Clinical trial: A Phase 4, Open-label Study of KRYSTEXXA® (Pegloticase) Co-administered With Methotrexate (MTX) in Patients With Uncontrolled Gout (FORWARD OL) (NCT04762498)

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 and <80 years of age.

          4. Uncontrolled gout, defined as meeting 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 one tophus

               -  Recurrent flares defined as 2 or more flares in the past 12 months prior to
                  screening

               -  Presence of chronic gouty arthritis as evidenced by either clinical signs
                  consistent with chronic synovitis on clinical examination or the presence of
                  typical gouty erosion(s) on hand and/or foot X-rays

          5. Willing to discontinue any oral urate lowering therapy for at least 7 days prior to
             MTX dosing at Week -4 and remain off while receiving pegloticase treatments.

          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 -4; subjects must agree to use 2
             reliable forms of contraception during the trial, 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) and continue for 4 weeks/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.

          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 trial, beginning with
             the initiation of MTX at Week -4 and continuing and for at least 3 months after the
             last dose of MTX.

          8. Able to tolerate MTX 15 mg orally for 4 weeks (Week -4 through Day 1) prior to
             enrollment.

        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 Day 1 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 RNA positivity, unless treated and viral load is
             negative.

          8. Known history of Human Immunodeficiency Virus (HIV) positivity.

          9. Glucose-6-phosphate dehydrogenase deficiency (tested at the Screening Visit centrally
             or locally).

         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 enrollment at Day 1.

         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 -4 or plans to take an investigational
             drug during the trial.

         18. Liver transaminase levels (AST or ALT) > 1.25 X 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 <4000/µl, hematocrit <32 percent, or platelet count <75,000/µl.

         21. Currently receiving systemic or radiologic treatment for ongoing cancer, excluding
             non-melanoma skin 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 trial, 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 trial.

         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.
No condition on gender to be admitted to the trial.
No healthy subjects accepted to join the trial.
Subject must be at least 18 Years old.
Subject must be at most 80 Years

Patient description (medical language): A 39-year-old man comes to the emergency department with an acute onset of severe left toe pain.  The toe is red and exhibits swelling. The patient is not febrile, and does not remember any recent trauma. Medical history is not significant except for the similar attacks and the diagnosis of gouty arthritis. His medication history includes Allopurinol to prevent gouty attacks. His father has the same medical condition. However, his older brother who is 41 years old is healthy with no history of gouty arthritis. Physical examination shows a swollen, tender first metatarsophalangeal joint.  Aspiration of the joint showed high leukocyte count, negative Gram stain, and numerous needle-shaped crystals, which is compatible with gouty arthritis.

Patient description (patient's own words): I'm a 39-year-old man and got admitted to the ER after an unbearable pain in my left toe. My toe was red and terribly swollen. I was still standing on my feet, not febrile and I don't remember hitting my head or anything. I don't have any special medical history, but I had been diagnosed with gout before. I take Lopurin to prevent my gouty attacks. My dad had the same problem, but my 41-year-old brother is healthy and does not have gouty attacks. The doctor did a physical exam and found that the joints between my toes and the rest of my foot were swollen and tender. The doctor renewed his diagnosis of gouty arthritis.

Does the patient match the trial criteria? Contradiction