Study of KRYSTEXXA® (Pegloticase) Plus Methotrexate in Participants With Uncontrolled Gout
Condition: Gout
MeSH terms: Gout
Intervention: Pegloticase; methotrexate; placebo; folic acid; gout flare prophylaxis regimen; fexofenadine; acetaminophen; methylprednisolone
Intervention description: IV pegloticase 8 mg Q2W; Oral MTX 15 mg weekly; Oral placebo for MTX; Folic acid 1 mg orally every day beginning at Week -6 until prior to the Week 52 Visit.; Prior to beginning the Pegloticase + IMM Period, participants must have been taking at least 1 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 to continue 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 participants with no tophi detected on physical exam, or 3) 6 months after achieving target serum urate (sUA < 5 mg/dL) for participants with one or more tophi detected on initial physical exam that then resolved.; For IR prophylaxis, fexofenadine (180 mg orally) taken the day before each infusion and on the morning of each infusion.; For IR prophylaxis, acetaminophen (1000 mg orally) taken the morning of each infusion.; For IR prophylaxis, methylprednisolone (125 mg IV) given over an infusion duration between 10 - 30 minutes, immediately prior to each infusion.
Intervention MeSH terms: Acetaminophen; Folic Acid; Fexofenadine; Methylprednisolone; Methotrexate
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 152.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: gout; uncontrolled gout

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.
    

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.