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

September 24, 2014 updated by: John Sundy

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

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Actual)

30

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • North Carolina
      • Durham, North Carolina, United States, 27710
        • Duke University Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Clinical Response: Number of Swollen and Tender Joints
Time Frame: Basline and day 134
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.
Time Frame: baseline and 7 weeks after last infusion
baseline and 7 weeks after last infusion
Reduction of the Ratio of Uric Acid:Creatinine in Urine
Time Frame: baseline then weekly
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
baseline, then prior to infusions and 7 wks after last infusion
Infusion 1: Maximum Concentration (Cmax) Value
Time Frame: 2 hours
The highest drug concentration in the blood after the first infusion of study drug.
2 hours
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.
21 days after the infusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

John Sundy

Collaborators

Savient Pharmaceuticals

Investigators

  • Principal Investigator: John S. Sundy, MD, PhD, Duke University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

December 1, 2004

Primary Completion (Actual)

July 1, 2009

Study Completion (Actual)

July 1, 2009

Study Registration Dates

First Submitted

May 24, 2005

First Submitted That Met QC Criteria

May 24, 2005

First Posted (Estimate)

May 25, 2005

Study Record Updates

Last Update Posted (Estimate)

October 3, 2014

Last Update Submitted That Met QC Criteria

September 24, 2014

Last Verified

September 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Pro00006845
  • FD-R-0002537 (Other Identifier: FDA OOPD)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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