Evaluate the PK, PD, and Safety of Arhalofenate in Combination With Febuxostat for Hyperuricemia in Patients With Gout

Study Overview
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Brief Summary
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The purpose of this study is to evaluate pharmacokinetics, pharmacodynamics, safety and potential for drug-drug interaction of arhalofenate when combined with febuxostat in adult population with gout.

Detailed Description
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Patients entering the six-week Treatment Period will receive once daily oral dosing of arhalofenate during Weeks 1 and 2 (Days 1 through 14), combined once daily oral dosing of arhalofenate and febuxostat during Weeks 3 and 4 (Days 15 through 28), and once daily oral dosing of febuxostat during Weeks 5 and 6 (Days 29 through 42). In addition, all patients will receive once daily oral dosing of colchicine throughout the Treatment Period.

Official Title
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A Phase 2, Open-label, Drug-Drug Interaction Study to Evaluate the Pharmacodynamics, Pharmacokinetics, and Safety of Arhalofenate in Combination With Febuxostat for the Treatment of Hyperuricemia in Patients With Gout

Conditions
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Gout, Hyperuricemia

Intervention / Treatment
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* Drug: Arhalofenate
* Drug: Febuxostat
* Drug: Arhalofenate
* Drug: Febuxostat
* Drug: Colchicine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patient, 18 to 75 years of age, inclusive Known gout diagnosis (per criteria of the American Rheumatism Association) Has an sUA ≥ 7.5 mg/dL A female patient must be surgically sterile or post-menopausal (at least 45 years of age with no history of menses for at least two years), or must agree to use two medically accepted methods of contraception including a barrier method for the entire duration of study participation unless she reports compete sexual abstinence. A female patient must also not be pregnant or lactating Estimated creatinine clearance (eCrCl) ≥ 60 ml/min, as calculated by Cockcroft-Gault method ALT or AST ≤ 3 times upper limit of normal (ULN) or total bilirubin ≤ 2 times ULN (Gilbert's syndrome is permitted) All other clinical laboratory parameters must be within normal limits or considered not clinically significant ECG must be normal, or if abnormal, considered not clinically significant A patient who is taking a medication or agent (other than a ULT) known to influence sUA levels must be on a stable dose and regimen of the medication for at least two weeks prior to screening and must be willing to continue the same dose and regimen during study participation Expected to be able to tolerate a short course of oral NSAIDs and/or oral steroids as may be needed to treat a gout flare Must be able to swallow tablets Exclusion Criteria: Treatment with any ULT (e.g., allopurinol, febuxostat, probenecid, or benzbromarone) within two weeks, or pegloticase within six months, prior to the sUA assessment at Day 1 Occurrence of a gout flare that has not resolved within one week prior to Day 1 Known or suspected secondary hyperuricemia (e.g., due to myeloproliferative disorder or organ transplant) Diagnosis of xanthinuria Fractional excretion of urate > 10% History of documented or suspected kidney stones within five years prior to screening Known infection with the human immunodeficiency virus (HIV) or history of hepatitis B or C Recent use/abuse of an illicit drug as determined by a positive urine drug screen Uncontrolled hypertension that, in the opinion of the Investigator, would preclude participation in the study History of stroke, transient ischemic attack, acute myocardial infarction, congestive heart failure (NYHA class II - IV), angina pectoris, coronary intervention procedure, lower extremity bypass procedure, systemic or intracoronary fibrinolytic therapy within 5 years of screening History of cancer within five years of screening, with the following exceptions: adequately treated non-melanoma skin cancer, non-metastatic prostate cancer, or in situ cervical cancer Body mass index (BMI) > 42 kg/m2 Current or expected requirement for anticoagulant therapy, except for low dose (≤ 81 mg/day) aspirin, clopidogrel (Plavix) ≤ 75 mg/day, or prasugrel (Effient) ≤ 10 mg/day Use of any of the following within eight weeks prior to screening: potent CYP3A4 inhibitors, cytotoxic agents (including azathioprine, mercaptopurine, cyclosporine, cyclophosphamide, etc.), ranolazine, digoxin, theophylline, sulphonylureas, thiazolidinediones (e.g., rosiglitazone or pioglitazone), desipramine, atypical antipsychotic agents, loop diuretics, warfarin, or phenytoin Chronic treatment with NSAIDs that cannot be safely discontinued-term use of NSAIDs is permitted, e.g., when used to treat gout flares Known hypersensitivity or intolerance to febuxostat or colchicine Treatment with any other investigational therapy within 30 days or within five half-lives, whichever is longer prior to Day 1 Any other condition that would compromise the safety of the patient, prevent compliance with the study protocol, or compromise the quality of the clinical study, as judged by the Investigator and/or Medical Monitor

