Study of KRYSTEXXA® (Pegloticase) Plus Methotrexate in Participants With Uncontrolled Gout
NCT ID: NCT03994731
Last Updated: 2024-06-26
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE4
152 participants
INTERVENTIONAL
2019-06-13
2022-04-11
Brief Summary
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
TRIPLE
Study Groups
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Pegloticase + MTX
Following the MTX Tolerability Assessment Period (Week -6 until the Week -4 visit, in which participants take oral MTX 15 mg weekly), participants tolerating MTX are randomized to receive blinded oral MTX 15 mg weekly during the Run-in Period (from Week -4 to Day 1).
During the Pegloticase + Immunomodulator (IMM) Period, in addition to oral 15 mg MTX, participants receive intravenous (IV) pegloticase 8 mg administered every 2 weeks (Q2W) for a total of 26 infusions from Day 1 through the Week 50 Visit.
Per protocol, participants are also required to take folic acid, at least one protocol standard gout flare prophylaxis regimen (i.e. colchicine and/or nonsteroidal anti-inflammatory drugs and/or low-dose prednisone ≤10 mg/day), and a regimen of fexofenadine, acetaminophen, and methylprednisolone for infusion reaction (IR) prophylaxis.
Pegloticase
IV pegloticase 8 mg Q2W
methotrexate
Oral MTX 15 mg weekly
folic acid
Folic acid 1 mg orally every day beginning at Week -6 until prior to the Week 52 Visit.
gout flare prophylaxis regimen
Prior to beginning the Pegloticase + IMM Period, participants must have been taking at least 1 protocol-standard gout flare prophylaxis regimen (i.e. colchicine and/or nonsteroidal anti-inflammatory drugs and/or low-dose prednisone ≤ 10 mg/day) for ≥ 1 week before the first dose of pegloticase and to continue flare prophylaxis per American College of Rheumatology guidelines \[Khanna D et al. 2012\] for the greater of 1) 6 months, 2) 3 months after achieving target serum urate (sUA \< 6 mg/dL) for participants with no tophi detected on physical exam, or 3) 6 months after achieving target serum urate (sUA \< 5 mg/dL) for participants with one or more tophi detected on initial physical exam that then resolved.
fexofenadine
For IR prophylaxis, fexofenadine (180 mg orally) taken the day before each infusion and on the morning of each infusion.
acetaminophen
For IR prophylaxis, acetaminophen (1000 mg orally) taken the morning of each infusion.
methylprednisolone
For IR prophylaxis, methylprednisolone (125 mg IV) given over an infusion duration between 10 - 30 minutes, immediately prior to each infusion.
Pegloticase + Placebo
Following the MTX Tolerability Assessment Period (Week -6 until the Week -4 visit, in which participants take oral MTX 15 mg weekly), participants tolerating MTX are randomized to receive blinded oral placebo for MTX weekly during the Run-in Period (from Week -4 to Day 1).
During the Pegloticase + IMM Period, in addition to oral placebo for MTX, all participants receive IV pegloticase 8 mg administered Q2W for a total of 26 infusions from Day 1 through the Week 50 Visit.
Per protocol, participants are also required to take folic acid, at least one protocol standard gout flare prophylaxis regimen (i.e. colchicine and/or nonsteroidal anti-inflammatory drugs and/or low-dose prednisone ≤10 mg/day), and a regimen of fexofenadine, acetaminophen, and methylprednisolone for IR prophylaxis.
Pegloticase
IV pegloticase 8 mg Q2W
methotrexate
Oral MTX 15 mg weekly
placebo
Oral placebo for MTX
folic acid
Folic acid 1 mg orally every day beginning at Week -6 until prior to the Week 52 Visit.
gout flare prophylaxis regimen
Prior to beginning the Pegloticase + IMM Period, participants must have been taking at least 1 protocol-standard gout flare prophylaxis regimen (i.e. colchicine and/or nonsteroidal anti-inflammatory drugs and/or low-dose prednisone ≤ 10 mg/day) for ≥ 1 week before the first dose of pegloticase and to continue flare prophylaxis per American College of Rheumatology guidelines \[Khanna D et al. 2012\] for the greater of 1) 6 months, 2) 3 months after achieving target serum urate (sUA \< 6 mg/dL) for participants with no tophi detected on physical exam, or 3) 6 months after achieving target serum urate (sUA \< 5 mg/dL) for participants with one or more tophi detected on initial physical exam that then resolved.
fexofenadine
For IR prophylaxis, fexofenadine (180 mg orally) taken the day before each infusion and on the morning of each infusion.
acetaminophen
For IR prophylaxis, acetaminophen (1000 mg orally) taken the morning of each infusion.
methylprednisolone
For IR prophylaxis, methylprednisolone (125 mg IV) given over an infusion duration between 10 - 30 minutes, immediately prior to each infusion.
