Study of Pegloticase (KRYSTEXXA®) Plus Methotrexate in Patients With Uncontrolled Gout

NCT03635957 | Completed Phase 4 Results DMC FDA Drug

• 1 other identifier: HZNP-KRY-201
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 6

Brief Summary

The overall objective of the study is to assess the efficacy, safety, tolerability, and pharmacokinetics (PK) of the concomitant use of pegloticase with methotrexate (MTX) to enhance the response rate seen with pegloticase alone in adults with uncontrolled gout.

Conditions

Gout

Keywords

gout; uncontrolled gout

Outcome Measures

Primary Outcomes (1)

• Percentage of Serum Uric Acid (sUA < 6 mg/dL) Responders During Month 6

  Serum uric acid (sUA \< 6 mg/dL) responders are defined as participants achieving and maintaining sUA \< 6 mg/dL for at least 80% of the time during Month 6 (Weeks 20, 22, and 24). Month 6 includes pre-infusion and post-infusion sUA assessments at Week 20, pre-infusion and post-infusion sUA assessments at Week 22, pre-infusion assessments at Week 24, and unscheduled sUA assessments between Week 20 and Week 24.

  Month 6 (Weeks 20, 22, and 24)

Secondary Outcomes (6)

• Percentage of Serum Uric Acid (sUA < 6 mg/dL) Responders During Month 3

  Month 3 (Weeks 10, 12, and 14)

• Percentage of Serum Uric Acid (sUA < 6 mg/dL) Overall Responders

  Month 3 and Month 6 combined (Weeks 10, 12, 14, 20, 22, and 24)

• Percentage of Serum Uric Acid (sUA < 5 mg/dL) Responders During Month 3

  Month 3 (Weeks 10, 12, and 14)

• Percentage of Serum Uric Acid (sUA < 5 mg/dL) Responders During Month 6

  Month 6 (Weeks 20, 22, and 24)

• Percentage of Serum Uric Acid (sUA < 5 mg/dL) Overall Responders

  Month 3 and Month 6 combined (Weeks 10, 12, 14, 20, 22, and 24)

Study Arms (1)

Pegloticase With Methotrexate (MTX)

EXPERIMENTAL

Run-In Period: oral MTX at a dose of 15 mg weekly for 4 weeks prior to the first dose of pegloticase. Pegloticase + Immunomodulator (IMM) Period: pegloticase 8 mg administered intravenously (IV) every 2 weeks from Day 1 through the Week 50 Visit for a total of 26 infusions. MTX 15 mg weekly on the same day each week, within 1 to 3 days prior to each pegloticase infusion and one additional weekly dose after the last infusion.

Biological: Pegloticase; Drug: Methotrexate (MTX); Drug: Standard Gout Flare Prophylaxis; Drug: Infusion Reaction (IR) Prophylaxis; Dietary Supplement: Folic Acid

Interventions

Pegloticase BIOLOGICAL

pegloticase administered intravenously (IV)

Pegloticase With Methotrexate (MTX)

Methotrexate (MTX) DRUG

oral MTX

Pegloticase With Methotrexate (MTX)

Standard Gout Flare Prophylaxis DRUG

It is required that before a subject begins the Pegloticase + IMM Period, he or she has been taking 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) for ≥1 week before the first dose of pegloticase and continues 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 patients with no tophi detected on physical exam, or 3) 6 months after achieving target serum urate (sUA \< 5 mg/dL) for patients with one or more tophi detected on initial physical exam that have since resolved.

Pegloticase With Methotrexate (MTX)

Infusion Reaction (IR) Prophylaxis DRUG

For IR prophylaxis, fexofenadine (60 mg or 180 mg orally based on the Principal Investigator's discretion) will be taken the day before each infusion; fexofenadine (60 mg or 180 mg orally based on the Principal Investigator's discretion) and acetaminophen (1000 mg orally) will be taken the morning of each infusion; and methylprednisolone (125 mg IV) given over the infusion duration 10-30 minutes (recommended) or hydrocortisone (200 mg IV) will be administered immediately prior to each infusion.

Pegloticase With Methotrexate (MTX)

Folic Acid DIETARY_SUPPLEMENT

Subjects will also take folic acid 1 mg orally every day beginning at Week -4 (the start of MTX) and continuing until prior to the Week 52 Visit.

Pegloticase With Methotrexate (MTX)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Willing and able to give informed consent.
• Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the study.
• Adult men or women ≥18 to ≤65 years of age.
• 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 the Screening/(methotrexate) MTX Run in Period; participants 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 -4 (start of MTX dosing) and continue for 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.
• Men who are not vasectomized must not impregnant their female partner during the study and for at least 3 months after the last dose of MTX.
• Hyperuricemia at the Screening, Week -4, or Week -2 Visit of the Screening/MTX Run in Period, as documented by sUA ≥6 mg/dL.
• Uncontrolled gout, defined as meeting the following criteria:
• serum uric acid (sUA) ≥6 mg/dL prior to entry into the pegloticase +IMM Period (any laboratory tests during screening up to and including during the MTX Run in Period) and at least 1 of the following: inability to maintain sUA \<6 mg/dL on other urate-lowering therapy; intolerable side effects associated with current urate-lowering therapy; functionally limiting tophaceous deposits (including those detected clinically or by dual-energy computed tomography \[DECT\] imaging)
• Able to tolerate MTX 15 mg for 4 weeks during the MTX Run-in Period prior to the first dose of pegloticase.

