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| ID | Type | Description | Link |
|---|---|---|---|
| FD-R-0002537 | Other Identifier | FDA OOPD |
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| Name | Class |
|---|---|
| Savient Pharmaceuticals | INDUSTRY |
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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
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pegloticase | Biological | 8 mg of Pegloticase administered IV every 3 weeks; total number of infusions is 5 |
|
| Measure | Description | Time Frame |
|---|---|---|
| Reduction in Plasma Uric Acid to Less Than 6 mg/dL. | Baseline to Day 105 |
| 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| John S. Sundy, MD, PhD | Duke University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Duke University Medical Center | Durham | North Carolina | 27710 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 11316859 | Background | 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. | |
| Background | Sundy 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 | ||
| 16356199 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Single Arm - Pegloticase |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Single Arm - Pegloticase |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Reduction in Plasma Uric Acid to Less Than 6 mg/dL. | Number | Participants | Baseline to Day 105 |
|
|
Day 134
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Single Arm - Pegloticase |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Gastrointestinal bleeding. | Gastrointestinal disorders | Physician defined. | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypertension | Cardiac disorders | Physician defined. | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| John S. Sundy, MD, PhD | Duke University Medical Center | 919-684-2347 | john.sundy@duke.edu |
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| ID | Term |
|---|---|
| D006073 | Gout |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D000070657 | Crystal Arthropathies |
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| ID | Term |
|---|---|
| C031545 | Pegloticase |
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| 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 |
| Background |
| 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. |
| 20660758 | Result | Hershfield 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. |
| 24602182 | Derived | Hershfield 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. |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Baseline urate concentration (pUA) | Mean | Standard Deviation | mg/dL |
|
|
| Secondary | Clinical Response: Number of Swollen and Tender Joints | Count of tenderness and swelling of 68 joints | 30 subject assesed at baseline. 21 subjects who completed study were assesed at day 134 | Median | Inter-Quartile Range | joints | Basline and day 134 |
|
|
|
| Secondary | 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. | Data was not collected for this outcome as a result of a separate pilot study demonstrating that the measure was not useful. | baseline and 7 weeks after last infusion |
|
|
| Secondary | Reduction of the Ratio of Uric Acid:Creatinine in Urine | These data were not calculated because the effect size of serum irate reduction in plasma was so robust that there was no utility in this assessment. | baseline then weekly |
|
|
| Secondary | Development of Antibodies to PEG-uricase | Number of patients who developed antibodies to PEG-uricase | One subject withdrew prior to completing the first infusion and is not included in this analysis. | Number | participants | baseline, then prior to infusions and 7 wks after last infusion |
|
|
|
| Secondary | Infusion 1: Maximum Concentration (Cmax) Value | The highest drug concentration in the blood after the first infusion of study drug. | One subject withdrew prior to completing the first infusion and is not included in this analysis. | Mean | Standard Deviation | mU/mL | 2 hours |
|
|
|
| Secondary | Infusion 1: Minimum Concentration (Cmin) | The lowest drug concentration in the blood after the first infusion of study drug. | One subject withdrew prior to completing the first infusion and is not included in this analysis. | Mean | Standard Deviation | mU/mL | 21 days after the infusion |
|
|
|
| 4 |
| 30 |
| 30 |
| 30 |
| Bowel perforation. | Gastrointestinal disorders | Physician defined. | Non-systematic Assessment |
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| Death | Cardiac disorders | Physician defined. | Non-systematic Assessment |
|
| Hyperglycemia | Endocrine disorders | Physician defined. | Non-systematic Assessment |
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| Hypotension | Cardiac disorders | Physician defined. | Non-systematic Assessment |
|
| Abdominal cramping | Gastrointestinal disorders | Physician defined. | Non-systematic Assessment |
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| Diarrhea | Gastrointestinal disorders | Physician defined. | Non-systematic Assessment |
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| Duodenal ulcer | Gastrointestinal disorders | Physician defined. | Non-systematic Assessment |
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| Heartburn | Gastrointestinal disorders | Physician defined. | Non-systematic Assessment |
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| Nausea | Gastrointestinal disorders | Physician defined. | Non-systematic Assessment |
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| Indigestion | Gastrointestinal disorders | Physician defined. | Non-systematic Assessment |
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| Chills | General disorders | Physician defined. | Non-systematic Assessment |
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| Fever | General disorders | Physician defined. | Non-systematic Assessment |
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| Lightheadedness | General disorders | Physician defined. | Non-systematic Assessment |
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| Urinary hesitancy | Renal and urinary disorders | Physician defined. | Non-systematic Assessment |
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| Toothache | Gastrointestinal disorders | Physician defined. | Non-systematic Assessment |
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| Gastroenteritis | Infections and infestations | Physician defined. | Non-systematic Assessment |
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| Infected tophus | Infections and infestations | Physician defined. | Non-systematic Assessment |
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| Rectal abscess | Infections and infestations | Physician defined. | Non-systematic Assessment |
