A Trial to Investigate the Non-inferiority of Pegloticase Administered Every 4 Weeks (Q4W) With MTX Compared With Every 2 Weeks (Q2W) With MTX in Participants With Uncontrolled Refractory Gout

A Phase 4, Randomized, Double-blind, Multicenter Non-inferiority Trial Evaluating the Efficacy and Safety of Intravenous KRYSTEXXA® (Pegloticase) Administered Every 4 Weeks Compared With KRYSTEXXA Administered Every 2 Weeks With Co-administration of Weekly Doses of Methotrexate, Followed by an Open-label Extension, in Participants With Uncontrolled Refractory Gout (FORWARD II)

The study consists of 24-week double-blind trial to evaluate the non-inferiority of the efficacy and safety of pegloticase Q4W with MTX versus pegloticase Q2W with MTX, followed by a 24-week open-label extension of pegloticase Q4W with MTX, in participants with uncontrolled refractory gout.

The main objective of the study is to evaluate the effect of pegloticase 16 mg administered Q4W with MTX versus pegloticase 8 mg administered Q2W with MTX, on the response rate during Month 6, as measured by the sustained normalization of sUA to < 6 mg/dL for at least 80% of the time.

Study Overview

• Status: Completed
• Conditions: Gout
• Intervention / Treatment: Drug: Methotrexate; Biological: Pegloticase

Detailed Description

Acquired from Horizon in 2024.