Interventions
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Pegloticase
IV pegloticase 8 mg Q2W
methotrexate
Oral MTX 15 mg weekly
placebo
Oral placebo for MTX
folic acid
Folic acid 1 mg orally every day beginning at Week -6 until prior to the Week 52 Visit.
gout flare prophylaxis regimen
Prior to beginning the Pegloticase + IMM Period, participants must have been taking at least 1 protocol-standard gout flare prophylaxis regimen (i.e. colchicine and/or nonsteroidal anti-inflammatory drugs and/or low-dose prednisone ≤ 10 mg/day) for ≥ 1 week before the first dose of pegloticase and to continue flare prophylaxis per American College of Rheumatology guidelines \[Khanna D et al. 2012\] for the greater of 1) 6 months, 2) 3 months after achieving target serum urate (sUA \< 6 mg/dL) for participants with no tophi detected on physical exam, or 3) 6 months after achieving target serum urate (sUA \< 5 mg/dL) for participants with one or more tophi detected on initial physical exam that then resolved.
fexofenadine
For IR prophylaxis, fexofenadine (180 mg orally) taken the day before each infusion and on the morning of each infusion.
acetaminophen
For IR prophylaxis, acetaminophen (1000 mg orally) taken the morning of each infusion.
methylprednisolone
For IR prophylaxis, methylprednisolone (125 mg IV) given over an infusion duration between 10 - 30 minutes, immediately prior to each infusion.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the study.
3. Adult men or women ≥18 years of age.
4. Uncontrolled gout, defined as meeting the following criteria:
* Hyperuricemia during the screening period defined as sUA ≥7 mg/dL, and;
* Failure to maintain normalization of sUA with xanthine oxidase inhibitors at the maximum medically appropriate dose, or with a contraindication to xanthine oxidase inhibitor therapy based on medical record review or subject interview, and;
* Symptoms of gout including at least 1 of the following:
* Presence of at least one tophus
* Recurrent flares defined as 2 or more flares in the past 12 months prior to screening
* Presence of chronic gouty arthritis
5. Willing to discontinue any oral urate lowering therapy for at least 7 days prior to MTX dosing at Week -6 and remain off when receiving pegloticase infusions.
6. Women of childbearing potential (including those with an onset of menopause \<2 years prior to screening, non-therapy-induced amenorrhea for \<12 months prior to screening, or not surgically sterile \[absence of ovaries and/or uterus\]) must have negative serum/urine pregnancy tests during Screening and Week -6; subjects must agree to use 2 reliable forms of contraception during the study, one of which is recommended to be hormonal, such as an oral contraceptive. Hormonal contraception must be started ≥1 full cycle prior to Week -6 (start of MTX) and continue for 30 days after the last dose of pegloticase, or at least one ovulatory cycle after the last dose of MTX or placebo for MTX (whichever is the longest duration after the last dose of pegloticase or MTX or placebo for MTX). Highly effective contraceptive methods (with a failure rate \<1% per year), when used consistently and correctly, include implants, injectables, combined oral contraceptives, some intrauterine devices, sexual abstinence, or vasectomized partner.
7. Men who are not vasectomized must agree to use appropriate contraception so as to not impregnate a female partner of reproductive potential during the study, beginning with the initiation of MTX at Week -6 and continuing and for at least 3 months after the last dose of MTX or placebo for MTX.
8. Able to tolerate MTX 15 mg orally for 2 weeks (Week -6 through Week -4) prior to randomization.
Exclusion Criteria
2. Any serious acute bacterial infection, unless treated and completely resolved with antibiotics at least 2 weeks prior to the Week -6 Visit.
3. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia or chronic bronchiectasis.