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arhalofenate with febuxostat (PK cohort)<br> | Drug: Arhalofenate<br>* 800 mg once daily orally for four weeks<br>Drug: Febuxostat<br>* 40 mg once daily orally for 1 week then up-titrated to 80 mg once daily orally for another three weeks<br>Drug: Colchicine<br>* 0.6 mg daily<br>|
| Experimental: Arhalofenate with febuxostat (non-PK cohort)<br> | Drug: Arhalofenate<br>* 600 mg once daily orally for four weeks<br>Drug: Febuxostat<br>* 80 mg once daily orally for 1 week then down-titrated to 40 mg once daily orally for another three weeks<br>Drug: Colchicine<br>* 0.6 mg daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients achieving a target sUA < 6.0, < 5.0, < 4.0, and < 3.0 mg/dL on Day 29 after treatment with arhalofenate 800 mg and febuxostat 80 mg |  | Day 29 | 
| Proportion of patients achieving an sUA reduction of ≥ 2.0, ≥ 3.0, and ≥ 4.0 mg/dL from baseline on Day 29 after treatment with arhalofenate 800 mg and febuxostat 80 mg |  | Day 29 | 
| Absolute and percent reduction in sUA from baseline on Day 29 after treatment with arhalofenate 800 mg and febuxostat 80 mg |  | Day 29 | 
| AUC(0-t) of arhalofenate 800 mg and febuxostat 80 mg when administered separately and in combination |  | Days 14, 28, and 42 | 
| AUC(0-tau) of arhalofenate 800 mg and febuxostat 80 mg when administered separately and in combination |  | Days 14, 28, and 42 | 
| Tmax of arhalofenate 800 mg and febuxostat 80 mg when administered separately and in combination |  | Days 14, 28, and 42 | 
| Cmax of arhalofenate 800 mg and febuxostat 80 mg when administered separately and in combination |  | Days 14, 28, and 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients achieving a target sUA < 6.0, < 5.0, < 4.0, and < 3.0 mg/dL on Day 29 after treatment with arhalofenate 600 mg and febuxostat 40 mg |  | Day 29 | 
| Proportion of patients achieving an sUA reduction of ≥ 2.0, ≥ 3.0, and ≥ 4.0 mg/dL from baseline on Day 29 after treatment with arhalofenate 600 mg and febuxostat 40 mg |  | Day 29 | 
| Absolute and percent reduction in sUA from baseline on Day 29 after treatment with arhalofenate 600 mg and febuxostat 40 mg |  | Day 29 | 
| Proportion of patients achieving a target sUA < 6.0, < 5.0, < 4.0, and < 3.0 mg/dL on Day 22 after treatment with arhalofenate 800 mg and febuxostat 40 mg, and with arhalofenate 600 mg and febuxostat 80 mg |  | Day 22 | 
| Proportion of patients achieving an sUA reduction of ≥ 2.0, ≥ 3.0, and ≥ 4.0 mg/dL from baseline on Day 22 after treatment with arhalofenate 800 mg and febuxostat 40 mg, and with arhalofenate 600 mg and febuxostat 80 mg |  | Day 22 | 
| Absolute and percent reduction in sUA from baseline on Day 22 after treatment with arhalofenate 800 mg and febuxostat 40 mg, and with arhalofenate 600 mg and febuxostat 80 mg |  | Day 22 | 
| Proportion of patients achieving a target sUA < 6.0, < 5.0, < 4.0, and < 3.0 mg/dL after monotherapy treatment with arhalofenate 600 or 800 mg, or febuxostat 40 or 80 mg |  | Day 15 or Day 43 | 
| Proportion of patients achieving an sUA reduction of ≥ 2.0, ≥ 3.0, and ≥ 4.0 mg/dL from baseline after monotherapy treatment with arhalofenate 600 or 800 mg, or febuxostat 40 or 80 mg |  | Day 15 or Day 43 | 
| Absolute and percent reduction in sUA from baseline on Day 15 after monotherapy treatment with arhalofenate 600 or 800 mg |  | Day 15 | 
| Absolute and percent reduction in sUA from baseline on Day 43 after monotherapy treatment with febuxostat 40 or 80 mg |  | Day 43 | 
| Kel and T1/2 of arhalofenate 800 mg and febuxostat 80 mg, if possible, when administered separately and in combination |  | Days 14, 28, and 42 |