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

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

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.

Study Overview

• Status: Completed
• Conditions: Gout
• Intervention / Treatment: Biological: pegloticase; Other: placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 225
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1M3
      • Manitoba Clinic
  • Ontario
    • London, Ontario, Canada, N6A 4V2
      • St. Joseph's Health Care
• Mexico
  • D.f.
    • Mexico, D.f., Mexico
      • Clinica para el Diagnostico y Tratamiento de las Enfermedades Rheumaticas
    • Mexico, D.f., Mexico
      • Hospital General de Mexico
  • Jalisco
    • Guadalajara, Jalisco, Mexico
      • Antiguo Hospital Civil de Guadalajara
    • Guadalajara, Jalisco, Mexico
      • Hospital Civil de Guadalajara
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • UAB Arthritis Clinical Intervention Program
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona Arthritis Center
  • Arkansas
    • Jonesboro, Arkansas, United States, 72401
      • NEA Clinic
  • California
    • La Jolla, California, United States, 92037-0943
      • UCSD Rheumatology Division
    • San Francisco, California, United States, 94118
      • Kaiser Permanente Medical Center, Clinical Trials Unit
    • Santa Maria, California, United States, 93454
      • Pacific Arthritis Center Medical Group
    • Whittier, California, United States, 90601
      • E. Robert Harris Medical Corporation
    • Whittier, California, United States, 90606
      • Agilence Arthritis & Osteoporosis Medical Center
  • Colorado
    • Colorado Springs, Colorado, United States, 80910
      • Arthritis Associates & Osteoporosis Center of Colorado Springs
  • District of Columbia
    • Washington, District of Columbia, United States, 20422
      • Veterans Affairs Medical Center
  • Florida
    • Aventura, Florida, United States, 33180
      • Arthritis & Rheumatic Disease Specialties
    • Gainesville, Florida, United States, 32608
      • Malcom Randall VA Medical Center
    • Hollywood, Florida, United States, 33021
      • Horizon Institute for Clinical Research
    • Ocala, Florida, United States, 34474
      • Ocala Rheumatology Research Center
    • Orange Park, Florida, United States, 32073
      • Arthritis & Osteoporosis Treatment Center, PA
    • St. Petersburg, Florida, United States, 33703
      • St. Petersburg Arthritis Center
  • Idaho
    • Boise, Idaho, United States, 83702
      • Idaho Arthritis & Osteoporosis Center
    • Idaho Falls, Idaho, United States, 83401
      • Institute of Arthritis Research
  • Illinois
    • Chicago, Illinois, United States, 60637
      • The University of Chicago
  • Kentucky
    • Bowling Green, Kentucky, United States, 42101
      • Graves Gilbert Clinic
  • Maryland
    • Baltimore, Maryland, United States, 21239
      • Peter A. Holt, M.D.
    • Hagerstown, Maryland, United States, 21740
      • Malamet & Klein, MD, PA
    • Wheaton, Maryland, United States, 20902
      • The Center for Rheumatology and Bone Research
  • Massachusetts
    • Worcester, Massachusetts, United States, 01605
      • Fallon Clinic, Inc
  • Michigan
    • Brighton, Michigan, United States, 48116
      • Michigan Arthritis Research Center
    • Lansing, Michigan, United States, 48910
      • Justus J. Fiechtner, MD, PC
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
    • St. Cloud, Minnesota, United States, 56377
      • CentraCare Clinic
  • New Jersey
    • Teaneck, New Jersey, United States, 07666
      • Rheumatology Associates of North Jersey
  • New York
    • New York, New York, United States, 10029-6574
      • Mount Sinai Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27302
      • Duke University Medical Center
    • Greenville, North Carolina, United States, 27834
      • Brody School of Medicine, East Carolina University
    • Greenville, North Carolina, United States, 27834
      • Physicians East, P.A.
    • Wilmington, North Carolina, United States, 28401
      • Carolina Atthritis Associates
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • New Horizons Clinical Research
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
    • Dayton, Ohio, United States, 45402
      • STAT Research, Inc.
    • Mayfield Village, Ohio, United States, 44143
      • David R. Mandel, MD, Inc.
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73139
      • Health Research of Oklahoma
  • Oregon
    • Portland, Oregon, United States, 97224
      • Portland Medical Associates
  • Pennsylvania
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Center For Clinical Research
    • Philadelphia, Pennsylvania, United States, 19154
      • Mid Atlantic Research Assoc.
  • South Carolina
    • Charleston, South Carolina, United States, 29407
      • Rheumatology Associates
    • Greenville, South Carolina, United States, 29601
      • Piedmont Arthritis, PA
  • Texas
    • Amarillo, Texas, United States, 79106
      • Aamr Research Clinic
    • San Antonio, Texas, United States, 78232
      • Arthritis & Osteoporosis Center of South Texas
    • Waco, Texas, United States, 76708
      • Arthritis & Osteoporosis Clinic Research Center of Central Texas
  • Washington
    • Spokane, Washington, United States, 99204
      • Arthritis Northwest, PLLC
  • Wisconsin
    • Glendale, Wisconsin, United States, 53217
      • Rheumatic Disease Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: q2 wks; 8 mg pegloticase every 2 weeks	Biological: pegloticase; 8 mg pegloticase by intravenous infusion; Other Names: Puricase; PEG-uricase
EXPERIMENTAL: q4 wks; 8 mg pegloticase every 4 weeks (alternating with placebo every 4 weeks)	Biological: pegloticase; 8 mg pegloticase by intravenous infusion; Other Names: Puricase; PEG-uricase
PLACEBO_COMPARATOR: placebo; placebo every 2 weeks	Other: placebo; placebo by intravenous infusion every 2 weeks

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Savient Pharmaceuticals
• Investigators: Study Director: Medical Director, MD, Savient Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2006
• Primary Completion (ACTUAL): October 1, 2007
• Study Completion (ACTUAL): December 1, 2007

Study Registration Dates

• First Submitted: May 10, 2006
• First Submitted That Met QC Criteria: May 10, 2006
• First Posted (ESTIMATE): May 12, 2006

Study Record Updates

• Last Update Posted (ESTIMATE): February 28, 2011
• Last Update Submitted That Met QC Criteria: February 24, 2011
• Last Verified: February 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Genetic Diseases, Inborn; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Metabolism, Inborn Errors; Crystal Arthropathies; Purine-Pyrimidine Metabolism, Inborn Errors; Hyperuricemia; Gout
• Other Study ID Numbers: C0405 & C0406