Combining Lesinurad With Allopurinol in Inadequate Responders

Study Overview
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Brief Summary
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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
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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

Official Title
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A Phase 3 Randomized, Double-Blind, Multicenter, Placebo-Controlled, Combination Study to Evaluate the Efficacy and Safety of Lesinurad and Allopurinol Compared to Allopurinol Alone in Subjects With Gout Who Have Had an Inadequate Hypouricemic Response to Standard of Care Allopurinol.

Conditions
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Gout

Intervention / Treatment
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* Drug: Lesinurad
* Drug: Lesinurad
* Drug: Placebo
* Drug: Allopurinol
* Drug: Allopurinol
* Drug: Allopurinol


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: lesinurad 200 mg + allopurinol<br> | Drug: Lesinurad<br>* Tablets, 200 mg once daily (qd)<br>Drug: Allopurinol<br>* Tablets, ≥ 300 mg QD (≥ 200 mg qd for subjects with moderate renal impairment)<br>|
| Experimental: lesinurad 400 mg + allopurinol<br> | Drug: Lesinurad<br>* Tablets, 400 mg qd<br>Drug: Allopurinol<br>* Tablets, ≥ 300 mg QD (≥ 200 mg qd for subjects with moderate renal impairment)<br>|
| Placebo Comparator: Placebo + allopurinol<br> | Drug: Placebo<br>* Tablets, Placebo qd<br>Drug: Allopurinol<br>* Tablets, ≥ 300 mg QD (≥ 200 mg qd for subjects with moderate renal impairment)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 12 Months | 
| Tophus | Proportion of subjects with ≥ 1 target tophus at Baseline who experience complete resolution of at least 1 target tophus by Month 12 | 12 Months |