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Pegloticase and Methotrexate Co-administered in Patients With Uncontrolled Gout Who Have Previously Failed Pegloticase Monotherapy

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ClinicalTrials.gov Identifier: NCT04772313
Recruitment Status : Recruiting
First Posted : February 26, 2021
Last Update Posted : August 30, 2021
Sponsor:
Information provided by (Responsible Party):
Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics Ireland DAC )

Brief Summary:

This is a Phase 4, multicenter, open-label trial of pegloticase with MTX (methotrexate) in adult participants with uncontrolled gout who were previously treated with pegloticase without a concomitant immunomodulator and stopped pegloticase due to failure to maintain sUA (serum uric acid) response and/or a clinically mild IR (infusion reaction). Approximately 30 participants will be enrolled. Pegloticase + MTX will be administered for approximately 24 weeks, with an optional extension up to 48 weeks.

The trial design will include 5 distinct components:

  1. Screening Period, lasting up to 42 days;
  2. 6-week MTX Tolerability Assessment Period (hereafter referred to as the MTX Run-in Period);
  3. 24-week Pegloticase + MTX Treatment Period, which will include a Week 24/End of Trial/Early Termination Visit (subjects that end MTX and pegloticase treatment prior to the Week 24 will remain on trial for follow up until the Week 24 visit);
  4. Optional Pegloticase + MTX Extension Period up to 24 weeks
  5. 30-Day Post Treatment Follow -up

Condition or disease Intervention/treatment Phase
Uncontrolled Gout Biological: Pegloticase Phase 4

Detailed Description:

All participants who meet eligibility criteria at Screening will begin once-weekly subcutaneous (SC) MTX Run-in period. Participants must be able to tolerate MTX at a minimum dose of 15 mg during the 6-week MTX Run-in Period to be eligible to participate in the Pegloticase + MTX Treatment Period.

All participants who meet the inclusion/exclusion criteria and complete the MTX Run-in Period will be considered enrolled participants. During the Pegloticase + MTX Treatment Period, pegloticase 8 mg will be administered IV every 2 weeks and MTX SC weekly.

Two sequential cohorts of participants will be enrolled in this trial. Cohort 1 is targeted to enroll 10 participants who previously failed to maintain sUA (serum uric acid) response with pegloticase monotherapy and stopped pegloticase treatment without a history of pegloticase-related infusion reaction. If the safety assessment during Cohort 1 indicates that the pegloticase infusions are well tolerated, then the trial can begin enrolling Cohort 2. 20 participants with a history pegloticase-related infusion reaction.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 4, Multicenter, Open-label, Efficacy and Safety Trial of Pegloticase and Methotrexate Co-administered in Patients With Uncontrolled Gout Who Have Previously Received Pegloticase Monotherapy But Did Not Maintain a Serum Uric Acid Response
Actual Study Start Date : March 8, 2021
Estimated Primary Completion Date : April 2023
Estimated Study Completion Date : June 2023

Resource links provided by the National Library of Medicine

MedlinePlus Genetics related topics: Gout
MedlinePlus related topics: Gout

Arm Intervention/treatment
Experimental: Pegloticase plus Methotrexate (MTX)
Pegloticase (8mg) intravenous (IV every two weeks). Methotrexate (15 or 25 mg weekly) subcutaneous (SC).
Biological: Pegloticase
Participants will receive MTX during the run-in period then pegloticase with MTX for up to 24 weeks during the treatment period. Participants may opt to receive pegloticase with MTX for an additional 24 weeks.
Other Name: methotrexate (MTX)




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


Secondary Outcome Measures :
  1. Proportion of Serum Uric Acid Responders (sUA < 6 mg/dL) During Month 3 [ Time Frame: Month 3 ]
    Serum uric acid (sUA) responders defined as participants achieving and maintaining sUA <6 mg/dL for at least 80% of the time during Month 3 (Weeks 10 to 14).

  2. Proportion of participants who experienced any of the following events from Day 1 to Week 24: IR (infusion reaction) leading to discontinuation of treatment, anaphylaxis or meeting Individual Subject sUA Discontinuation Criteria [ Time Frame: Day1 to Week 24 ]
    Incidence of any of the events listed during the period Day 1 to Week 24.

  3. Proportion of time sUA<6mg/dL between first infusion and Week 24 [ Time Frame: Day1 to Week 24 ]
  4. Mean change from Baseline in urate deposition volume (measured by DECT) to Week 24 [ Time Frame: Baseline to Week 24 ]
    Dual Energy Computed Tomography (DECT) scan which measures urate deposition volume.

  5. Mean change from Baseline in HAQ-DI score at Weeks 14 and 24 [ Time Frame: Baseline, Week 14, Week 24 ]
    HAQ-DI (range: 0 to 3) is a self-report functional status instrument that is filled out by the participant and measures disability over the past week via 20 questions relating to 8 domains of function: dressing grooming, arising, eating, walking, hygiene, reach, grip, usual activities.

