Gout
Conditions
Brief summary
This study that compare the serum uric acid lowering effects, clinical benefits, and safety of lesinurad in combination with allopurinol to allopurinol alone in subjects with gout who have had an inadequate response to allopurinol.
Detailed description
Allopurinol is the standard of care for the treatment of gout. Nevertheless, most patients treated with allopurinol do not achieve the recommended serum urate (sUA) target of \< 6.0 mg/dL and need additional therapy to achieve the target. Probenecid and benzbromarone are uric acid transporter 1 (URAT1) inhibitors, generally recommended as second-line agents for patients who are either resistant to or intolerant of allopurinol. However, benzbromarone is not available in the US and probenecid is rarely used. Consequently, there is a clear unmet medical need for a new safe and effective therapy for gout, such as lesinurad, a potent URAT1 inhibitor, that can be used in combination with allopurinol in patients not responding adequately to allopurinol monotherapy so that very high rates of response can be achieved by nearly all gout patients, rather than a minority.The subjects selected for this study will have moderate to severe gout with an inadequate response to allopurinol
Interventions
DRUGLesinurad
Tablets, 200 mg once daily (qd)
DRUGPlacebo
Tablets, Placebo qd
DRUGAllopurinol
Tablets, ≥ 300 mg QD (≥ 200 mg qd for subjects with moderate renal impairment)
Sponsors
Ardea Biosciences, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
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 meets the diagnosis of gout as per the American Rheumatism Association Criteria for the Classification of Acute Arthritis of Primary Gout. * Subject has been taking allopurinol as the sole urate-lowering therapy indicated for the treatment of gout for at least 8 weeks prior to the Screening Visit at a stable, medically appropriate dose, as determined by the investigator, of at least 300 mg per day (at least 200 mg for subjects with moderate renal impairment). * Subject must be able to take gout flare prophylaxis with colchicine or an Nonsteroidal anti-inflammatory drug (NSAID) (including Cox-2 selective NSAID) ± PPI. * Subject has an sUA level ≥ 6.5 mg/dL at the Screening Visit and ≥ 6.0 mg/dL at Day -7 Visit. * Subject has reported at least 2 gout flares in the prior 12 months. * Body mass index (BMI) \< 45 kg/m2
Exclusion criteria
* Subject with known hypersensitivity or allergy to allopurinol. * Subject who is taking any other approved urate-lowering medication that is indicated for the treatment of gout other than allopurinol within 8 weeks of the Screening Visit. * Subject who is pregnant or breastfeeding. * 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 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 class III or IV heart failure, myocardial infarction, stroke, or deep venous thrombosis; or subjects currently receiving anticoagulants. * Subject with uncontrolled hypertension. * Subject with an estimated creatinine clearance \< 30 mL/min. * 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 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 |
|---|---|
| Proportion of Subjects With an sUA Level That is < 6.0 mg/dL | 6 Months, analysis after all subjects complete 12 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Gout Flares | 12 Months | Mean rate of gout flares requiring treatment for the 6-month period from the end of Month 6 to the end of Month 12 |
| Tophus | 12 Months | Proportion of subjects with ≥ 1 target tophus at Baseline who experience complete resolution of at least 1 target tophus by Month 12 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Lesinurad 200 mg + Allopurinol lesinurad 200 mg qd plus allopurinol | 201 |
| Lesinurad 400 mg + Allopurinol lesinurad 400 mg qd plus allopurinol | 201 |
| Placebo + Allopurinol placebo qd plus allopurinol | 201 |
| Total | 603 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 7 | 8 | 5 |
| Overall Study | Death | 1 | 0 | 0 |
| Overall Study | Gout flare | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 13 | 16 | 9 |
| Overall Study | Protocol Violation | 17 | 16 | 24 |
| Overall Study | Sponsor terminated study. | 2 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 10 | 13 | 10 |
Baseline characteristics
| Characteristic | Lesinurad 200 mg + Allopurinol | Lesinurad 400 mg + Allopurinol | Placebo + Allopurinol | Total |
|---|---|---|---|---|
| Age, Continuous | 51.6 Years STANDARD_DEVIATION 10.7 | 52.3 Years STANDARD_DEVIATION 11.5 | 51.7 Years STANDARD_DEVIATION 11.7 | 51.9 Years STANDARD_DEVIATION 11.3 |
| Age, Customized <65 | 181 Participants | 168 Participants | 169 Participants | 518 Participants |
| Age, Customized >=65 | 20 Participants | 33 Participants | 32 Participants | 85 Participants |
| Region of Enrollment United States | 201 Participants | 201 Participants | 201 Participants | 603 Participants |
| Sex: Female, Male Female | 9 Participants | 15 Participants | 12 Participants | 36 Participants |
| Sex: Female, Male Male | 192 Participants | 186 Participants | 189 Participants | 567 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 | 147 / 201 | 156 / 201 | 138 / 201 |
| serious Total, serious adverse events | 9 / 201 | 16 / 201 | 11 / 201 |
Outcome results
Primary
Proportion of Subjects With an sUA Level That is < 6.0 mg/dL
Time frame: 6 Months, analysis after all subjects complete 12 months
Population: Intent-to-Treat Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lesinurad 200 mg + Allopurinol | Proportion of Subjects With an sUA Level That is < 6.0 mg/dL | 0.542 Proportion of Subjects |
| Lesinurad 400 mg + Allopurinol | Proportion of Subjects With an sUA Level That is < 6.0 mg/dL | 0.592 Proportion of Subjects |
| Placebo + Allopurinol | Proportion of Subjects With an sUA Level That is < 6.0 mg/dL | 0.279 Proportion of Subjects |
p-value: <0.000195% CI: [0.17, 0.36]Cochran-Mantel-Haenszel
p-value: <0.000195% CI: [0.22, 0.41]Cochran-Mantel-Haenszel
Secondary
Gout Flares
Mean rate of gout flares requiring treatment for the 6-month period from the end of Month 6 to the end of Month 12
Time frame: 12 Months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lesinurad 200 mg + Allopurinol | Gout Flares | .60 Gout Flares | Standard Deviation 1.2 |
| Lesinurad 400 mg + Allopurinol | Gout Flares | .50 Gout Flares | Standard Deviation 1.2 |
| Placebo + Allopurinol | Gout Flares | .60 Gout Flares | Standard Deviation 1.3 |
p-value: 0.979695% CI: [0.61, 1.61]Negative Binomial Regression
p-value: 0.612595% CI: [0.54, 1.43]Negative Binomial Regression
Secondary
Tophus
Proportion of subjects with ≥ 1 target tophus at Baseline who experience complete resolution of at least 1 target tophus by Month 12
Time frame: 12 Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lesinurad 200 mg + Allopurinol | Tophus | 0 Proportion of Subjects |
| Lesinurad 400 mg + Allopurinol | Tophus | 0.211 Proportion of Subjects |
| Placebo + Allopurinol | Tophus | 0.294 Proportion of Subjects |
p-value: 0.018395% CI: [-0.51, -0.08]Cochran-Mantel-Haenszel
p-value: 0.597495% CI: [-0.37, 0.2]Cochran-Mantel-Haenszel