• Study Type: Interventional
• Enrollment (Actual): 262
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • The University of Alabama at Birmingham (UAB)
  • Alaska
    • Anchorage, Alaska, United States, 99508-5234
      • Orthopedic Physicians Alaska - Rheumatology and Infusion
  • Arizona
    • Chandler, Arizona, United States, 85225-2915
      • Arizona Arthritis and Rheumatology Associates - Chandler
    • Flagstaff, Arizona, United States, 86001
      • Arizona Arthritis and Rheumatology Rese
    • Gilbert, Arizona, United States, 85297
      • Arizona Arthritis & Rheumatology Research, PLLC
    • Mesa, Arizona, United States, 85032
      • Arizona Arthritis & Rheumatology Research, PLLC
    • Mesa, Arizona, United States, 85210
      • Arizona Arthritis and Rheumatology Research, PLLC
    • Phoenix, Arizona, United States, 85037
      • Arizona Arthritis and Rheumatology Research
    • Phoenix, Arizona, United States, 85037-4403
      • Arizona Arthritis and Rheumatology Research, PLLC
    • Sun City, Arizona, United States, 85351
      • Arizona Arthritis & Rheumatology Research, PLLC
    • Tucson, Arizona, United States, 85704
      • Arizona Arthritis and Rheumatology
  • California
    • Covina, California, United States, 91722
      • Covina Arthritis Clinic
    • Hemet, California, United States, 92543
      • Medvin Clinical Research- Riverside
    • North Hollywood, California, United States, 83642
      • Velocity Clinical Research - Boise - ERN - PPDS
    • San Diego, California, United States, 92108
      • TriWest Research Associates
    • San Leandro, California, United States, 94578-2630
      • Precision Comprehensive Clinical Research Solutions
    • Santa Monica, California, United States, 90404
      • Saint John's Health Center - Providence St John's Health Ctr
    • Temecula, California, United States, 92592
      • C.V. Mehta MD Medical Corporation
    • Tujunga, California, United States, 91042
      • Foothill Arthritis
    • Whittier, California, United States, 90602
      • Medvin Clinical Research
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
    • Colorado Springs, Colorado, United States, 80918
      • Lynn Institute of the Rockies
    • Denver, Colorado, United States, 80230
      • Denver Arthritis Clinic - Rheumatology
  • Florida
    • Aventura, Florida, United States, 33180-1204
      • Arthritis & Rheumatic Disease
    • Doral, Florida, United States, 33166
      • Prohealth Research Center
    • Margate, Florida, United States, 33063-5675
      • LIFE Clinical Trials
    • Miami, Florida, United States, 33155
      • D&H National Research Centers, Inc.
    • Miami, Florida, United States, 33173
      • Well Pharma
    • Miami, Florida, United States, 33184
      • Felicidad Medical Research, LLC.
    • Miami, Florida, United States, 33032-8225
      • Homestead Associates in Research,Inc
    • Naples, Florida, United States, 34104
      • New Generation of Medical Research
    • Plantation, Florida, United States, 33324
      • IRIS Research & Development
    • Pompano Beach, Florida, United States, 33064
      • D&H Pompano Research Center
    • Tamarac, Florida, United States, 33321
      • D&H Tamarac Research Center
    • Tampa, Florida, United States, 33609
      • GCP Clinical Research
    • Tampa, Florida, United States, 33613
      • ClinPro Research Solutions, LLC
  • Georgia
    • Gainesville, Georgia, United States, 30501
      • Arthritis Center of North Georgia
    • Newnan, Georgia, United States, 30265
      • Vista Clinical Research, LLC
  • Illinois
    • Chicago, Illinois, United States, 60625
      • Great Lakes Clin. Trials
    • Chicago, Illinois, United States, 60637
      • Conquest Research - Anesthesiology/Pain Medicine
    • Highland Park, Illinois, United States, 60035
      • Great Lakes Clinical Trials - Gurnee
    • Hinsdale, Illinois, United States, 60521
      • Crowley CORE - Illinois Bone and Joint Institute
  • Indiana
    • New Albany, Indiana, United States, 47150
      • Lake Cumberland Rheumatology, PLLC
  • Kentucky
    • Louisville, Kentucky, United States, 40213
      • L-MARC Research Center
  • Louisiana
    • Covington, Louisiana, United States, 70433
      • Velocity CR - New Orleans
    • New Orleans, Louisiana, United States, 70121-2429
      • Velocity CR - New Orleans
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Michigan Medicine
    • Lansing, Michigan, United States, 48911
      • June DO,PC
    • Saint Clair Shores, Michigan, United States, 48081
      • Clinical Research Institute of Michigan, LLC
  • New Mexico
    • Santa Fe, New Mexico, United States, 87505
      • Inspire Santa Fe Medical Group
  • New York
    • Vestal, New York, United States, 13850
      • Velocity Clinical Research-Vestal
  • North Carolina
    • Charlotte, North Carolina, United States, 28226
      • OnSite Clinical Solutions, LLC
    • Denver, North Carolina, United States, 28037
      • Research Carolina Elite
    • Greensboro, North Carolina, United States, 27410
      • Triad Clinical Trials - Gastroenterology
    • Hickory, North Carolina, United States, 28602
      • Accellacare of Hickory
    • Leland, North Carolina, United States, 28451-4168
      • Cape Fear Arthritis Care
    • Shelby, North Carolina, United States, 28152
      • Shelby Clinical Research - Family Medicine
  • Ohio
    • Cincinnati, Ohio, United States, 45242
      • Velocity Clinical Research- Cincinatti
    • Cleveland, Ohio, United States, 44122
      • Velocity Clinical Research - Cleveland
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73111-3324
      • Lynn Health Science Institute
  • Pennsylvania
    • Duncansville, Pennsylvania, United States, 16635
      • Altoona Center For Clinical Research
  • South Carolina
    • Greenville, South Carolina, United States, 29615
      • Velocity Clinical Research, Spartanburg - Pulmonology
    • Rock Hill, South Carolina, United States, 29732
      • Premier Clinics Pa - Rock Hill, Sc
    • Summerville, South Carolina, United States, 29486-7887
      • Low Country Rheumatology
  • Texas
    • Amarillo, Texas, United States, 79124
      • Amarillo Center for Clinical Research, Ltd.
    • Austin, Texas, United States, 78750
      • Clinical Trial Network
    • Houston, Texas, United States, 77099
      • Pioneer Research Solutions, Inc.
    • Houston, Texas, United States, 77061
      • Synergy Groups Medical LLC
    • Plano, Texas, United States, 75093
      • AIM Trials - Internal Medicine
    • San Antonio, Texas, United States, 78229
      • Clinical Trials of Texas, Inc.
    • Sugar Land, Texas, United States, 77479
      • Texas Research Center
  • Utah
    • West Jordan, Utah, United States, 84088
      • Velocity Clinical Research - Salt Lake City (West Jordan)
  • Virginia
    • Portsmouth, Virginia, United States, 23703-3200
      • Velocity Clinical Research-Portsmouth
  • Washington
    • Spokane, Washington, United States, 99204
      • Arthritis Northwest, PLLC - Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult men or women ≥ 18 years of age

2. 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 participant interview, and;
   • Symptoms of gout
3. Willing to discontinue any oral ULT for at least 7 days prior to MTX dosing at Week -4 and continue not receiving any oral ULT when receiving pegloticase/placebo for pegloticase infusions
4. Women of childbearing potential must have negative serum/urine pregnancy tests during screening and Week -4.
5. Men who are not vasectomized must agree to use appropriate contraception, so as to not impregnate a female partner of reproductive potential during the trial.

