Clinical trial NCT00325195: Safety and Efficacy Study of PEG-uricase in the Treatment of Hyperuricemic Patients With Symptomatic Gout
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Gout
Lead sponsor: Savient Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2006-05-12
Enrollment: 225
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Outpatients of either gender, age 18 or older ( no upper age limit).
2. Patient is hyperuricemic: screening serum uric acid must be ≥8 mg/dL.
3. 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).
4. 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.
5. 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).
6. 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:

1. The patient has unstable angina.
2. The patient has uncontrolled arrhythmia.
3. The patient has non-compensated congestive heart failure.
4. The patient has uncontrolled hypertension (above 150/95).
5. The patient has a history of end stage renal disease requiring dialysis.
6. The patient has hemoglobin \< 8 g/dL (males) or \< 7 g/dL (females).
7. The patient is an organ transplant recipient
8. The patient has had prior treatment with PEG-uricase, or other recombinant uricase, or any concomitant therapy with a PEG-conjugated drug.
9. 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).
10. The patient has glucose-6-phosphate dehydrogenase (G6PD) deficiency.
11. The patient has a history of anaphylactic reaction to a recombinant protein or porcine product, or hypersensitivity to PEG.
12. The patient is pregnant or breast feeding.
13. 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.
14. The patient has a known allergy to urate oxidase or PEGylated products.
15. 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.

Primary outcomes:
measure: Plasma Uric Acid (PUA) Responder
timeFrame: Months 3 and 6
Secondary outcomes:
measure: Reduction in Tophus Burden
timeFrame: Baseline and Final Visit (6 months or LOCF)
measure: Percentage of Subjects With Gout Flare Per 3-month Period
timeFrame: Months 1-3 and Months 4-6
measure: Change in Number of Swollen Joints
timeFrame: Baseline and Final Visit (Month 6 or LOCF)
measure: Change in Number of Tender Joints
timeFrame: Baseline and Final Visit (Month 6 or LOCF)
measure: Change in Patient Reported Outcomes of Pain, Physical Function and Quality of Life
timeFrame: Baseline to Final Visit (Month 6 or LOCF)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: UAB Arthritis Clinical Intervention Program
state: Alabama
city: Tucson
country: United States
facility: University of Arizona Arthritis Center
state: Arizona
city: Jonesboro
country: United States
facility: NEA Clinic
state: Arkansas
city: La Jolla
country: United States
facility: UCSD Rheumatology Division
state: California
city: San Francisco
country: United States
facility: Kaiser Permanente Medical Center, Clinical Trials Unit
state: California
city: Santa Maria
country: United States
facility: Pacific Arthritis Center Medical Group
state: California
city: Whittier
country: United States
facility: E. Robert Harris Medical Corporation
state: California
city: Whittier
country: United States
facility: Agilence Arthritis & Osteoporosis Medical Center
state: California
city: Colorado Springs
country: United States
facility: Arthritis Associates & Osteoporosis Center of Colorado Springs
state: Colorado
city: Washington
country: United States
facility: Veterans Affairs Medical Center
state: District of Columbia
city: Aventura
country: United States
facility: Arthritis & Rheumatic Disease Specialties
state: Florida
city: Gainesville
country: United States
facility: Malcom Randall VA Medical Center
state: Florida
city: Hollywood
country: United States
facility: Horizon Institute for Clinical Research
state: Florida
city: Ocala
country: United States
facility: Ocala Rheumatology Research Center
state: Florida
city: Orange Park
country: United States
facility: Arthritis & Osteoporosis Treatment Center, PA
state: Florida
city: St. Petersburg
country: United States
facility: St. Petersburg Arthritis Center
state: Florida
city: Boise
country: United States
facility: Idaho Arthritis & Osteoporosis Center
state: Idaho
city: Idaho Falls
country: United States
facility: Institute of Arthritis Research
state: Idaho
city: Chicago
country: United States
facility: The University of Chicago
state: Illinois
city: Bowling Green
country: United States
facility: Graves Gilbert Clinic
state: Kentucky
city: Baltimore
country: United States
facility: Peter A. Holt, M.D.
state: Maryland
city: Hagerstown
country: United States
facility: Malamet & Klein, MD, PA
state: Maryland
city: Wheaton
country: United States
facility: The Center for Rheumatology and Bone Research
state: Maryland
city: Worcester
country: United States
facility: Fallon Clinic, Inc
state: Massachusetts
city: Brighton
country: United States
facility: Michigan Arthritis Research Center
state: Michigan
city: Lansing
country: United States
facility: Justus J. Fiechtner, MD, PC
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: St. Cloud
country: United States
facility: CentraCare Clinic
state: Minnesota
city: Teaneck
country: United States
facility: Rheumatology Associates of North Jersey
state: New Jersey
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Greenville
country: United States
facility: Brody School of Medicine, East Carolina University
state: North Carolina
city: Greenville
country: United States
facility: Physicians East, P.A.
