Efficacy and Safety of Extended Release and Immediate Release Febuxostat in Participants With Gout and Moderate Renal Impairment

A Phase 2, Randomized, Double Blind, Multicenter, Placebo Controlled Study to Evaluate the Efficacy and Safety of Febuxostat 40 mg XR, 80 mg XR, 40 mg IR and 80 mg IR in Subjects With Gout and Moderate Renal Impairment

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 gout participants with moderate renal impairment.

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 with moderate renal impairment. 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 200 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the five treatment groups-which will remain undisclosed to the participant 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 other day or naproxen 250 mg twice a day with lansoprazole 15 mg once a day to prevent gout flare ups.

This multi-center 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.

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) [Modification of Diet in Renal Disease (MDRD)] ≥30 mL/min and <60 mL/min at 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 dependant 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 either a myocardial infarction (MI), stroke, hospitalized unstable angina, cardiac or cerebrovascular revascularization procedure or hospitalized transient ischemic attack (TIA).
14. Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 5 years prior to the Screening visit. Participant consumes >14 alcoholic beverages/week.
15. Has participated in another investigational study within the 30 days prior to the Screening Visit.
16. Has a known history of infection with hepatitis B, hepatitis C, or human immunodeficiency virus.
17. Is required to take excluded medications.