GoutPhase 2NCT00111657
Pegylated Recombinant Mammalian Uricase (PEG-uricase) as Treatment for Refractory Gout
A Phase 2 study testing Pegloticase in people with Gout, run by John Sundy at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Gout
- What is being tested?
- Pegloticase
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 30 participants
- Where
- 1 siteUnited States
- Study dates
- Dec 2004to Jul 2009
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Duke University Medical Center
Durham, North Carolina, 27710
About this study
Official title: 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
Read the 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.
- Conditions
- Gout
- Being tested
- Pegloticase
- Keywords
- Gout, Tophi, Tophaceous gout, Allergy to allopurinol, Post-transplant gout
- Medical subject headings
- Gout
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PegloticaseBiological
Also called PEG-uricase, PEGylated recombinant mammalian urate oxidase
8 mg of Pegloticase administered IV every 3 weeks; total number of infusions is 5
| Study group | Role | What they receive |
|---|---|---|
| pegloticase | Experimental | 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. Receives: Biological: Pegloticase |
What is being measured
The primary outcome is the main question the study is designed to answer.
Reduction in Plasma Uric Acid to Less Than 6 mg/dL.
Measured: Baseline to Day 105
Secondary outcomes (6)
Clinical Response: Number of Swollen and Tender Joints
Count of tenderness and swelling of 68 joints
Measured: 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.
Measured: baseline and 7 weeks after last infusion
Reduction of the Ratio of Uric Acid:Creatinine in Urine
Measured: baseline then weekly
Development of Antibodies to PEG-uricase
Number of patients who developed antibodies to PEG-uricase
Measured: 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.
Measured: 2 hours
Infusion 1: Minimum Concentration (Cmin)
The lowest drug concentration in the blood after the first infusion of study drug.
Measured: 21 days after the infusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 May 2005 (estimated)
- Study startDec 2004
- Primary completionJul 2009
- Study completionJul 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for GoutStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 30 participants (actual)
Sponsor and investigators
- Lead sponsor
- John Sundy
- Sponsor type
- University, hospital or other
- Collaborators
- Savient Pharmaceuticals
- Responsible party
- Sponsor-investigator, John Sundy, Duke University
- Investigators
- John S. Sundy, MD, PhD, Principal investigator, Duke University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00111657
- Sponsor's protocol ID
- Pro00006845
- Other IDs
- FD-R-0002537
- Status last verified
- Sep 2014
- First submitted
- 24 May 2005
- Last updated
- 3 Oct 2014
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Kelly SJ, Delnomdedieu M, Oliverio MI, Williams LD, Saifer MGP, Sherman MR, Coffman TM, Johnson GA, Hershfield MS. Diabetes insipidus in uricase-deficient mice: a model for evaluating therapy with poly(ethylene glycol)-modified uricase. J Am Soc Nephrol. 2001 May;12(5):1001-1009. doi: 10.1681/ASN.V1251001.
PubMed 11316859Sundy JS, Ganson N, Kelly SJ, Scarlett EL, Hershfield MS. A Phase I Study of PEGylated Uricase (Puricase®) in Subjects with Gout. Arthritis Rheum 50(9):S337-S338. 2004
Ganson NJ, Kelly SJ, Scarlett E, Sundy JS, Hershfield MS. Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase. Arthritis Res Ther. 2006;8(1):R12. doi: 10.1186/ar1861.
PubMed 16356199Hershfield MS, Roberts LJ 2nd, Ganson NJ, Kelly SJ, Santisteban I, Scarlett E, Jaggers D, Sundy JS. Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo. Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14351-6. doi: 10.1073/pnas.1001072107. Epub 2010 Jul 26.
PubMed 20660758Hershfield MS, Ganson NJ, Kelly SJ, Scarlett EL, Jaggers DA, Sundy JS. Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients. Arthritis Res Ther. 2014 Mar 7;16(2):R63. doi: 10.1186/ar4500.
PubMed 24602182
Study at a glance
From the registry record, last updated by the sponsor on 3 Oct 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Multidose Study of Intravenous PEG-uricase in Patients With Refractory Gout
- ClinicalTrials.gov ID
- NCT00111657
- Acronym / sponsor ID
- Pro00006845
- Conditions
- Gout
- Keywords
- Gout, Tophi, Tophaceous gout, Allergy to allopurinol, Post-transplant gout
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 30 participants (actual)
- Lead sponsor
- John SundyUniversity, hospital or other
- Collaborators
- Savient Pharmaceuticals
- Study start
- Dec 2004
- Primary completion
- Jul 2009 (actual)
- Study completion
- Jul 2009 (actual)
- First posted
- 25 May 2005 (estimated)
- Results
- Posted 18 Jan 2013
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| pegloticase | Experimental | Biological: PegloticaseAll 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (6 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PegloticaseAlso: PEG-uricase, PEGylated recombinant mammalian urate oxidase8 mg of Pegloticase administered IV every 3 weeks; total number of infusions is 5 | Biological | pegloticase |
Primary outcome
Reduction in Plasma Uric Acid to Less Than 6 mg/dL.
Time frame: Baseline to Day 105
6 secondary outcomes
Clinical Response: Number of Swollen and Tender Joints
Time frame: 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
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
Infusion 1: Maximum Concentration (Cmax) Value
Time frame: 2 hours
Infusion 1: Minimum Concentration (Cmin)
Time frame: 21 days after the infusion
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Oct 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 11316859Kelly SJ, Delnomdedieu M, Oliverio MI, Williams LD, Saifer MGP, Sherman MR, Coffman TM, Johnson GA, Hershfield MS. Diabetes insipidus in uricase-deficient mice: a model for evaluating therapy with poly(ethylene glycol)-modified uricase. J Am Soc Nephrol. 2001 May;12(5):1001-1009. doi: 10.1681/ASN.V1251001.
- BackgroundSundy JS, Ganson N, Kelly SJ, Scarlett EL, Hershfield MS. A Phase I Study of PEGylated Uricase (Puricase®) in Subjects with Gout. Arthritis Rheum 50(9):S337-S338. 2004
- Background: PubMed 16356199Ganson NJ, Kelly SJ, Scarlett E, Sundy JS, Hershfield MS. Control of hyperuricemia in subjects with refractory gout, and induction of antibody against poly(ethylene glycol) (PEG), in a phase I trial of subcutaneous PEGylated urate oxidase. Arthritis Res Ther. 2006;8(1):R12. doi: 10.1186/ar1861.
- Results publication: PubMed 20660758Hershfield MS, Roberts LJ 2nd, Ganson NJ, Kelly SJ, Santisteban I, Scarlett E, Jaggers D, Sundy JS. Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo. Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14351-6. doi: 10.1073/pnas.1001072107. Epub 2010 Jul 26.
- Derived from this study: PubMed 24602182Hershfield MS, Ganson NJ, Kelly SJ, Scarlett EL, Jaggers DA, Sundy JS. Induced and pre-existing anti-polyethylene glycol antibody in a trial of every 3-week dosing of pegloticase for refractory gout, including in organ transplant recipients. Arthritis Res Ther. 2014 Mar 7;16(2):R63. doi: 10.1186/ar4500.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
John S. Sundy, MD, PhD principal investigator
Duke University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Pegloticase in people with Gout, run by John Sundy at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Oct 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 18 Jan 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Reduction in Plasma Uric Acid to Less Than 6 mg/dL. (time frame: Baseline to Day 105). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00111657, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Oct 2014.