Safety and Efficacy Study of PEG-uricase in the Treatment of Hyperuricemic Patients With Symptomatic Gout

Study Overview
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Brief Summary
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These are two replicate studies to evaluate the safety and efficacy of PEG (polyethylene glycol)-uricase in controlling the uric acid level in symptomatic gout patients with high uric acid levels who are unable to take standard gout therapies, or for whom those therapies have been unsuccessful in controlling their uric acid level.

Detailed Description
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The primary objective of each of the studies is to demonstrate superiority in the response rate (control of uric acid levels to below 6 mg/dL) in the PEG-uricase treatment groups compared to the placebo-control group. While reduction or resolution of tophi have been reported in the setting of prolonged urate-lowering therapy, there is photographic and additional anecdotal evidence from the Phase 2 PEG-uricase study of resolution or significant reduction of tophi after 3 months of therapy. Therefore, an assessment of changes in tophi over time will be conducted through the use of digital photographs obtained in a standardized manner from all subjects during the study. The effect on other clinical outcomes, including quality of life, health-related disability measures, gout flares and the number of swollen and tender joints will also be compared between the treatment groups and control group. Subjects will be randomized to one of the three treatment arms in a 2:2:1 ratio: 8 mg PEG-uricase every 2 weeks; 8 mg PEG-uricase every 4 weeks; or placebo. All subjects will receive an intravenous infusion (PEG-uricase or placebo) every two weeks in order to maintain the blind throughout the study. Study duration is approximately 26 weeks, including two weeks for screening and 24 weeks (6 months) of treatment.

Official Title
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Randomized, Multicenter, Double-blind, Placebo-controlled Efficacy and Safety Study of 8 mg PEG-uricase in Two Dose Regimens in Hyperuricemic Subjects With Symptomatic Gout

Conditions
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Gout

Intervention / Treatment
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* Other: placebo
* Biological: pegloticase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Outpatients of either gender, age 18 or older ( no upper age limit). Patient is hyperuricemic: screening serum uric acid must be ≥8 mg/dL. Patient has symptomatic gout (presence of at least 3 gout flares in the 18 months prior to entry, or at least one gout tophus, or gouty arthritis). Conventional therapy is contraindicated or has been ineffective in this patient, i.e., patient has a history (either by medical record or patient interview) of hypersensitivity or of failure to normalize SUA with at least 3 months treatment with allopurinol at the maximum labeled dose (800 mg/dL in the U.S.), or at a medically appropriate lower dose based on dose-limiting toxicity or dose-limiting co-morbidity. Patient is willing and able to give informed consent and adhere to visit/protocol schedules (informed consent must be given before the first study procedure is performed, including washout). If the patient is a woman of childbearing potential, she must have had a negative screening serum pregnancy test and must use a medically approved form of birth control during her participation in the protocol. Such methods include oral, injectable or implantable contraceptives; IUDs and barrier contraceptives in combination with spermicide. (If male or surgically sterile, check N/A.) Exclusion Criteria: The patient has unstable angina. The patient has uncontrolled arrhythmia. The patient has non-compensated congestive heart failure. The patient has uncontrolled hypertension (above 150/95). The patient has a history of end stage renal disease requiring dialysis. The patient has hemoglobin < 8 g/dL (males) or < 7 g/dL (females). The patient is an organ transplant recipient The patient has had prior treatment with PEG-uricase, or other recombinant uricase, or any concomitant therapy with a PEG-conjugated drug. The patient has had a gout flare at screening that is resolved for less than one week prior to first treatment with study drug (exclusive of chronic synovitis/ arthritis). The patient has glucose-6-phosphate dehydrogenase (G6PD) deficiency. The patient has a history of anaphylactic reaction to a recombinant protein or porcine product, or hypersensitivity to PEG. The patient is pregnant or breast feeding. The patient has taken an investigational drug within 4 weeks prior to study drug administration or plans to take an investigational agent during the study. The patient has a known allergy to urate oxidase or PEGylated products. The patient has any other medical or psychological condition which, in the opinion of the investigator, might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements, or to complete the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: q2 wks<br>8 mg pegloticase every 2 weeks | Biological: pegloticase<br>* 8 mg pegloticase by intravenous infusion<br>* Other names: Puricase;|
| Experimental: q4 wks<br>8 mg pegloticase every 4 weeks (alternating with placebo every 4 weeks) | Biological: pegloticase<br>* 8 mg pegloticase by intravenous infusion<br>* Other names: Puricase;|
| Placebo Comparator: placebo<br>placebo every 2 weeks | Other: placebo<br>* placebo by intravenous infusion every 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Uric Acid (PUA) Responder | PUA Responder was defined as a participant who achieved and maintained plasma uric acid concentrations < 6 mg/dL for at least 80% of the time during months 3 and 6 combined. Participants who withdrew from the study before month 6 were considered non-responders. | Months 3 and 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in Tophus Burden | percentage of tophaceous subjects who demonstrated a complete resolution (100 % decrease in measured area or complete disappearance)of at least one tophus in the absence of other tophus progression or new tophi, as assessed by a blinded Central Reader using standardized digital photographs and image analysis software. | Baseline and Final Visit (6 months or LOCF) | 
| Percentage of Subjects With Gout Flare Per 3-month Period | Percent of participants reporting a gout flare during Months 1-3 and Months 4-6. Denominator during the respective period was based upon number of participants during that period. | Months 1-3 and Months 4-6 | 
| Change in Number of Swollen Joints | Change from Baseline to Month 6 (or last observation carried forward)in number of swollen joints per subject. Values were inputed using last observation carried forward analysis for subjects who did not complete the studies. | Baseline and Final Visit (Month 6 or LOCF) | 
| Change in Number of Tender Joints | Change from Baseline to Month 6 (or last observation carried forward) in number of tender joints per participant | Baseline and Final Visit (Month 6 or LOCF) | 
| Change in Patient Reported Outcomes of Pain, Physical Function and Quality of Life | Health Assessment Questionnaire(HAQ: VAS pain scale where 0 (no pain)-100 (severe pain); HAQ disability index (HAQ-DI) on a scale from 0(no disability) to 3 (completely disabled), and a unit change of > or =0.22 is considerd a mimimal clinically important difference(MCID). SF-36 Physical Component Summary Score (SF36-PCS), a composite score where 0 is the worst score and 100 the best possible, and where a change of > or =2.5 units in the PCS is considered a MCID. | Baseline to Final Visit (Month 6 or LOCF) |