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A Phase 4, Open-label Study of KRYSTEXXA® (Pegloticase) Co-administered With Methotrexate (MTX) in Patients With Uncontrolled Gout (FORWARD OL) (FORWARD OL)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04762498
Recruitment Status : Recruiting
First Posted : February 21, 2021
Last Update Posted : December 13, 2022
Information provided by (Responsible Party):
Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics Ireland DAC )

Brief Summary:
This trial is to assess efficacy, safety, blood levels and bodily effects of up to 2 dose levels of intravenous (IV) pegloticase (KRYSTEXXA) infusions at every 4 week intervals (Q4 Weeks) for up to 6 months (Day 1 to 24 weeks with an optional 24 - 48 weeks treatment duration) when given in combination with weekly oral doses of methotrexate (MTX). The goal is to identify an appropriate dose to be administered every 4 weeks to be used for future clinical trials for patients with chronic gout that does not adequately respond to conventional therapy.

Condition or disease Intervention/treatment Phase
Uncontrolled Gout Chronic Gout Biological: Pegloticase and Methotrexate (MTX) Phase 4

Detailed Description:
The primary objective is to choose a dose for further investigation by assessing the effect of up to 2 dose levels of pegloticase administered IV Q4 weeks, co-administered with weekly doses of oral MTX, as measured by the sustained normalization of serum uric acid (sUA) to < 6 mg/dL for at least 80% of the time during Month 6 and the duration of sUA to < 6 mg/dL over 24 week treatment period in adult participants with chronic gout refractory to conventional therapy.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Screening period up to 35 days, followed by 4-week methotrexate (MTX) tolerability run-in. Treatment consists of pegloticase IV Q4 Wks dose for a total of 6 infusions (24 Weeks) with co-administered weekly oral MTX. Optional extension treatment (24-48 weeks) will be available for 6 more infusions (total of 12). Study will consist of Cohort 1: 16 mg pegloticase, co-administered with weekly doses of oral MTX; and, potential Cohort 2: 24 to 32 mg pegloticase, co-administered with weekly doses of oral MTX and/or potential infusion duration reduction to 60 min.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 4, Open-Label, Multicenter, Efficacy, Safety, Pharmacokinetics and Pharmacodynamics Trial of Intravenous KRYSTEXXA® (Pegloticase) Administered Every 4 Weeks With Co-Administration of Weekly Doses of Methotrexate in Patients With Uncontrolled Refractory Gout (FORWARD Open-Label [OL] Trial)
Actual Study Start Date : January 26, 2021
Estimated Primary Completion Date : August 31, 2023
Estimated Study Completion Date : October 2, 2023

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Gout
MedlinePlus related topics: Gout

Arm Intervention/treatment
Experimental: Pegloticase 16mg cohort
16 mg IV dose of pegloticase q4 weeks with 15 mg methotrexate (MTX) weekly
Biological: Pegloticase and Methotrexate (MTX)
16 mg IV dose of pegloticase q4 weeks co-administered with 15 mg oral dose methotrexate weekly

Experimental: Pegloticase 24/32mg cohort
24 to 32 mg IV dose of pegloticase q4 weeks with 15 mg MTX weekly
Biological: Pegloticase and Methotrexate (MTX)
Potential higher IV dose of pegloticase (between 24-32 mg) q4 weeks co-administered with 15 mg oral dose methotrexate weekly and/or potential reduction of infusion duration

Primary Outcome Measures :
  1. Participants achieving and maintaining serum uric acid (sUA) concentration <6 mg/dL for at least 80% of the time [ Time Frame: Month 6 ]
    Proportion of responders at Month 6 (Weeks 20, 21, 22, 23 and 24), defined as subjects achieving and maintaining sUA <6 mg/dL for at least 80% of the time during Month 6

  2. Total duration of sUA concentration <6 mg/dL [ Time Frame: Week 24 ]
    Time to first sUA ≥6 mg/dL after first achieving sUA <6 mg/dL, from the first pegloticase infusion until Week 24

Secondary Outcome Measures :
  1. Pharmacokinetic parameters (e.g., AUC, Cmax and Ctrough) [ Time Frame: Baseline to 24 months ]
  2. Proportion of subjects with pre-infusion sUA <6 mg/dL at each scheduled visit [ Time Frame: Baseline to 25 months ]
  3. Area under the sUA concentration vs time curve from Day 1 to Week 24 and Day 1 to Week 48 [ Time Frame: Day 1 to Week 24 and Day 1 to Week 48 ]
  4. Proportion of the subjects sustained sUA< 6 mg/dL from Day 1 to Week 24 and Day 1 to Week 48 [ Time Frame: Day 1 to Week 24 and Day 1 to Week 48 ]
  5. Proportion of subjects with anti-uricase antibodies and the proportion of subjects with anti-poly (ethylene glycol) antibodies and their titers at each scheduled visit [ Time Frame: Baseline to 24 months ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Willing and able to give informed consent.
  2. Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.
  3. Adult men or women ≥18 and <80 years of age.
  4. Uncontrolled gout, defined as meeting the following criteria:

