Lesinurad Monotherapy in Gout Subjects Intolerant to Xanthine Oxidase Inhibitors

A Phase 3 Randomized, Double-Blind, Multicenter, Placebo- Controlled Study to Assess the Efficacy and Safety of Lesinurad Monotherapy Compared to Placebo in Subjects With Gout and an Intolerance or Contraindication to a Xanthine Oxidase Inhibitor

This study will assess the serum uric acid lowering effects and safety of lesinurad compared to placebo in patients who are intolerant or have a contraindication to allopurinol or febuxostat.

Allopurinol is the standard of care for the treatment of gout. In practice, approximately 20% of patients report side effects with allopurinol and 5% discontinue allopurinol due to side effects. Allopurinol can cause gastrointestinal intolerance, such as nausea and diarrhea, which appears to be dosedependent. Rash develops in about 2% of patients treated with allopurinol, and in about 20% of patients treated with allopurinol and ampicillin or amoxicillin. Allopurinol hypersensitivity syndrome remains a major concern among physicians. Mortality has been estimated to be up to nearly one quarter of AHS cases, with multiorgan system disease including hepatocellular changes and renal failure being a serious concern. Allopurinol is also relatively contraindicated for use in combination with 6-mercaptopurine and azathioprine, for which 1/4 to 1/3 lower doses must be given in order to avoid hematologic toxicity. Febuxostat, in clinical trials, has shown a similar AE profile to allopurinol. Liver function abnormalities, nausea, arthralgia and rash were the most commonly reported AEs. In postmarketing experience, Stevens Johnson Syndrome and hypersensitivity rashes have been reported (febuxostat prescribing information). Withdrawals due to AEs were similar in frequency to allopurinol as well. Relative contraindications in combination with 6-mercaptopurine and azathioprine are similar to allopurinol as well. Lesinurad may be an important therapeutic option for patients who either cannot tolerate or who have a contraindication to the use of allopurinol or febuxostat.

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 an sUA level ≥ 6.5 mg/dL at the Screening and Day -7 Visits.
• Subject must be able to take gout flare prophylaxis with colchicine or NSAID (including Cox-2 selective NSAID) ± PPI.
• Subject has a history (either by medical record or subject interview) of intolerance or a contraindication to either allopurinol or febuxostat.
• Body mass index (BMI) < 45 kg/m2

Exclusion Criteria:

• Subject who is taking any other approved urate-lowering medication that is indicated for the treatment of gout at the Screening Visit.
• Subject with a documented history or suspicion of kidney stones.
• 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 a 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 active liver disease, or hepatic dysfunction.
• Subject receiving chronic treatment with more than 325 mg 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.