state: North Carolina
city: Wilmington
country: United States
facility: Carolina Atthritis Associates
state: North Carolina
city: Cincinnati
country: United States
facility: New Horizons Clinical Research
state: Ohio
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Dayton
country: United States
facility: STAT Research, Inc.
state: Ohio
city: Mayfield Village
country: United States
facility: David R. Mandel, MD, Inc.
state: Ohio
city: Oklahoma City
country: United States
facility: Health Research of Oklahoma
state: Oklahoma
city: Portland
country: United States
facility: Portland Medical Associates
state: Oregon
city: Duncansville
country: United States
facility: Altoona Center for Clinical Research
state: Pennsylvania
city: Philadelphia
country: United States
facility: Mid Atlantic Research Assoc.
state: Pennsylvania
city: Charleston
country: United States
facility: Rheumatology Associates
state: South Carolina
city: Greenville
country: United States
facility: Piedmont Arthritis, PA
state: South Carolina
city: Amarillo
country: United States
facility: AAMR Research Clinic
state: Texas
city: San Antonio
country: United States
facility: Arthritis & Osteoporosis Center of South Texas
state: Texas
city: Waco
country: United States
facility: Arthritis & Osteoporosis Clinic Research Center of Central Texas
state: Texas
city: Spokane
country: United States
facility: Arthritis Northwest, PLLC
state: Washington
city: Glendale
country: United States
facility: Rheumatic Disease Center
state: Wisconsin
city: Winnipeg
country: Canada
facility: Manitoba Clinic
state: Manitoba
city: London
country: Canada
facility: St. Joseph's Health Care
state: Ontario
city: Mexico
country: Mexico
facility: Clinica para el Diagnostico y Tratamiento de las Enfermedades Rheumaticas
state: D.f.
city: Mexico
country: Mexico
facility: Hospital General de mexico
state: D.f.
city: Guadalajara
country: Mexico
facility: Antiguo Hospital Civil de Guadalajara
state: Jalisco
city: Guadalajara
country: Mexico
facility: Hospital Civil de Guadalajara
state: Jalisco
Study officials:
affiliation: Savient Pharmaceuticals, Inc.
name: Medical Director, MD
role: STUDY_DIRECTOR
References:
citation: Pillinger MH, Fields TR, Yeo AE, Lipsky PE. Dissociation Between Clinical Benefit and Persistent Urate Lowering in Patients with Chronic Refractory Gout Treated with Pegloticase. J Rheumatol. 2020 Apr;47(4):605-612. doi: 10.3899/jrheum.190161. Epub 2019 Jun 15.
citation: Johnson RJ, Choi HK, Yeo AE, Lipsky PE. Pegloticase Treatment Significantly Decreases Blood Pressure in Patients With Chronic Gout. Hypertension. 2019 Jul;74(1):95-101. doi: 10.1161/HYPERTENSIONAHA.119.12727. Epub 2019 May 13.
citation: Lipsky PE, Calabrese LH, Kavanaugh A, Sundy JS, Wright D, Wolfson M, Becker MA. Pegloticase immunogenicity: the relationship between efficacy and antibody development in patients treated for refractory chronic gout. Arthritis Res Ther. 2014 Mar 4;16(2):R60. doi: 10.1186/ar4497.
citation: Yood RA, Ottery FD, Irish W, Wolfson M. Effect of pegloticase on renal function in patients with chronic kidney disease: a post hoc subgroup analysis of 2 randomized, placebo-controlled, phase 3 clinical trials. BMC Res Notes. 2014 Jan 21;7:54. doi: 10.1186/1756-0500-7-54.
citation: Baraf HS, Becker MA, Gutierrez-Urena SR, Treadwell EL, Vazquez-Mellado J, Rehrig CD, Ottery FD, Sundy JS, Yood RA. Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy. Arthritis Res Ther. 2013 Sep 26;15(5):R137. doi: 10.1186/ar4318.
citation: Sundy JS, Baraf HS, Yood RA, Edwards NL, Gutierrez-Urena SR, Treadwell EL, Vazquez-Mellado J, White WB, Lipsky PE, Horowitz Z, Huang W, Maroli AN, Waltrip RW 2nd, Hamburger SA, Becker MA. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011 Aug 17;306(7):711-20. doi: 10.1001/jama.2011.1169.