  6. Mean change from Baseline HAQ pain score at Weeks 14 and 24 [ Time Frame: Baseline, Week 14, Week 24 ]
    The HAQ pain scale asks participants to record how much pain they have had in the past week on a scale of 0-100 where zero represents no pain and 100 represents severe pain.

  7. Mean change from Baseline in HAQ health score at Weeks 14 and 24 [ Time Frame: Baseline, Week 14, Week 24 ]
    The HAQ health scale is a measure of overall health. Participants are asked to rate how well they are doing on a scale of 0 to 100, where zero represents very well and 100 represents very poor health.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 years of age.
  4. Uncontrolled gout, defined by 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 1 tophus
      • Recurrent flares, defined as 2 or more flares in the 12 months prior to Screening
      • Presence of chronic gouty arthritis
  5. Subject was previously treated with pegloticase without concomitant immunomodulation and stopped pegloticase due to failure to maintain sUA reduction response (had ≥1 sUA >6 mg/dL within 2 weeks post pegloticase infusion) and did not experience an IR (Cohort 1) and/or stopped pegloticase treatment due to pegloticase-related clinically mild IR (Cohort 2).
  6. Subject for whom the last pegloticase infusion occurred >6 months prior to Screening.
  7. Willing to discontinue any oral urate-lowering therapy for at least 7 days prior to Day 1 and remain off other urate-lowering therapy during the Pegloticase + MTX Treatment Period.
  8. 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 pregnancy tests during Screening:

    Subjects must agree to use 2 reliable forms of contraception during the trial, 1 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 1 ovulatory cycle after the last dose of MTX (whichever is the longer duration after the last dose of pegloticase). 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.

  9. 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 -6 and continuing for at least 3 months after the last dose of MTX.
  10. Able to tolerate MTX at SC doses of at least 15 mg during the MTX Run-in Period, regardless of eGFR status.

Exclusion Criteria:

  1. Known history of medically confirmed prior anaphylactic reaction.
  2. Known history of moderate or severe IR (including but not limited to difficulty in breathing, hypotension, generalized urticaria, generalized erythema, angioedema and/or required treatment with IV steroids or epinephrine; or other SAEs related to pegloticase or any other pegylated product treatment.
  3. Weight >160 kg (352 pounds) at Screening.
  4. Any serious acute bacterial infection, unless treated and completely resolved with antibiotics at least 2 weeks prior to the Week -6 Visit.
  5. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia or chronic bronchiectasis.
  6. Current or chronic treatment with systemic immunosuppressive agents, such as MTX, azathioprine, cyclosporine, leflunomide, cyclophosphamide or mycophenolate mofetil.
  7. Current treatment with prednisone >10 mg/day or equivalent dose of another corticosteroid on a chronic basis (defined as 3 months or longer).
  8. Known history of any solid organ transplant surgery requiring maintenance immunosuppressive therapy.
  9. Known history of hepatitis B virus surface antigen positivity or hepatitis B DNA positivity, unless treated, viral load is negative and no chronic or active infection confirmed by hepatitis B virus serology.
  10. Known history of hepatitis C virus RNA positivity, unless treated and viral load is negative.
  11. Known history of human immunodeficiency virus positivity.
  12. G6PD deficiency (tested at the Screening Visit).
  13. Severe chronic renal impairment (eGFR <30 mL/min/1.73 m^2) at the Screening Visit based on 4 variable Modification of Diet in Renal Disease [MDRD] formula or currently on dialysis.
  14. Non-compensated congestive heart failure, hospitalization for congestive heart failure or treatment for acute coronary syndrome (myocardial infarction or unstable angina) within 3 months of the Screening Visit, current uncontrolled arrhythmia or current uncontrolled blood pressure (>160/100 mmHg) prior to Week -6.
  15. 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.
  16. Prior treatment with another recombinant uricase (rasburicase) or concomitant therapy with a PEG-conjugated drug.
  17. Known allergy to pegylated products or history of anaphylactic reaction to a recombinant protein or porcine product.
  18. Contraindication to MTX treatment or MTX treatment considered inappropriate.
  19. Known intolerance to MTX.
  20. Receipt of an investigational drug within 4 weeks or 5 half-lives, whichever is longer, prior to MTX administration at Week -6 or plan to take an investigational drug during the trial.
  21. Current liver disease, as determined by alanine transaminase (ALT) or aspartate transaminase (AST) >1.25 × upper limit of normal (ULN) or albumin <lower limit of normal at the Screening Visit.
  22. Currently receiving systemic or radiologic treatment for ongoing cancer, excluding nonmelanoma skin cancer.
  23. History of malignancy within 5 years other than non-melanoma skin cancer or in situ carcinoma of cervix.
  24. White blood cell count <4.0 × 10^9/L, hematocrit <32% or platelet count <75 × 10^9/L.
  25. Diagnosis of osteomyelitis.
  26. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as Lesch-Nyhan and Kelley-Seegmiller syndrome.
  27. Unsuitable candidate for the trial (e.g., cognitive impairment), based on the opinion of the Investigator, 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.
  28. Alcohol use in excess of 3 alcoholic beverages per week.
  29. A known intolerance to all protocol standard gout flare prophylaxis regimen (i.e., unable to tolerate any of the following 3 agents: colchicine, NSAIDs or low- dose prednisone ≤10 mg/day).
  30. 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 ClinicalTrials.gov identifier (NCT number): NCT04772313