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| Skin abscess | Infections and infestations | Physician defined. | Non-systematic Assessment |
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| Thrush | Infections and infestations | Physician defined. | Non-systematic Assessment |
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| Upper respiratory infection | Infections and infestations | Physician defined. | Non-systematic Assessment |
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| Tooth abscess | Infections and infestations | Physician defined. | Non-systematic Assessment |
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| Urinary tract infection | Infections and infestations | Physician defined. | Non-systematic Assessment |
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| Anemia | Blood and lymphatic system disorders | Physician defined. | Non-systematic Assessment |
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| Hyperkalemia | Endocrine disorders | Physician defined. | Non-systematic Assessment |
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| Arthralgia | Musculoskeletal and connective tissue disorders | Physician defined. | Non-systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | Physician defined. | Non-systematic Assessment |
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| Bursitis | Musculoskeletal and connective tissue disorders | Physician defined. | Non-systematic Assessment |
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| Charcot joint | Musculoskeletal and connective tissue disorders | Physician defined. | Non-systematic Assessment |
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| Draining tophus | Musculoskeletal and connective tissue disorders | Physician defined. | Non-systematic Assessment |
|
| Gout flare | Musculoskeletal and connective tissue disorders | Physician defined. | Non-systematic Assessment |
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| Joint stiffness | Musculoskeletal and connective tissue disorders | Physician defined. | Non-systematic Assessment |
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| Pain in limb | Musculoskeletal and connective tissue disorders | Physician defined. | Non-systematic Assessment |
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| Headache | Nervous system disorders | Physician defined. | Non-systematic Assessment |
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| Parasthesia | Nervous system disorders | Physician defined. | Non-systematic Assessment |
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| Tremor | Nervous system disorders | Physician defined. | Non-systematic Assessment |
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| Blurred vision | Eye disorders | Physician defined. | Non-systematic Assessment |
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| Conjunctival injection | Eye disorders | Physician defined. | Non-systematic Assessment |
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| Confusion | Psychiatric disorders | Physician defined. | Non-systematic Assessment |
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| Decreased libido | Psychiatric disorders | Physician defined. | Non-systematic Assessment |
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| Excessive sleepiness | Psychiatric disorders | Physician defined. | Non-systematic Assessment |
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| Hallucinations | Psychiatric disorders | Physician defined. | Non-systematic Assessment |
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| Insomnia | Psychiatric disorders | Physician defined. | Non-systematic Assessment |
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| Labile affect | Psychiatric disorders | Physician defined. | Non-systematic Assessment |
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| Chest pain | Respiratory, thoracic and mediastinal disorders | Physician defined. | Non-systematic Assessment |
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| Chest tightness | Respiratory, thoracic and mediastinal disorders | Physician defined. | Non-systematic Assessment |
|
| Dyspnea | Respiratory, thoracic and mediastinal disorders | Physician defined. | Non-systematic Assessment |
|
| Obstructive sleep apnea | Respiratory, thoracic and mediastinal disorders | Physician defined. | Non-systematic Assessment |
|
| Hypoxemia | Respiratory, thoracic and mediastinal disorders | Physician defined. | Non-systematic Assessment |
|
| Shortness of breath | Respiratory, thoracic and mediastinal disorders | Physician defined. | Non-systematic Assessment |
|
| Acne | Skin and subcutaneous tissue disorders | Physician defined. | Non-systematic Assessment |
|
| Contact dermatitis | Skin and subcutaneous tissue disorders | Physician defined. | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | Physician defined. | Non-systematic Assessment |
|
| Foot ulcer | Skin and subcutaneous tissue disorders | Physician defined. | Non-systematic Assessment |
|
| Hair loss | Skin and subcutaneous tissue disorders | Physician defined. | Non-systematic Assessment |
|
| Leg ulcer | Skin and subcutaneous tissue disorders | Physician defined. | Non-systematic Assessment |
|
| Petechiae | Skin and subcutaneous tissue disorders | Physician defined. | Non-systematic Assessment |
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| Pruritis | Skin and subcutaneous tissue disorders | Physician defined. | Non-systematic Assessment |
|
| Swellng of toes | Skin and subcutaneous tissue disorders | Physician defined. | Non-systematic Assessment |
|
| Urticaria | Skin and subcutaneous tissue disorders | Physician defined. | Non-systematic Assessment |
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| Nevi | Skin and subcutaneous tissue disorders | Physician defined. | Non-systematic Assessment |
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| Seborrheic keratosis | Skin and subcutaneous tissue disorders | Physician defined. | Non-systematic Assessment |
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| Edema | Cardiac disorders | Physician defined. | Non-systematic Assessment |
|
| Hyperglycemia | Endocrine disorders | Physician defined. | Non-systematic Assessment |
|
| Syncope | Cardiac disorders | Physician defined. | Non-systematic Assessment |
|
| Chronic gouty arthritis | Musculoskeletal and connective tissue disorders | Physician defined. | Non-systematic Assessment |
|
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| D012216 |
| Rheumatic Diseases |
| D011686 | Purine-Pyrimidine Metabolism, Inborn Errors |
| D008661 | Metabolism, Inborn Errors |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
|
| Number of Swollen jonts at day 134 |
|