Clinical trial NCT03994731: Study of KRYSTEXXA® (Pegloticase) Plus Methotrexate in Participants With Uncontrolled Gout
Official title: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy and Safety Study of Methotrexate to Increase Response Rates in Patients With Uncontrolled Gout Receiving KRYSTEXXA® (Pegloticase) (MIRROR Randomized Controlled Trial [RCT])
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Gout
Keywords: gout
uncontrolled gout
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2019-06-21
Enrollment: 152
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the potential for pegloticase with methotrexate (MTX) to increase the response rate seen with pegloticase alone, and to characterize the safety, tolerability and pharmacokinetics (PK) of the concomitant use of pegloticase with MTX, by comparing pegloticase co-administered with MTX to pegloticase co-administered with placebo for MTX in adults with uncontrolled gout.

Detailed description: Study acquired from Horizon in 2024.

Eligibility 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 study.
3. Adult men or women ≥18 years of age.
4. 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 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
5. Willing to discontinue any oral urate lowering therapy for at least 7 days prior to MTX dosing at Week -6 and remain off when receiving pegloticase infusions.
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 -6; subjects 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 -6 (start of MTX) and continue for 30 days after the last dose of pegloticase, or at least one ovulatory cycle after the last dose of MTX or placebo for MTX (whichever is the longest duration after the last dose of pegloticase or MTX or placebo for 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 study, beginning with the initiation of MTX at Week -6 and continuing and for at least 3 months after the last dose of MTX or placebo for MTX.
8. Able to tolerate MTX 15 mg orally for 2 weeks (Week -6 through Week -4) prior to randomization.

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 Week -6 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 ribonucleic acid (RNA) positivity.
8. Known history of Human Immunodeficiency Virus (HIV) positivity.
9. Glucose-6-phosphate dehydrogenase deficiency (tested at the Screening Visit).
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 Randomization at Week -4.
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 -6 or plans to take an investigational drug during the study.
18. Liver transaminase levels (aspartate aminotransferase \[AST\] or alanine aminotransferase \[ALT\]) \> 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 \< 4,000/µL, hematocrit \< 32 percent, or platelet count \< 75,000/µL.
21. Currently receiving systemic or radiologic treatment for ongoing 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 study, 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 study.
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.