Exclusion Criteria:

1. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia or chronic bronchiectasis
2. Current or chronic treatment with systemic immunosuppressive agents, such as MTX, azathioprine or mycophenolate mofetil; prednisone > 10 mg/day or equivalent dose of other corticosteroid on a chronic basis (3 months or longer)
3. History of any transplant surgery requiring maintenance immunosuppressive therapy
4. Known history of hepatitis B virus surface antigen positivity or hepatitis B DNA positivity
5. Known history of hepatitis C virus RNA positivity, unless treated and viral load is negative
6. Known history of human immunodeficiency virus (HIV) positivity
7. G6PD deficiency (quantitative test at the Screening Visit centrally or locally)
8. 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 Week -4
9. 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
10. Prior treatment with pegloticase, another recombinant uricase (rasburicase) or concomitant therapy with a PEG-conjugated drug
11. Unable to tolerate MTX 15 mg orally during the MTX Run-in Period
12. Chronic liver disease
13. White blood cell count < 4,000/μL, hematocrit < 32% or platelet count < 75,000/μL
14. Currently receiving systemic or radiologic treatment for ongoing cancer
15. History of malignancy within 5 years other than non-melanoma skin cancer or in situ carcinoma of cervix
16. Diagnosis of osteomyelitis
17. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as Lesch-Nyhan and Kelley-Seegmiller syndrome
18. A known intolerance to all protocol-standard gout flare prophylaxis regimens (i.e., participant must be able to tolerate at least 1 of the following: colchicine and/or non-steroidal anti-inflammatory drugs and/or low-dose prednisone ≤ 10 mg/day)
19. Current pulmonary fibrosis, bronchiectasis or interstitial pneumonitis. If deemed necessary by the Investigator, a chest X-ray may be performed during Screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pegloticase + Methotrexate Q4W; 16 mg pegloticase will be administered intravenously every 4 weeks for 24 weeks during double blind treatment and 24 weeks during open label.	Drug: Methotrexate; Oral; Biological: Pegloticase; IV infusion; Other Names: Krystexxa
Experimental: Pegloticase + Methotrexate Q2W; 8 mg pegloticase will be administered intravenously every 2 weeks for 24 weeks during double blind treatment and 16 mg pegloticase every 4 weeks for 24 weeks during open label.	Drug: Methotrexate; Oral; Biological: Pegloticase; IV infusion; Other Names: Krystexxa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the effect of pegloticase 16 mg administered Q4W with MTX versus pegloticase 8 mg administered Q2W with MTX, on the response rate as measured by the sustained normalization of sUA to < 6 mg/dL for at least 80% of the time	Proportion of participants achieving and maintaining serum uric acid (sUA) < 6 mg/dL at least 80% of the time	Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the effect of pegloticase 16 mg Q4W with MTX compared with pegloticase 8 mg Q2W with MTX on tophi resolution	Proportion of Participants with complete resolution of ≥ 1 tophus in participants with tophi at Baseline	Week 24

Collaborators and Investigators

• Sponsor: Amgen
• Investigators: Study Director: MD, Amgen

Publications and helpful links

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): March 18, 2024
• Primary Completion (Actual): July 30, 2025
• Study Completion (Actual): March 11, 2026

Study Registration Dates

• First Submitted: January 19, 2024
• First Submitted That Met QC Criteria: January 19, 2024
• First Posted (Actual): January 29, 2024

Study Record Updates

• Last Update Posted (Actual): April 9, 2026
• Last Update Submitted That Met QC Criteria: April 7, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Methotrexate; pegloticase; Uncontrolled Gout; Krystexxa; Chronic Gout
• Additional Relevant MeSH Terms: Crystal Arthropathies; Musculoskeletal Diseases; Arthritis; Joint Diseases; Rheumatic Diseases; Purine-Pyrimidine Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Gout; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pterins; Pteridines; Aminopterin; Methotrexate; Pegloticase
• Other Study ID Numbers: HZNP-KRY-409

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors. If not approved, a Data Sharing Independent Review Panel will arbitrate and make the final decision. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the URL below.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No