5. History of any transplant surgery requiring maintenance immunosuppressive therapy.
6. Known history of hepatitis B virus surface antigen positivity or hepatitis B DNA positivity.
7. Known history of hepatitis C virus ribonucleic acid (RNA) positivity.
8. Known history of Human Immunodeficiency Virus (HIV) positivity.
9. Glucose-6-phosphate dehydrogenase deficiency (tested at the Screening Visit).
10. Chronic renal impairment defined as estimated glomerular filtration rate (eGFR) \< 40 mL/min/1.73 m\^2 or currently on dialysis.
11. Non-compensated congestive heart failure or hospitalization for congestive heart failure within 3 months of the Screening Visit, uncontrolled arrhythmia, treatment for acute coronary syndrome (myocardial infarction or unstable angina), or uncontrolled blood pressure (\>160/100 mmHg) prior to Randomization at Week -4.
12. Pregnant, planning to become pregnant, breastfeeding, planning to impregnate female partner, or not on an effective form of birth control, as determined by the Investigator.
13. Prior treatment with pegloticase, another recombinant uricase (rasburicase), or concomitant therapy with a polyethylene glycol-conjugated drug.
14. Known allergy to pegylated products or history of anaphylactic reaction to a recombinant protein or porcine product.
15. Contraindication to MTX treatment or MTX treatment considered inappropriate.
16. Known intolerance to MTX.
17. Receipt of an investigational drug within 4 weeks or 5 half-lives, whichever is longer, prior to MTX administration at Week -6 or plans to take an investigational drug during the study.
18. Liver transaminase levels (aspartate aminotransferase \[AST\] or alanine aminotransferase \[ALT\]) \> upper limit of normal (ULN) or albumin \< the lower limit of normal (LLN) at the Screening Visit).
19. Chronic liver disease.
20. White blood cell count \< 4,000/µL, hematocrit \< 32 percent, or platelet count \< 75,000/µL.
21. Currently receiving systemic or radiologic treatment for ongoing cancer.
22. History of malignancy within 5 years other than non-melanoma skin cancer or in situ carcinoma of cervix.
23. Diagnosis of osteomyelitis.
24. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
25. Unsuitable candidate for the study, based on the opinion of the Investigator (e.g., cognitive impairment), such that participation might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements or complete the study.
26. Alcohol use in excess of 3 alcoholic beverages per week.
27. A known intolerance to all protocol standard gout flare prophylaxis regimens (i.e. subject must be able to tolerate at least one: colchicine and/or non-steroidal anti inflammatory drugs and/or low dose prednisone ≤10 mg/day).
28. Current pulmonary fibrosis, bronchiectasis or interstitial pneumonitis. If deemed necessary by the Investigator, a chest X-ray may be performed during Screening.
18 Years
ALL
No
Sponsors
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Amgen
INDUSTRY
Responsible Party
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Principal Investigators
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MD
Role: STUDY_DIRECTOR
Amgen
Locations
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University of Alabama
Birmingham, Alabama, United States
Orthopedic Physicians Alaska
Anchorage, Alaska, United States
Arizona Arthritis and Rheumatology Research, PLLC - Flagstaff
Flagstaff, Arizona, United States
Arizona Arthritis and Rheumatology Research, PLLC-West
Glendale, Arizona, United States
Arizona Arthritis and Rheumatology Research, PLLC-East
Mesa, Arizona, United States
Applied Research Center of Arkansas, Inc
Little Rock, Arkansas, United States
TriWest Research Associates
El Cajon, California, United States
Advanced Investigative Medicine, Inc.
Hawthorne, California, United States
Axis Clinical Trials
Los Angeles, California, United States
ACRC Studies
Poway, California, United States
ClinEdge Sierra Rheumatology, Inc.
Roseville, California, United States
East Bay Rheumatology Medical Group, Inc.