Primary outcomes:
measure: Percentage of Serum Uric Acid (sUA) Responders (sUA < 6 mg/dL) During Month 6
timeFrame: Month 6 (Weeks 20, 21, 22, 23 and 24)
Secondary outcomes:
measure: Percentage of sUA (sUA < 6 mg/dL) Responders During Month 12
timeFrame: Month 12 (Weeks 48, 50 and 52)
measure: Percentage of Participants With Complete Resolution of ≥ 1 Tophi at Week 52
timeFrame: Baseline, Week 52
measure: Mean Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Score at Week 52
timeFrame: Baseline, Week 52
measure: Mean Change From Baseline HAQ Pain Score at Week 52
timeFrame: Baseline, Week 52
measure: Mean Change From Baseline in HAQ Health Score at Week 52
timeFrame: Baseline, Week 52
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Anchorage
country: United States
facility: Orthopedic Physicians Alaska
state: Alaska
city: Flagstaff
country: United States
facility: Arizona Arthritis and Rheumatology Research, PLLC - Flagstaff
state: Arizona
city: Glendale
country: United States
facility: Arizona Arthritis and Rheumatology Research, PLLC-West
state: Arizona
city: Mesa
country: United States
facility: Arizona Arthritis and Rheumatology Research, PLLC-East
state: Arizona
city: Little Rock
country: United States
facility: Applied Research Center of Arkansas, Inc
state: Arkansas
city: El Cajon
country: United States
facility: TriWest Research Associates
state: California
city: Hawthorne
country: United States
facility: Advanced Investigative Medicine, Inc.
state: California
city: Los Angeles
country: United States
facility: Axis Clinical Trials
state: California
city: Poway
country: United States
facility: ACRC Studies
state: California
city: Roseville
country: United States
facility: ClinEdge Sierra Rheumatology, Inc.
state: California
city: San Leandro
country: United States
facility: East Bay Rheumatology Medical Group, Inc.
state: California
city: Santa Monica
country: United States
facility: Providence St. John's Health Clinic
state: California
city: Tujunga
country: United States
facility: Medvin Clinical Research
state: California
city: Van Nuys
country: United States
facility: San Fernando Valley Health Institute
state: California
city: Ventura
country: United States
facility: Ventura Clinical Trials
state: California
city: Aurora
country: United States
facility: University of Colorado Division of Rheumatology
state: Colorado
city: Denver
country: United States
facility: Denver Arthritis Clinic
state: Colorado
city: DeLand
country: United States
facility: Avail Clinical Research
state: Florida
city: Doral
country: United States
facility: Prohealth Research Center
state: Florida
city: Orlando
country: United States
facility: Omega Research Maitland
state: Florida
city: Pinellas Park
country: United States
facility: DMI Research
state: Florida
city: Pompano Beach
country: United States
facility: Napa Research Center
state: Florida
city: Tampa
country: United States
facility: GCP Clinical Research
state: Florida
city: Zephyrhills
country: United States
facility: Florida Medical Clinic, LLC
state: Florida
city: Meridian
country: United States
facility: St. Luke's Clinic - Rheumatology
state: Idaho
city: Oxon Hill
country: United States
facility: MD Medical Research
state: Maryland
city: Wheaton
country: United States
facility: The Center for Rheumatology and Bone Research
state: Maryland
city: Grand Rapids
country: United States
facility: Infusion Associates
state: Michigan
city: Saint Clair Shores
country: United States
facility: Clinical Research Institute of Michigan, LLC
state: Michigan
city: Great Falls
country: United States
facility: Benefis Hospital
state: Montana
city: Lincoln
country: United States
facility: Physician Research Collaboration, LLC
state: Nebraska
city: Santa Fe
country: United States
facility: Santa Fe Rheumatology
state: New Mexico
city: Babylon
country: United States
facility: Long Island Arthritis & Osteoporosis Care
state: New York
city: Orchard Park
country: United States
facility: Buffalo Rheumatology and Medicine
state: New York
city: Concord
country: United States
facility: NorthEast Rheumatology/Atrium Health
state: North Carolina
city: Concord
country: United States
facility: NorthEast Rheumatology
state: North Carolina
city: Greensboro
country: United States
facility: Medication Management, LLC
state: North Carolina
city: Hickory
country: United States
facility: ClinEdge PMG Research of Hickory, LLC
state: North Carolina
city: Salisbury
country: United States
facility: ClinEdge PMG Research of Salisbury, LLC
state: North Carolina
city: Shelby
country: United States
facility: Shelby Clinical Research, LLC
state: North Carolina
city: Wilmington
country: United States
facility: PMG Research of Wilmington, LLC
state: North Carolina
city: Dayton
country: United States
facility: Premier Clinical/STAT Research
state: Ohio
city: Middleburg Heights
country: United States
facility: Paramount Medical Research & Consulting, LLC
state: Ohio
city: Perrysburg
country: United States
facility: Clinical Research Source Inc.
state: Ohio
city: Springboro
country: United States
facility: Premier Clinical/STAT Research - Springboro
state: Ohio
city: Duncansville
country: United States
facility: Altoona Center for Clinical Research
state: Pennsylvania
city: Greenville
country: United States
facility: Piedmont Arthritis Clinic
state: South Carolina
city: Summerville
country: United States
facility: Articularis Healthcare Group
state: South Carolina
city: Jackson
country: United States
facility: West Tennessee Research Institute
state: Tennessee
city: Memphis
country: United States
facility: Ramesh C. Gupta, M.D.
state: Tennessee
city: Houston
country: United States
facility: Diagnostic and Interventional Nephrology Of Houston
state: Texas
city: Houston
country: United States
facility: Research Consultants - Frostwood
state: Texas
city: Houston
country: United States
facility: Research Consultants - Astoria
state: Texas
city: San Marcos
country: United States
facility: Arthritis Clinic of Central Texas
state: Texas
city: Waco
country: United States
facility: Arthritis & Osteoporosis Clinic - Waco
state: Texas
city: Webster
country: United States
facility: Clear Lake Specialties
state: Texas
city: Bothell
country: United States
facility: Western Washington Arthritis Clinic
state: Washington
city: Spokane
country: United States
facility: Arthritis Northwest
state: Washington
city: Glendale
country: United States
facility: Rheumatic Disease Center
state: Wisconsin
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References: