Study of Pegloticase (KRYSTEXXA®) Plus Methotrexate in Patients With Uncontrolled Gout
Condition: Gout
MeSH terms: Gout
Intervention: Pegloticase; Methotrexate (MTX); Standard Gout Flare Prophylaxis; Infusion Reaction (IR) Prophylaxis; Folic Acid
Intervention description: pegloticase administered intravenously (IV); oral MTX; 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.; 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.; 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.
Intervention MeSH terms: Folic Acid; Methotrexate
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: gout; uncontrolled gout

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.
    

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 to ≤65 years of age.

          4. 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.

          5. 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.

          6. Hyperuricemia at the Screening, Week -4, or Week -2 Visit of the Screening/MTX Run in
             Period, as documented by sUA ≥6 mg/dL.

          7. 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)

          8. Able to tolerate MTX 15 mg for 4 weeks during the MTX Run-in Period prior to the first
             dose of pegloticase.

        Exclusion Criteria:

          1. Weight >160 kg (352 pounds).

          2. 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.

          3. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia or
             chronic bronchiectasis.

          4. Current immunocompromised condition, including current or chronic treatment with
             systemic immunosuppressive agents, including prednisone >10 mg/day or equivalent dose
             of other corticosteroid.

          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.

          8. Human immunodeficiency virus (HIV) positivity (tested at the Screening Visit).

          9. Glucose-6-phosphate dehydrogenase (G6PD) deficiency (tested at the Screening Visit).

         10. Severe chronic renal impairment (glomerular filtration rate <25 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) at the end of the Screening/MTX Run-in Period.

         12. 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.

         13. Prior treatment with pegloticase (KRYSTEXXA®), 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 study.

         18. Current liver disease, as determined by alanine transaminase or aspartate transaminase
             levels >3 times upper limit of normal at the Screening Visit.

         19. Currently receiving systemic or radiologic treatment for ongoing cancer, excluding non
             melanoma skin cancer.

         20. History of malignancy within 5 years other than non-melanoma skin cancer or in situ
             carcinoma of cervix.

         21. Uncontrolled hyperglycemia with a plasma glucose value >240 mg/dL at screening that is
             not subsequently controlled by the end of the Screening/MTX Run-in Period.

         22. Diagnosis of osteomyelitis.

         23. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such as
             Lesch-Nyhan and Kelley-Seegmiller syndrome.

         24. 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
             participant or interfere with the participant's ability to comply with the protocol
             requirements or complete the study.

         25. Alcohol use in excess of 3 alcoholic beverages per week.

         26. Currently receiving allopurinol and unable to discontinue medication 7 days prior to
             MTX dosing at Week -4 and unable to discontinue treatment during the duration of the
             study.