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

• ClinicalTrials.gov Identifier: NCT04772313
• Recruitment Status: Recruiting
• First Posted: February 26, 2021
• Last Update Posted: January 6, 2022
• Sponsor: Horizon Therapeutics Ireland DAC
• Information provided by (Responsible Party): Horizon Pharma Ireland, Ltd., Dublin Ireland ( Horizon Therapeutics Ireland DAC )

Study Description

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 for 20 participants who failed to maintain sUA response with pegloticase monotherapy with or without a history of pegloticase-related clinically mild infusion reactions.

Study Design

• 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

Arms and Interventions

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)

Outcome Measures

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. 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.
4. 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.
5. 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.
6. 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.

Eligibility Criteria

• 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.

Contacts and Locations

Contacts

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

Locations

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

East Bay Rheumatology Medical Group; 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; 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

• Study Director: Colleen Canavan; Horizon Therapeutics

More Information

• Responsible Party: Horizon Therapeutics Ireland DAC
• ClinicalTrials.gov Identifier: NCT04772313
• Other Study ID Numbers: HZNP-KRY-407
• First Posted: February 26, 2021
• Last Update Posted: January 6, 2022
• Last Verified: December 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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:

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