A Study Exploring Efficacy of Pegloticase in Subjects With Asymptomatic Hyperuricemia

Study Overview
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Brief Summary
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The main purpose To evaluate the safety and tolerability of pegloticase in subjects with asymptomatic hyperuricemia by single intravenous infusion at different doses, and to provide a basis for multiple doses of Pegloticase in subjects with asymptomatic hyperuricemia. A secondary purpose To evaluate the pharmacokinetics, pharmacodynamics and immunogenicity of Pegloticase with single-pass intravenous drip in subjects with asymptomatic hyperuricemia. Exploratory purpose Plasma uricase activity (pUox) analysis of pegloticase with single-pass intravenous drip in subjects with asymptomatic hyperuricemia.

Detailed Description
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To evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics analysis of pegloticase in subjects with asymptomatic hyperuricemia. This is a phase I randomized, double-blind, placebo-controlled and dose-increasing single dosing study. Five dose groups of 1, 2, 4, 8 or 12 mg were planned to explore the most appropriate dose and to provide a basis for multiple doses of Pegloticase in subjects with asymptomatic hyperuricemia.

Official Title
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A Phase I Randomized, Double-blind, Placebo-controlled, Dose-increasing Single Dose Study Evaluating the Safety, Tolerability，Pharmacokinetics and Pharmacodynamics Analysis of Pegloticase in Subjects With Asymptomatic Hyperuricemia

Conditions
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Asymptomatic Hyperuricemia

