Pegloticase and Methotrexate Co-administered in Participants With Uncontrolled Gout Who Previously Failed Pegloticase Monotherapy
Condition: Uncontrolled Gout
MeSH terms: Gout
Intervention: Pegloticase; Methotrexate (MTX)
Intervention description: Participants will receive 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.; 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.
Intervention MeSH terms: Methotrexate
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 11.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Gout

Summary:

      This is a Phase 4, multicenter, open-label trial of pegloticase with methotrexate (MTX) in
      adult participants with uncontrolled gout who were previously treated with pegloticase
      without a concomitant immunomodulator and stopped pegloticase due to failure to maintain
      serum uric acid (sUA) response and/or a clinically mild infusion reaction (IR). 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
    

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 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 estimated glomerular filtration rate (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 serious adverse events
             (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. glucose-6-phosphate dehydrogenase (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 mm Hg) 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,nonsteroidal
             anti-inflammatory drugs (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.