San Leandro, California, United States
Providence St. John's Health Clinic
Santa Monica, California, United States
Medvin Clinical Research
Tujunga, California, United States
San Fernando Valley Health Institute
Van Nuys, California, United States
Ventura Clinical Trials
Ventura, California, United States
University of Colorado Division of Rheumatology
Aurora, Colorado, United States
Denver Arthritis Clinic
Denver, Colorado, United States
Avail Clinical Research
DeLand, Florida, United States
Prohealth Research Center
Doral, Florida, United States
Omega Research Maitland
Orlando, Florida, United States
DMI Research
Pinellas Park, Florida, United States
Napa Research Center
Pompano Beach, Florida, United States
GCP Clinical Research
Tampa, Florida, United States
Florida Medical Clinic, LLC
Zephyrhills, Florida, United States
St. Luke's Clinic - Rheumatology
Meridian, Idaho, United States
MD Medical Research
Oxon Hill, Maryland, United States
The Center for Rheumatology and Bone Research
Wheaton, Maryland, United States
Infusion Associates
Grand Rapids, Michigan, United States
Clinical Research Institute of Michigan, LLC
Saint Clair Shores, Michigan, United States
Benefis Hospital
Great Falls, Montana, United States
Physician Research Collaboration, LLC
Lincoln, Nebraska, United States
Santa Fe Rheumatology
Santa Fe, New Mexico, United States
Long Island Arthritis & Osteoporosis Care
Babylon, New York, United States
Buffalo Rheumatology and Medicine
Orchard Park, New York, United States
NorthEast Rheumatology/Atrium Health
Concord, North Carolina, United States
NorthEast Rheumatology
Concord, North Carolina, United States
Medication Management, LLC
Greensboro, North Carolina, United States
ClinEdge PMG Research of Hickory, LLC
Hickory, North Carolina, United States
ClinEdge PMG Research of Salisbury, LLC
Salisbury, North Carolina, United States
Shelby Clinical Research, LLC
Shelby, North Carolina, United States
PMG Research of Wilmington, LLC
Wilmington, North Carolina, United States
Premier Clinical/STAT Research
Dayton, Ohio, United States
Paramount Medical Research & Consulting, LLC
Middleburg Heights, Ohio, United States
Clinical Research Source Inc.
Perrysburg, Ohio, United States
Premier Clinical/STAT Research - Springboro
Springboro, Ohio, United States
Altoona Center for Clinical Research
Duncansville, Pennsylvania, United States
Piedmont Arthritis Clinic
Greenville, South Carolina, United States
Articularis Healthcare Group
Summerville, South Carolina, United States
West Tennessee Research Institute
Jackson, Tennessee, United States
Ramesh C. Gupta, M.D.
Memphis, Tennessee, United States
Diagnostic and Interventional Nephrology Of Houston
Houston, Texas, United States
Research Consultants - Frostwood
Houston, Texas, United States
Research Consultants - Astoria
Houston, Texas, United States
Arthritis Clinic of Central Texas
San Marcos, Texas, United States
Arthritis & Osteoporosis Clinic - Waco
Waco, Texas, United States
Clear Lake Specialties
Webster, Texas, United States
Western Washington Arthritis Clinic
Bothell, Washington, United States
Arthritis Northwest
Spokane, Washington, United States
Rheumatic Disease Center
Glendale, Wisconsin, United States
Countries
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References
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Botson J, Obermeyer K, LaMoreaux B, Padnick-Silver L, Verma S, Weinblatt ME, Peterson J. Quality of life and clinical gout assessments during pegloticase with and without methotrexate co-therapy: MIRROR randomized controlled trial exploratory findings. Rheumatol Adv Pract. 2024 Nov 29;8(4):rkae145. doi: 10.1093/rap/rkae145. eCollection 2024.
Dalbeth N, Botson J, Saag K, Kumar A, Padnick-Silver L, LaMoreaux B, Becce F. Monosodium urate crystal depletion and bone erosion remodeling during pegloticase treatment in patients with uncontrolled gout: Exploratory dual-energy computed tomography findings from MIRROR RCT. Joint Bone Spine. 2024 Jul;91(4):105715. doi: 10.1016/j.jbspin.2024.105715. Epub 2024 Mar 4.
Botson JK, Saag K, Peterson J, Parikh N, Ong S, La D, LoCicero K, Obermeyer K, Xin Y, Chamberlain J, LaMoreaux B, Verma S, Sainati S, Grewal S, Majjhoo A, Tesser JRP, Weinblatt ME. A Randomized, Placebo-Controlled Study of Methotrexate to Increase Response Rates in Patients with Uncontrolled Gout Receiving Pegloticase: Primary Efficacy and Safety Findings. Arthritis Rheumatol. 2023 Feb;75(2):293-304. doi: 10.1002/art.42335. Epub 2022 Dec 16.
Provided Documents
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Document Type: Study Protocol
Document Type: Statistical Analysis Plan
Other Identifiers
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HZNP-KRY-202
Identifier Type: -
Identifier Source: org_study_id
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