A Trial to Investigate the Non-inferiority of Pegloticase Administered Every 4 Weeks (Q4W) With MTX Compared With Every 2 Weeks (Q2W) With MTX in Participants With Uncontrolled Refractory Gout

Inclusion Criteria:

1. Adult men or women ≥ 18 years of age

2. 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 atthe maximum medically appropriate dose, or with a contraindication to xanthineoxidase inhibitor therapy based on medical record review or participantinterview, and;

• Symptoms of gout

3. Willing to discontinue any oral ULT for at least 7 days prior to MTX dosing at Week -4 and continue not receiving any oral ULT when receiving pegloticase/placebo forpegloticase infusions

4. Women of childbearing potential must have negative serum/urine pregnancy testsduring screening and Week -4.

5. Men who are not vasectomized must agree to use appropriate contraception, so as tonot impregnate a female partner of reproductive potential during the trial.

Exclusion Criteria:

1. Severe chronic or recurrent bacterial infections, such as recurrent pneumonia orchronic bronchiectasis

2. Current or chronic treatment with systemic immunosuppressive agents, such as MTX,azathioprine or mycophenolate mofetil; prednisone > 10 mg/day or equivalent dose ofother corticosteroid on a chronic basis (3 months or longer)

3. History of any transplant surgery requiring maintenance immunosuppressive therapy

4. Known history of hepatitis B virus surface antigen positivity or hepatitis B DNApositivity

5. Known history of hepatitis C virus RNA positivity, unless treated and viral load isnegative

6. Known history of human immunodeficiency virus (HIV) positivity

7. G6PD deficiency (quantitative test at the Screening Visit centrally or locally)

8. Non-compensated congestive heart failure or hospitalization for congestive heartfailure within 3 months of the Screening Visit, uncontrolled arrhythmia, treatmentfor acute coronary syndrome (myocardial infarction or unstable angina) oruncontrolled blood pressure (> 160/100 mmHg) prior to Week -4

9. Pregnant, planning to become pregnant, breastfeeding, planning to impregnate femalepartner or not on an effective form of birth control, as determined by theInvestigator

10. Prior treatment with pegloticase, another recombinant uricase (rasburicase) orconcomitant therapy with a PEG-conjugated drug

11. Unable to tolerate MTX 15 mg orally during the MTX Run-in Period

12. Chronic liver disease

13. White blood cell count < 4,000/μL, hematocrit < 32% or platelet count < 75,000/μL

14. Currently receiving systemic or radiologic treatment for ongoing cancer

15. History of malignancy within 5 years other than non-melanoma skin cancer or in situcarcinoma of cervix

16. Diagnosis of osteomyelitis

17. Known history of hypoxanthine-guanine phosphoribosyl-transferase deficiency, such asLesch-Nyhan and Kelley-Seegmiller syndrome

18. A known intolerance to all protocol-standard gout flare prophylaxis regimens (i.e.,participant must be able to tolerate at least 1 of the following: colchicine and/ornon-steroidal anti-inflammatory drugs and/or low-dose prednisone ≤ 10 mg/day)

19. Current pulmonary fibrosis, bronchiectasis or interstitial pneumonitis. If deemednecessary by the Investigator, a chest X-ray may be performed during Screening.