Working… Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00111657
Recruitment Status : Completed
First Posted : May 25, 2005
Results First Posted : January 18, 2013
Last Update Posted : October 3, 2014
Savient Pharmaceuticals
Information provided by (Responsible Party):
John Sundy, Duke University

Brief Summary:

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

Condition or disease Intervention/treatment Phase
Gout Biological: Pegloticase Phase 2

Detailed Description:

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.

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 30 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Multidose Study of Intravenous PEG-uricase in Patients With Refractory Gout
Study Start Date : December 2004
Actual Primary Completion Date : July 2009
Actual Study Completion Date : July 2009

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Gout
MedlinePlus related topics: Gout
Drug Information available for: Pegloticase

Arm Intervention/treatment
Experimental: pegloticase

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
8 mg of Pegloticase administered IV every 3 weeks; total number of infusions is 5
Other Names:
  • PEG-uricase
  • PEGylated recombinant mammalian urate oxidase

Primary Outcome Measures :
  1. Reduction in Plasma Uric Acid to Less Than 6 mg/dL. [ Time Frame: Baseline to Day 105 ]

Secondary Outcome Measures :
  1. Clinical Response: Number of Swollen and Tender Joints [ Time Frame: Basline and day 134 ]
    Count of tenderness and swelling of 68 joints

  2. 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. [ Time Frame: baseline and 7 weeks after last infusion ]
  3. Reduction of the Ratio of Uric Acid:Creatinine in Urine [ Time Frame: baseline then weekly ]
  4. Development of Antibodies to PEG-uricase [ Time Frame: baseline, then prior to infusions and 7 wks after last infusion ]
    Number of patients who developed antibodies to PEG-uricase

  5. Infusion 1: Maximum Concentration (Cmax) Value [ Time Frame: 2 hours ]
    The highest drug concentration in the blood after the first infusion of study drug.

  6. Infusion 1: Minimum Concentration (Cmin) [ Time Frame: 21 days after the infusion ]
    The lowest drug concentration in the blood after the first infusion of study drug.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00111657

Layout table for location information
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
John Sundy
Savient Pharmaceuticals
Layout table for investigator information
Principal Investigator: John S. Sundy, MD, PhD Duke University
Publications of Results:
Other Publications:
Publications automatically indexed to this study by Identifier (NCT Number):
Layout table for additonal information
Responsible Party: John Sundy, Associate Professor of Medicine, Duke University Identifier: NCT00111657    
Other Study ID Numbers: Pro00006845
FD-R-0002537 ( Other Identifier: FDA OOPD )
First Posted: May 25, 2005    Key Record Dates
Results First Posted: January 18, 2013
Last Update Posted: October 3, 2014
Last Verified: September 2014
Keywords provided by John Sundy, Duke University:
Tophaceous gout
Allergy to allopurinol
Post-transplant gout
Additional relevant MeSH terms:
Layout table for MeSH terms
Joint Diseases
Musculoskeletal Diseases
Crystal Arthropathies
Rheumatic Diseases
Purine-Pyrimidine Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Gout Suppressants
Antirheumatic Agents