Contacts
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Contact: Horizon Therapeutics 1-866-479-6742 clinicaltrials@horizontherapeutics.com

Locations
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United States, Alabama
University of Alabama at Birmingham (UAB) - Center for Education & Research on Therapeutics of Musculoskeletal Disorders Recruiting
Birmingham, Alabama, United States, 35294-0002
Contact: S Biggers       sbiggers@uabmc.edu   
Principal Investigator: Kenneth Saag, MD         
United States, Arizona
Arizona Arthritis and Rheumatology Associates Recruiting
Flagstaff, Arizona, United States, 86001
Contact: D Boyd    480-443-8400    Delia.boyd@azarthritis.com   
Principal Investigator: Alexander Hu, DO         
Arizona Arthritis and Rheumatology Associates Recruiting
Glendale, Arizona, United States, 85306
Contact: D Santimaw       gloria.santimaw@azarthritis.com   
Principal Investigator: John Tesser, MD         
Arizona Arthritis and Rheumatology Associates Recruiting
Mesa, Arizona, United States, 85210
Contact: Brittany Blackwell       Brittany.blackwell@azarthritis.com   
Principal Investigator: Ralph Bennett, MD         
United States, California
UCLA Withdrawn
Los Angeles, California, United States, 90095
East Bay Rheumatology Medical Group Not yet recruiting
San Leandro, California, United States, 94578
Contact: S Radillo       sradilo@ebrri.com   
Principal Investigator: Sundeep Grewal, MD         
Providence St. John's Health Clinic Recruiting
Santa Monica, California, United States, 90404
Contact: O Pimienta       olga.pimienta@providence.org   
Principal Investigator: Orrin Troum, MD         
United States, Colorado
University of Colorado Anschutz Medical Campus Not yet recruiting
Aurora, Colorado, United States, 80045-2536
Contact: Chong Pedrick       CHONG.PEDRICK@CUANSCHUTZ.EDU   
Principal Investigator: Christopher Striebich, MD         
United States, Florida
Life Clinical Trials Recruiting
Margate, Florida, United States, 33063
Contact: L hernandez       lhernandez@lifeclinicaltrials.com   
Principal Investigator: Jirair Shah, MD         
IRIS Research and Development, LLC Recruiting
Plantation, Florida, United States, 33324
Contact: K Perez, MD       kperez@irisrheumatology.com   
Principal Investigator: Guillermo Valenzuela, MD         
Napa Research Recruiting
Pompano Beach, Florida, United States, 33046
Contact: G Fernandez       gfernandez@napatrials.com   
Principal Investigator: Naval Parikh, MD         
GCP Clinical Research, LLC Recruiting
Tampa, Florida, United States, 33609
Contact: M Klingeman       Study-Team@GCPclinicalresearch.com   
Principal Investigator: Karon Locicero, MD         
United States, Maryland
The Center for Rheumatology and Bone Research Recruiting
Wheaton, Maryland, United States, 20902
Contact: M Lormore       mlormore@arapc.com   
Principal Investigator: Herbert S Baraf, MD         
United States, Pennsylvania
Altoona Center for Clinical Research Recruiting
Duncansville, Pennsylvania, United States, 16635
Contact: Pam Morrison         
Principal Investigator: Alan Kivitz, MD         
United States, Texas
Biopharma Informatic, LLC Recruiting
Houston, Texas, United States, 77043
Contact: O Adewola       olajumoke@biopharmainfo.net   
Principal Investigator: Abigail Neiman, MD         
United States, Washington
Western Washington Arthritis Clinic Recruiting
Bothell, Washington, United States, 98021
Contact: K Lockhart       klockhart@wwmedgroup.com   
Principal Investigator: Jeff Peterson, MD         
Sponsors and Collaborators
Horizon Therapeutics Ireland DAC
Investigators
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Study Director: Colleen Canavan Horizon Therapeutics
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Responsible Party: Horizon Therapeutics Ireland DAC
ClinicalTrials.gov Identifier: NCT04772313    
Other Study ID Numbers: HZNP-KRY-407
First Posted: February 26, 2021    Key Record Dates
Last Update Posted: August 30, 2021
Last Verified: August 2021
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
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics Ireland DAC ):
Gout
Additional relevant MeSH terms:
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Gout
Arthritis
Joint Diseases
Musculoskeletal Diseases
Crystal Arthropathies
Rheumatic Diseases
Purine-Pyrimidine Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Methotrexate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors
Folic Acid Antagonists
Immunosuppressive Agents
Immunologic Factors
Antirheumatic Agents
Nucleic Acid Synthesis Inhibitors