Intervention / Treatment
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* Drug: SIBP-R002
* Drug: Dexamethasone or Methyl prednisolone
* Drug: Diphenhydramine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The subjects voluntarily participated in the study and signed the informed consent. Male and female aged between 18 and 65 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), and no central obesity (waist circumference <90 cm for men, waist circumference <85 cm for women); Patients diagnosed as hyperuricemia according to The Chinese Guidelines for the Diagnosis and Treatment of Hyperuricemia and Gout (2019), namely, patients whose blood uric acid level exceeds 480 μmol/L twice on other days, and no clinical symptoms related to hyperuricemia such as arthritis; Agree to use effective contraceptive methods (including but not limited to abstinence, physical or hormonal contraception, but not hormonal contraception during the study) from signing the informed consent form until 6 months after the infusion of the study drug; The subjects can attend the interview on time and complete the interview content. Exclusion Criteria: People who have a history of gout and are using or have used other medications to control uric acid levels in the last 3 months, Asymptomatic hyperuricemia patients who stopped taking uricate-lowering drugs for more than 3 months were excluded. Secondary hyperuricemia (such as kidney disease, blood system disease, tumor chemotherapy or drug induced). Urolithiasis, or renal, ureteral calculi, urate crystal deposition indicated by ultrasound during screening; The presence of tophi or joint/bursa involvement was indicated by junction ultrasonography. Autoimmune disease, allergic disease, prior known food or drug allergy. Allergic reactions to recombinant proteins or pig products, or to uricase, polyethylene glycol, corticosteroids and antihistamines. Patients who have previously been treated with pegyluricase or other recombinant uricase, or who have been treated with other pegylated biological products. 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%), end-stage renal disease (CKD4-5), acute stroke, chest imaging suggesting active or severe lung disease, requiring dialysis, organ transplant recipients, and patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Serum creatinine was 1.5 times higher than the upper limit of normal value, and serum transaminase baseline level was 1.5 times higher than the upper limit of normal value. Hepatitis B surface antigen positive, hepatitis C antibody positive, treponema pallidum antibody positive or HIV antibody positive in serum virology examination. Patients who have been treated with any other investigational drug or participated in another interventional clinical trial within 3 months prior to screening. Patients complicated with malignant tumor or undergoing anti-tumor therapy. Patients have serious mental and psychological disorders, cognitive disorders and the existence of a history of mental illness. Patients have been alcohol abuse within 3 months prior to screening (drinking more than 14 units of alcohol per week (1 unit ≈360 mL beer or 45 mL 40% spirits or 150 mL wine)); Alcohol breath test positive at screening or admission. Patients who smoked more than 5 cigarettes a day during the 3 months prior to the study and were unwilling to stop smoking during the study period. Patients had been excessive drinking of tea , coffee or caffeinated beverages for a long time (more than 8 cups per day, 1 cup =250 mL); Or any food or beverage containing caffeine or xanthine (such as coffee, strong tea, chocolate, etc.) within 48 hours prior to initial administration. Patients have a history of drug or substance abuse, or a positive drug screening test. Women who are pregnant or breast-feeding or who plan to become pregnant or breast-feeding during the study period, or who have a positive pregnancy test at the screening stage or baseline. The investigator considers that the patient has any other medical or psychological conditions that may pose an undue risk to the subject or interfere with the subject's ability to comply with study protocol requirements or complete the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a phase I randomized, double-blind, placebo-controlled and dose-increasing single dosing study.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br>Drug: SIBP-R002 & Dexamethasone/Methyl prednisolone & Diphenhydramine Starting from the lowest dose, when the former dose does not meet the termination criteria, then start the next dose group study until Maximum Tolerated Dose (MTD). | Drug: SIBP-R002<br>* SIBP-R002: injection; strength: 1, 2, 4, 8 or 12 mg; dose escalation and the first group is 1mg (intravenous infusion, 5 groups, the first group consisted of four people, and the other groups consisted of eight).<br>Drug: Dexamethasone or Methyl prednisolone<br>* Intravenous infusion, 5mg or 1 2mg/kg. These were administered within 30 minutes prior to infusion of the experimental drug.<br>Drug: Diphenhydramine<br>* 10mg, intramuscular injection.These were administered within 30 minutes prior to infusion of the experimental drug.<br>|
| Placebo Comparator: Placebo control group<br>Placebo control: The same volume of placebo as SIBP-R002 & Dexamethasone/Methyl prednisolone & Diphenhydramine The rule and dose of placebo were the same as SIBP-R002. | Drug: Dexamethasone or Methyl prednisolone<br>* Intravenous infusion, 5mg or 1 2mg/kg. These were administered within 30 minutes prior to infusion of the experimental drug.<br>Drug: Diphenhydramine<br>* 10mg, intramuscular injection.These were administered within 30 minutes prior to infusion of the experimental drug.<br>Drug: Placebo<br>* The same volume of placebo as SIBP-R002: injection; strength: the same volume of placebo as SIBP-R002 of 1, 2, 4, 8 or 12 mg (intravenous infusion, 5 groups, the first group consisted of one people, and the other groups consisted of two). The rule and dose of placebo were the same as SIBP-R002.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of any adverse events (AE) | All subjects were observed during the trial for any AE that occurred during the clinical study, including clinical symptoms and life abnormal physical signs, abnormalities in electrocardiogram and laboratory tests. Attention should be paid to the occurrence of AE related to infusion reaction, allergic reaction, vomiting and watery stools/loose stools, acute attack of gout, cardiovascular adverse events and so on. | 35 days after the last dose | 
| The number of serious adverse events (SAE) | That is serious adverse events, any serious adverse events that occurred to the subject during the study period. | 35 days after the last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC 0-t (Area Under The Plasma Concentration Versus Time Curve) | Area under the blood concentration-time curve from 0 to T. It shows the degree to which a drug is absorbed and used in the body. | 35 days after the last dose | 
| Cmax(Peak Plasma Concentration) | It shows the highest plasma concentration of a drug that can be achieved after administration. | 35 days after the last dose | 
| AUC inf (Area Under The Plasma Concentration Versus Time Curve) | Area under the blood concentration-time curve from 0 to unlimited time. It shows the degree to which a drug is absorbed and used in the body. | 35 days after the last dose | 
| Tmax(Peak Time) | That is peak time of drug action, it shows the time required to reach the maximum concentration on the subject plasma concentration curve after administration. | 35 days after the last dose | 
| T ½(Terminal elimination half-life) | It reflects how quickly the drug is eliminated from the body. | 35 days after the last dose | 
| CL(Clearance Rate) | Apparent volume of drug distribution removed from the body per unit time. | 35 days after the last dose | 
| The uric acid to creatinine ratio in Urine | To evaluate the effect of single use of peruricase on uric acid to creatinine ratio (UAc:Cr) in 24h urine of patients with hyperuricemia. | 35 days after the last dose | 
| Vd(Apparent volume of distribution) | Apparent volume of distribution refers to the ratio of the amount of drug in vivo to the concentration of drug in blood when a drug reaches dynamic equilibrium in the body. It is a widely used parameters for drug distribution. | 35 days after the last dose | 
| λz | Elimination rate constant of a drug.It is a common pharmacokinetic indicator. | 35 days after the last dose | 
| The positive rate of anti-uricase antibody | An evaluation index of immunogenicity of an experimental drug. If detected, it is positive. | 35 days after the last dose | 
| The positive rate of anti-PEG antibody | An evaluation index of immunogenicity of an experimental drug. If detected, it is positive. | 35 days after the last dose | 
| The positive rate of anti-PEG-uricase antibody | An evaluation index of immunogenicity of an experimental drug. If detected, it is positive. | 35 days after the last dose | 
| Antibody titer of anti-uricase antibody | An evaluation index of immunogenicity of an experimental drug. | 35 days after the last dose | 
| Antibody titer of anti-PEG Antibody | An evaluation index of immunogenicity of an experimental drug. | 35 days after the last dose | 
| Antibody titer of anti-PEG-uricase Antibody | An evaluation index of immunogenicity of an experimental drug. | 35 days after the last dose | 
| Positive rate of neutralizing antibody(NAb) | NAb positive rate was assessed by detecting neutralizing antibodies in blood samples. | 35 days after the last dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperuricemia, Pegloticase, Safety, Tolerability