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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

Tracking Information
First Submitted Date  ICMJE May 24, 2005
First Posted Date  ICMJE May 25, 2005
Results First Submitted Date December 12, 2012
Results First Posted Date January 18, 2013
Last Update Posted Date October 3, 2014
Study Start Date  ICMJE December 2004
Actual Primary Completion Date July 2009   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 12, 2012)
Reduction in Plasma Uric Acid to Less Than 6 mg/dL. [ Time Frame: Baseline to Day 105 ]
Original Primary Outcome Measures  ICMJE
 (submitted: June 23, 2005)
  • Reduction in plasma uric acid to less than 6 mg/dL
  • Reduction of the ratio of uric acid:creatinine in urine
  • Development of antibodies to PEG-uricase
  • Pharmacokinetics of PEG-uricase
Change History Complete list of historical versions of study NCT00111657 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 24, 2014)
  • Clinical Response: Number of Swollen and Tender Joints [ Time Frame: Basline and day 134 ]
    Count of tenderness and swelling of 68 joints
  • 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 ]
  • Reduction of the Ratio of Uric Acid:Creatinine in Urine [ Time Frame: baseline then weekly ]
  • 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
  • Infusion 1: Maximum Concentration (Cmax) Value [ Time Frame: 2 hours ]
    The highest drug concentration in the blood after the first infusion of study drug.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 23, 2005)
  • Clinical Response Will be Evaluated, Including the Frequency of Gout Flares, Number and Distribution of Swollen/Tender Joints, Change in Size of Tophi, Change in Functional Status
  • 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.
Current Other Outcome Measures  ICMJE Not Provided
Original Other Outcome Measures  ICMJE Not Provided
Descriptive Information
Brief Title  ICMJE Pegylated Recombinant Mammalian Uricase (PEG-uricase) as Treatment for Refractory Gout
Official Title  ICMJE A Phase II Multidose Study of Intravenous PEG-uricase in Patients With Refractory Gout
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

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.

Study Type  ICMJE Interventional
Study Phase Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Gout
Intervention  ICMJE 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
Study Arms 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.

Intervention: Biological: Pegloticase
Publications *

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 23, 2005)
Original Enrollment  ICMJE Same as current
Actual Study Completion Date July 2009
Actual Primary Completion Date July 2009   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sexes Eligible for Study: All
Ages 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00111657
Other Study ID Numbers  ICMJE Pro00006845
FD-R-0002537 ( Other Identifier: FDA OOPD )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Responsible Party John Sundy, Duke University
Study Sponsor  ICMJE John Sundy
Collaborators  ICMJE Savient Pharmaceuticals
Investigators  ICMJE
Principal Investigator: John S. Sundy, MD, PhD Duke University
PRS Account Duke University
Verification Date September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP