A Phase Ib Clinical Trial of Peguricase for Injection With Methotrexate in Patients With Uncontrolled Gout.

A Phase Ib Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamic Characteristics, and Initial Efficacy of Single and Multiple Dosing of Peguricase for Injection With Methotrexate in Patients With Gout.

To evaluate the safety and tolerability of peguricase for injection with methotrexate in patients with gout who remain uncontrolled after standardized treatment with conventional uric acid-lowering drugs, to determine the recommended dose for phase II clinical trials, and to provide basis for formulation of administration regimen for phase II clinical trials.

To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamic characteristics, and initial efficacy of single and multiple dosing of peguricase for injection with methotrexate in patients with gout who remain uncontrolled after standardized treatment with conventional uric acid-lowering drugs.

This study is a phase Ib single and multiple dosing, dose-increasing. Three dose groups of 4, 8 or 12 mg were planned, then exploring the most appropriate dose for phase II clinical trials, and to provide basis for formulation of administration regimen for phase II clinical trials.

Inclusion Criteria:

• Willing and able to give informed consent.
• Male and female aged between 18 and 70 years old , regardless of gender.
• Male weight ≥50 kg, female weight ≥45 kg, body mass index (BMI) in the range of (19-30) kg/m2 (including 19 and 30)；
• The clinical diagnosis of gout met the criteria of American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) in 2015，patients were in non-acute attack at screening or at least 2 weeks after complete remission of acute attack, and sUA ≥420 μmol/L at screening；
• Patients whose serum uric acid level could not reach the target after standard treatment with conventional uric acid-lowering drugs or who were contraindicated or intolerant to conventional uric acid-lowering drugs；
• Patients who were willing to stop taking any uric-acid-lowering drug at least 7 days before using methotrexate during the run-in period;
• Could tolerate the prescribed dose of methotrexate during the run-in period;
• Patients were able to attend and complete the visit on time.

Exclusion Criteria:

• Patients had active systemic infection within 2 weeks before enrollment，including an infection for which treatment was being received；
• Having a chronic or recurrent infection, such as recurrent pneumonia or chronic bronchitis; Patients with active or severe lung disease or pulmonary insufficiency on chest imaging, or current pulmonary fibrosis or bronchiectasis；
• Patients who are on anti-TB treatment or have active TB；
• Diagnosis of osteomyelitis；
• Ongoing or long-term use of immune system modulating drugs, such as methotrexate, mercaptopurine, mycophanolate, long-term use (≥3 months) of prednisone ≥10 mg/ day or equivalent dose of corticosteroids; Or have a history of transplant surgery requiring long-term immunotherapy; Or a known history of autoimmune disease, allergic disease;
• Known allergy to recombinant proteins or porcine products, or history of allergy to uricase, pegylated products, corticosteroids and antihistamines, or known intolerance to methotrexate, fexofenadine, acetaminophen or contraindications to methotrexate, fexofenadine, acetaminophen;
• Patients who are known to be intolerant to all gout attack management regiments (participants must be able to tolerate at least one: Colchicine and/or Nsaids and/or Prednisone 0.5 mg/kg daily；
• Patients who have previously been treated with pegyluricase or other recombinant uricase, or who have been treated with other pegylated biological products;
• Participation in other clinical study with a drug intervention within 4 weeks before initiation of methotrexate or the drug was still in the elimination phase before screening (within 5 half-lives), whichever is older;
• Patients with chronic liver disease such as hepatitis, cirrhosis, alcoholic liver disease;
• Patients have unstable angina, severe arrhythmias requiring drug intervention, congestive heart failure (NYHA grade≥Ⅱ), uncontrolled hypertension (over 150/95 mmHg), poor glycemic control in diabetics ( HbA1c≥7%), acute stroke, Severe or chronic hemorrhagic digestive disease, pleural and abdominal effusion;
• A history of hypoxanthine-guanine phosphoribosyltransferase deficiency, such as Lesch-Nyhan and Kelley-Seegmiller syndrome;
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency or G6PD test values below the lower limit of normal;
• Estimated glomerular filtration rate (eGFR) ≤40 mL/min/1.73m2, or currently receiving dialysis, or end-stage renal disease (CKD4-5);
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) above the upper limit of normal value or albumin below the lower limit of normal value during screening (before methotrexate treatment);
• Use of any blood component, short-acting or long-acting growth factor drugs within 14 days prior to screening, or white blood cell count < 4×109/L, hematopoietic volume < 32%, or platelet count < 75×109/L;
• Receiving anticoagulant therapy or international normalized ratio (INR) > 1.5×ULN or activated partial thromboplastin time (APTT) > 1.5×ULN before enrollment;
• Receiving systemic or local radiotherapy for tumors, or history of malignancy within 5 years other than non-melanoma skin cancer or in situ carcinoma of cervix;
• Any acute illness that was considered by the investigator to be likely to affect the study occurred within 1 month before screening;
• Donated (or lost) blood and donated (or lost) ≥400 mL or received blood transfusion within 3 months before screening;
• If any one of the five serological tests of hepatitis B was positive except for hepatitis B surface antibody, or hepatitis C antibody positive, treponema pallidum antibody positive or HIV antibody positive in serum virology examination;
• History of drug or substance abuse, or a positive drug screening test;
• History of alcohol abuse in the 3 months before screening [drinking more than 14 units of alcohol per week (1 unit ≈360 mL of beer)] or 45 mL of 40% spirits or 150 mL of wine)]; or positive alcohol breath test on admission;
• Lactating women, as well as male participants (or their partners) or female participants 30 days before the study to the end of the study, who have plans for pregnancy or sperm or egg donation within 6 months and are unwilling to take effective contraceptive measures;
• Patients have serious mental and psychological disorders, cognitive disorders and the existence of a history of mental illness.
• The investigator considered it inappropriate to participate in the study.