Pegylated Recombinant Mammalian Uricase (PEG-uricase) as Treatment for Refractory Gout

Study Overview
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Brief Summary
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The purpose of this study is to determine whether PEG-uricase (a chemically modified recombinant mammalian enzyme that degrades uric acid) is effective in controlling hyperuricemia in patients with chronic gout, who cannot tolerate, or have not responded adequately, to conventional therapy for gout. Funding Source - FDA OOPD

Detailed Description
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Inflammatory arthritis in patients with gout is caused by crystals of monosodium urate (MSU) that form as a result of chronically elevated levels of uric acid in plasma and extracellular fluids. Recurrent attacks can usually be prevented by treatment with drugs that block urate synthesis by inhibiting xanthine oxidase, or that promote uric acid excretion. If for various reasons (noncompliance, drug intolerance, inadequate dosage, or inefficacy) therapy fails to maintain serum urate concentration below about 6 mg/dL, gout can progress to a chronic stage characterized by destructive arthropathy, deposition of urate crystals in soft tissues (tophi), and nephropathy. The management of chronic gout in such patients is often complicated by co-morbidities such as hypertension, heart disease, diabetes, and renal insufficiency, which may limit the use of anti-inflammatory agents to treat arthritis. Urate levels are low and gout does not occur in species that express the enzyme urate oxidase (uricase), which converts urate to the more soluble and easily excreted compound allantoin. Humans do not express this enzyme owing to a mutation of the uricase gene during evolution. Parenteral uricase is thus a potential means of controlling hyperuricemia and depleting urate stores in patients with chronic, refractory gout. Infusion of recombinant fungal uricase is effective in preventing acute uric acid nephropathy due to tumor lysis in patients with malignancies. However, the short circulating life and potential immunogenicity of fungal uricase prevents its chronic use for treating gout. PEG-uricase is a recombinant porcine urate oxidase to which multiple strands of polyethylene glycol (PEG) of average molecular weight 10,000 have been attached. PEGylation is intended to reduce the immunogenicity of uricase, and greatly prolong its circulating life. This mammalian PEG-uricase was non-immunogenic and effective in preventing uric acid nephropathy in a uricase-deficient strain of mice (Kelly et al, J Am Soc Nephrol 12:1001-09, 2001). It has been licensed to Savient Pharmaceuticals for clinical development, and has received Orphan Drug designation for the treatment of refractory gout by the FDA Office of Orphan Product Development. In a Phase I trial sponsored by Savient Pharmaceuticals in 24 subjects with symptomatic gout, single intravenous (IV) infusions of 0.5 to 12 mg of PEG-uricase were well tolerated, and at doses of 4 mg to 12 mg, were effective in normalizing plasma and urinary uric acid levels over a 21-day period post-infusion. Some subjects in this trial developed antibodies to PEG-uricase, but the only serious adverse events observed were attacks of gout. The present Phase II clinical trial in subjects with refractory gout will evaluate the efficacy, safety, and immunogenicity of PEG-uricase when administered at a dose of 8 mg by IV infusion once every 3 weeks, for a total of 5 infusions. The primary measure of efficacy will be a reduction in plasma uric acid to less than 6 mg/dL, and reduction in the ratio of uric acid to creatinine in urine to <0.2. In addition, the ability of PEG-uricase to lower the total uric acid pool size will be evaluated in a subset of treatment subjects. Uric acid pool size will be measured by a method that involves an infusion of uric acid labeled with N15, a stable (non-radioactive) isotope of nitrogen.

Official Title
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A Phase II Multidose Study of Intravenous PEG-uricase in Patients With Refractory Gout

Conditions
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Gout

Intervention / Treatment
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* Biological: Pegloticase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years Symptomatic gout Serum uric acid >7 mg/dL Intolerance of, or inadequate response to, conventional therapy for gout Women of childbearing potential must have a negative serum pregnancy test and must use an approved birth control method Exclusion Criteria: End stage renal failure that requires dialysis Concurrent use of uric-acid lowering agents Glucose-6-phosphate dehydrogenase (G6PD) deficiency A history of anaphylactic reaction to a recombinant protein Concurrent use of immunosuppressive therapy (except as needed for prevention of rejection of a transplanted organ, or prednisone at 10 mg a day or less for treatment of gout flares) A medical or psychological condition which, in the opinion of the investigator, might create undue risk to the subject

Ages Eligible for Study
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Minimum Age: 18 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: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: pegloticase<br>All study participants received intravenous pegloticase at dose of 8 mg, administered every 21 days for a maximum of 5 doses. There was no control group for this open label study. | Biological: Pegloticase<br>* 8 mg of Pegloticase administered IV every 3 weeks; total number of infusions is 5<br>* Other names: PEGylated recombinant mammalian urate oxidase;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in Plasma Uric Acid to Less Than 6 mg/dL. |  | Baseline to Day 105 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Response: Number of Swollen and Tender Joints | Count of tenderness and swelling of 68 joints | Basline and day 134 | 
| In a Subset of Subjects Who Volunteer Separately, Change in Uric Acid Pool Size Will be Assessed by a Method That Involves Infusion of Uric Acid Labeled With N15, a Stable (Nonradioactive) Isotope of Nitrogen. |  | baseline and 7 weeks after last infusion | 
| Reduction of the Ratio of Uric Acid:Creatinine in Urine |  | baseline then weekly | 
| Development of Antibodies to PEG-uricase | Number of patients who developed antibodies to PEG-uricase | baseline, then prior to infusions and 7 wks after last infusion | 
| Infusion 1: Maximum Concentration (Cmax) Value | The highest drug concentration in the blood after the first infusion of study drug. | 2 hours | 
| Infusion 1: Minimum Concentration (Cmin) | The lowest drug concentration in the blood after the first infusion of study drug. | 21 days after the infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gout, Tophi, Tophaceous gout, Allergy to allopurinol, Post-transplant gout