211 Proportion of Subjects |
p-value: 0.445395% CI: [-0.07, 0.16]Cochran-Mantel-Haenszel
p-value: 0.114995% CI: [-0.02, 0.21]Cochran-Mantel-Haenszel
Secondary
Quality of Life
Proportion of subjects with an improvement from Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) of at least 0.25 at Month 12. The HAQ-DI assesses a patient's level of functional ability with items scores ranging from 0-3 with 0 being the least disability.
Time frame: 12 Months
Population: Intent-to-Treat Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lesinurad 200 mg + Febuxostat 80 mg | Quality of Life | 0.442 Proportion of Subjects |
| Lesinurad 400 mg + Febuxostat 80 mg | Quality of Life | 0.333 Proportion of Subjects |
| Placebo + Febuxostat 80 mg | Quality of Life | 0.525 Proportion of Subjects |
p-value: 0.303495% CI: [-0.24, 0.07]Cochran-Mantel-Haenszel
p-value: 0.02195% CI: [-0.34, -0.04]Cochran-Mantel-Haenszel