You may not qualify if:

• Weight \>160 kg (352 pounds).
• Any serious acute bacterial infection, unless treated and completely resolved with antibiotics at least 2 weeks prior to the Week -4 Visit of the MTX Run-in Period.
• Severe chronic or recurrent bacterial infections, such as recurrent pneumonia or chronic bronchiectasis.
• Current immunocompromised condition, including current or chronic treatment with systemic immunosuppressive agents, including prednisone \>10 mg/day or equivalent dose of other corticosteroid.
• History of any transplant surgery requiring maintenance immunosuppressive therapy.
• Known history of hepatitis B virus surface antigen positivity or hepatitis B DNA positivity.
• Known history of hepatitis C virus RNA positivity.
• Human immunodeficiency virus (HIV) positivity (tested at the Screening Visit).
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency (tested at the Screening Visit).
• Severe chronic renal impairment (glomerular filtration rate \<25 mL/min/1.73 m\^2) or currently on dialysis.
• 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) at the end of the Screening/MTX Run-in Period.
• Pregnant, planning to become pregnant, breastfeeding, planning to impregnant female partner, or not on an effective form of birth control, as determined by the Investigator.
• Prior treatment with pegloticase (KRYSTEXXA®), another recombinant uricase (rasburicase), or concomitant therapy with a polyethylene glycol-conjugated drug.
• Known allergy to pegylated products or history of anaphylactic reaction to a recombinant protein or porcine product.
• Contraindication to MTX treatment or MTX treatment considered inappropriate.

Sponsors & Collaborators

• Amgen: lead

Study Sites (6)

Orthopedic Physicians Alaska

Anchorage, Alaska, 99508, United States

Location

Arizona Arthritis & Rheumatology -West Valley

Glendale, Arizona, 85306, United States

Location

Arizona Arthritis & Rheumatology -East Valley

Mesa, Arizona, 85210, United States

Location

Avail Clinical Research

DeLand, Florida, 32720, United States

Location

Western Washington Arthritis Clinic

Bothell, Washington, 98021, United States

Location

Arthritis Northwest PLLC

Spokane, Washington, 99204, United States

Location

Related Publications (4)

• Botson JK, Obermeyer K, LaMoreaux B, Zhao L, Weinblatt ME, Peterson J. Improved joint and patient-reported health assessments with pegloticase plus methotrexate co-therapy in patients with uncontrolled gout: 12-month exploratory outcomes of the MIRROR open-label trial. Arthritis Res Ther. 2022 Dec 27;24(1):281. doi: 10.1186/s13075-022-02979-4.

  PMID: 36575505 DERIVED

• Botson JK, Tesser JRP, Bennett R, Kenney HM, Peloso PM, Obermeyer K, Song Y, LaMoreaux B, Zhao L, Xin Y, Chamberlain J, Ramanathan S, Weinblatt ME, Peterson J. A multicentre, efficacy and safety study of methotrexate to increase response rates in patients with uncontrolled gout receiving pegloticase (MIRROR): 12-month efficacy, safety, immunogenicity, and pharmacokinetic findings during long-term extension of an open-label study. Arthritis Res Ther. 2022 Aug 25;24(1):208. doi: 10.1186/s13075-022-02865-z.

  PMID: 36008814 DERIVED

• Dalbeth N, Becce F, Botson JK, Zhao L, Kumar A. Dual-energy CT assessment of rapid monosodium urate depletion and bone erosion remodelling during pegloticase plus methotrexate co-therapy. Rheumatology (Oxford). 2022 Nov 28;61(12):4898-4904. doi: 10.1093/rheumatology/keac173.

  PMID: 35293984 DERIVED

• Botson JK, Tesser JRP, Bennett R, Kenney HM, Peloso PM, Obermeyer K, LaMoreaux B, Weinblatt ME, Peterson J. Pegloticase in Combination With Methotrexate in Patients With Uncontrolled Gout: A Multicenter, Open-label Study (MIRROR). J Rheumatol. 2021 May;48(5):767-774. doi: 10.3899/jrheum.200460. Epub 2020 Sep 15.

  PMID: 32934137 DERIVED

MeSH Terms

Conditions

Gout

Interventions

Pegloticase; Methotrexate; Folic Acid

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Crystal Arthropathies; Rheumatic Diseases; Purine-Pyrimidine Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

One participant was dosed with MTX in the Run-In Period (MTX tolerance period) but was lost to follow up prior to the per protocol enrollment at Day 1. This participant was a screen failure but is included in Run-in period data (including safety).

Results Point of Contact

• Title: Paul Peloso, MD
• Organization: Horizon Therapeutics Ireland DAC

clinicaltrials@horizontherapeutics.com

866-479-6742

Study Officials

• MD

  Amgen

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 9, 2018
• First Posted: August 17, 2018
• Study Start: September 26, 2018
• Primary Completion: October 23, 2019
• Study Completion: October 26, 2020
• Last Updated: June 26, 2024
• Results First Posted: November 18, 2020

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• 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 (or other new use) 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.
• 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, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. 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.

Locations

US (6)