    • Hyperuricemia during the screening period defined as sUA ≥6 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 as evidenced by either clinical signs consistent with chronic synovitis on clinical examination or the presence of typical gouty erosion(s) on hand and/or foot X-rays
  5. Willing to discontinue any oral urate lowering therapy for at least 7 days prior to MTX dosing at Week -4 and remain off while receiving pegloticase treatments.
  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 -4; subjects must agree to use 2 reliable forms of contraception during the trial, one of which is recommended to be hormonal, such as an oral contraceptive. Hormonal contraception must be started ≥1 full cycle prior to Week -4 (start of MTX) and continue for 4 weeks/30 days after the last dose of pegloticase, or at least one ovulatory cycle after the last dose of MTX (whichever is the longest duration after the last dose of pegloticase or 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 trial, beginning with the initiation of MTX at Week -4 and continuing and for at least 3 months after the last dose of MTX.
  8. Able to tolerate MTX 15 mg orally for 4 weeks (Week -4 through Day 1) prior to enrollment.

Exclusion Criteria:

  1. Weight >160 kg (352 pounds) at Screening.
  2. Any serious acute bacterial infection, unless treated and completely resolved with antibiotics at least 2 weeks prior to the Day 1 Visit.
  3. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia or chronic bronchiectasis.
  4. 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) would also meet exclusion criteria.
  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 RNA positivity, unless treated and viral load is negative.
  8. Known history of Human Immunodeficiency Virus (HIV) positivity.
  9. Glucose-6-phosphate dehydrogenase deficiency (tested at the Screening Visit centrally or locally).
  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 enrollment at Day 1.
  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 -4 or plans to take an investigational drug during the trial.
  18. Liver transaminase levels (AST or ALT) > 1.25 X 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 <4000/µl, hematocrit <32 percent, or platelet count <75,000/µl.
  21. Currently receiving systemic or radiologic treatment for ongoing cancer, excluding non-melanoma skin 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 trial, 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 trial.
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT04762498

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Contact: Horizon Therapeutics 1-866-479-6742

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United States, Alaska
Orthopedic Physicians Alaska Recruiting
Anchorage, Alaska, United States, 99508
Contact: Anna Campione    907-341-5220   
Principal Investigator: John Botson, MD         
United States, Arizona
Arizona Arthritis & Rheumatology Research, PLLC Recruiting
Glendale, Arizona, United States, 85306
Contact: Rebecca Martinez    480-626-6650   
Principal Investigator: John Tesser, MD         
United States, California
East Bay Rheumatology Medical Group, Inc. Recruiting
San Leandro, California, United States, 94578
Contact: Jacquelene Catap    510-357-1040   
Principal Investigator: Suneet Grewal, MD         
United States, Florida
ProHealth Research Center Recruiting
Doral, Florida, United States, 33166
Contact: Johanna Garcia    305-960-7934   
Principal Investigator: David Jativa, MD         
Napa Research Center Recruiting
Pompano Beach, Florida, United States, 33064
Contact: Magda Hernandez    954-773-9890   
Principal Investigator: Naval Parikh, MD         
GCP Clinical Research Not yet recruiting
Tampa, Florida, United States, 33064
Contact: Marlene Klingeman    321-315-0780   
Principal Investigator: Karon Locicero, MD         
United States, Maryland
The Center for Rheumatology and Bone Research Recruiting
Wheaton, Maryland, United States, 20902
Contact: Megan Lormore    301-942-6610   
Principal Investigator: Jeffrey Potter, MD         
United States, North Carolina
Shelby Clinical Research, LLC Not yet recruiting
Shelby, North Carolina, United States, 28150
Contact: Pamela Seagle    980-552-9230   
Principal Investigator: Christopher Martin, MD         
United States, Pennsylvania
Altoona Center for Clinical Research Recruiting
Duncansville, Pennsylvania, United States, 16635
Contact: Lisa Claycomb, CRCP    814-296-6101   
Principal Investigator: Alan Kivitz, MD         
United States, Texas
Biopharma Informatic, LLC Recruiting
Houston, Texas, United States, 77043
Contact: Hassan Khan    281-944-3610   
Principal Investigator: Abigail Neiman, MD         
United States, Washington
Arthritis Clinic: Western Washington Medical Group Recruiting
Bothell, Washington, United States, 98021
Contact: Kathryn Lockhart    425-248-2635   
Principal Investigator: Jeff Peterson, MD         
Arthritis Northwest PLLC Recruiting
Spokane, Washington, United States, 99204
Contact: Terri Cone, BSN    509-838-6500 ext 310   
Principal Investigator: Howard Kenney, MD         
Sponsors and Collaborators
Horizon Therapeutics Ireland DAC
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Study Director: Supra Verma, MD Horizon Therapeutics
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Responsible Party: Horizon Therapeutics Ireland DAC Identifier: NCT04762498    
Other Study ID Numbers: HZNP-KRY-408
First Posted: February 21, 2021    Key Record Dates
Last Update Posted: December 13, 2022
Last Verified: December 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics Ireland DAC ):
Uncontrolled gout
Additional relevant MeSH terms:
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Joint Diseases
Musculoskeletal Diseases
Crystal Arthropathies
Rheumatic Diseases
Purine-Pyrimidine Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors