Gout Dose Response Study

Study Overview
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Brief Summary
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To compare the proportion of subjects whose serum urate (sUA) level is < 6.0 mg/dL after 28 days of dosing by treatment group.

Official Title
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Randomized, Double-Blind, Multicenter, Placebo-Controlled, Safety and Efficacy Study of RDEA594 Versus Placebo in the Treatment of Hyperuricemia in Patients With Gout

Conditions
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Hyperuricemia

Intervention / Treatment
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* Drug: RDEA594
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or post-menopausal or surgically sterile female. 18 - 75 years of age. Hyperuricemic (i.e., screening sUA ≥8 mg/dL). Meets criteria for the diagnosis of gout as per the American Rheumatism Association (ARA) Criteria for the Classification of Acute Arthritis of Primary Gout. Willing and able to give informed consent and adhere to visit/protocol schedules (informed consent must be given before the first study procedure is performed). Subjects entering the optional Extension Period must have successfully completed the Double-Blind Treatment Period and Follow-up Period within approximately 4 months and must not have experienced any serious adverse events considered possibly related to study drug. Exclusion Criteria: Classified as an overproducer of urine urate (Cur > 6.0 ml/min/1.73 m2 24- hour urine). Consumes more than 14 drinks of alcohol per week (e.g., 1 drink = 5 oz [150 ml] of wine, 12 oz [360 ml] of beer, or 1.5 oz [45 ml] of hard liquor). History or suspicion of drug abuse. Documented history of or suspicion of kidney stones. History of rheumatoid arthritis or other autoimmune disease. Confirmed (positive serology to HIV1 and HIV 2) or suspected HIV infection. Positive serology to HCV antibodies (Abs), and/or hepatitis B surface antigen (HBsAg). History of malignancy, except treated non-melanomatous skin cancer or cervical dysplasia. History of cardiac abnormalities, including abnormal and clinically relevant ECG changes such as bradycardia (sinus rate <45 bpm), complete left bundle branch block (LBBB), second or third degree heart block, intraventricular conduction delay with QRS duration >120 msec, symptomatic or asymptomatic arrhythmias with the exception of sinus arrhythmia, evidence of ventricular pre-excitation, frequent palpitations or syncopal episodes, heart failure, hypokalemia, family history of Long QT Syndrome, and/or family history of sudden death in an otherwise healthy individual between the ages of 1 and 30 years. Any condition predisposing them to QT prolongation including pathological Q-wave (defined as Q-wave >40 msec or depth > 0.4-0.5 mV). Any use of a concomitant medication that prolong the QT/QTc interval within the 14 days prior to Baseline (Day 0) QT interval corrected for heart rate according to Fridericia (QTcF) > 450 msec at Screening or pre-dose at Baseline (Day 0) Uncontrolled hypertension (above 150/95) Inadequate renal function Hemoglobin < 10 g/dL (males) or < 9 g/dL (females) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x upper limit of normal (ULN) Gamma glutamyl transferase (GGT) > 3 x ULN Active peptic ulcer disease requiring treatment History of xanthinuria, active liver disease, or hepatic dysfunction. Requires therapy with any other urate-lowering medication, other than the study medication. Requires long-term use of salicylates; diuretics; azathioprine; mercaptopurine; theophylline; intravenous colchicine; cyclosporine; cyclophosphamide; pyrazinamide; sulfamethoxazole; or trimethoprim Taking medications known as enzyme inducers Receiving a strong or moderate inhibitor of CYP3A4 or a P-gp inhibitor within 1 month prior to study drug dosing Gout flare at screening that is resolved for less than one week prior to the first treatment with study medication (exclusive of chronic synovitis/ arthritis) Female of childbearing potential Received an investigational medication within 4 weeks prior to study medication administration Previously participated in a clinical study involving RDEA806 or RDEA594. Known hypersensitivity or allergy to RDEA594 or colchicine or any components in their formulations. Body mass index (BMI) >40 kg/m2. Taking greater than 1000 mg/day of Vitamin C. 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. Inadequate renal function after completing the Double-Blind Treatment period prior to entering Extension Period. Requiring treatment with prohibited medications noted in exclusion criteria numbers 20-23 after completing the Double-Blind Treatment Period prior to entering the Extension Period. Clinically relevant medical event as determined by the investigator in consultation with medical monitor prior to entering the Extension Period.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RDEA594 200 mg qd for 28 days<br> | Drug: RDEA594<br>* Uricosuric agent for the treatment of gout<br>|
| Experimental: RDEA594 200 mg, 400 mg<br>RDEA594 200 mg qd for 7 days followed by 400 mg qd for 21 days | Drug: RDEA594<br>* Uricosuric agent for the treatment of gout<br>|
| Experimental: RDEA594 200 mg, 400 mg and 600 mg<br>RDEA594 200 mg qd for 7 days followed by 400 mg qd for 7 days followed by 600 mg qd for 14 days | Drug: RDEA594<br>* Uricosuric agent for the treatment of gout<br>|
| Placebo Comparator: Matching placebo<br>RDEA594 matching placebo qd for 28 days | Drug: Placebo<br>* Matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the proportion of subjects whose serum urate (sUA) level is < 6.0 mg/dL after 28 days of dosing by treatment group. |  | 28 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the proportion of subjects whose sUA levels are <6.0 mg/dL, <5.0 mg/dL and <4.0 mg/dL at each weekly study visit during the Double-Blind Period. |  | 28 Days | 
| To evaluate the absolute and percent reduction from baseline in sUA levels at each weekly study visit. |  | 28 Days and through extension | 
| To evaluate the percentage change in 24-hour urine urate level (excretion) from baseline to Day 28. |  | 28 Days and through extension | 
| To evaluate the incidence of gout flares. |  | 28 Days and through extension | 
| To evaluate the safety and tolerability of RDEA594 in subjects with gout. |  | 28 Days and through extension | 
| To evaluate the proportion of subjects whose sUA level decreases to or is maintained at <6.0 mg/dL in the Open-Label Extension Period. |  | 18 Months |