Multiple Doses Study of SHR4640 in Male Subjects With High Serum Uric Acid Level

Study Overview
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Brief Summary
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This is a single-Center, randomized, double-Blind, placebo-controlled, multiple ascending-dose Phase I trail.

Official Title
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A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of SHR4640 in Male Subjects With High Serum Uric Acid Level

Conditions
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Gout, Hyperuricemia

Intervention / Treatment
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* Drug: SHR4640


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male, aged between 18 and 65 years, inclusive. Body weight ≥ 50 kg and body mass index between 18.0 and 35.0 kg/m2, inclusive. Screening sUA level ≥0.36 mmol/L. Considered generally healthy upon completion of medical history, full physical examination, vital signs, laboratory parameters (including thyroid function and serological tests, hematology, urinalysis, and biochemistry), 12-lead ECG, and abdominal ultrasound, as judged by the Investigator. Agrees to use a highly effective method of contraception, i.e. condom and suitable contraception for his female partner e.g. oral contraceptive or intrauterine contraceptive device during heterosexual intercourse or be non-heterosexually active, or practice sexual abstinence throughout the study period and for 30 days following final dose of study drug, and must agree to refrain from sperm donation from Day -2 until at least 30 days following final dose of study drug. Negative drug screen (including alcohol) at screening and on admission to clinical site. Able to understand the study procedures and the risks involved and must be willing to provide a written informed consent before any study-related activity. Exclusion Criteria: History of hypersensitivity to SHR4640 or its analogues. History of gout. Screening alanine aminotransferase, aspartate aminotransferase, total bilirubin, or gamma glutamyl transferase > 1.5 × upper limit of normal. Positive result for human immunodeficiency virus (HIV). Positive result for hepatitis B surface antigen or hepatitis C virus antibody. History or presence of kidney stones. Acute or chronic illness that, in the opinion of the Investigator, might confound the results of the trial or pose risk to the subject when administering the trial product. Undergone major surgery within 3 months of Day 1 or has surgery planned during study participation. Donated any blood or plasma in the past month or more than 400 mL within 3 months of Day 1. Has unsuitable venous for blood sampling. Use of tobacco products within 30 days of Day 1. Heavy caffeine drinker (more than 5 cups or glasses of caffeinated beverages per day). History of drug and/or alcohol abuse in the last year. Consumes more than 14 units of alcohol per week (1 unit = 250 mL beer, 25 mL of 40% spirits and 125 mL glass of wine). Consumes grapefruit and/or poppy seed within 5 days of Day 1. Unable to refrain from strenuous exercises, tobacco products, alcohol, grapefruit, and/or poppy seed from Day -2 to Day 10. Use of any of the following, unless agreed as nonclinically relevant by the Investigator and the Sponsor: 1) Prescription medication within 2 weeks of Day 1. 2) Over-the-counter medication within 1 week of Day 1. 3) Use of any over the-counter, nutraceuticals, or prescription medications that might interfere with the absorption, distribution, metabolism, or excretion of SHR4640 (proton-pump inhibitor, fluconazole, indomethacin, ranitidine, flurbiprofen, probenecid, aprepitant, etc.) within 1 month of Day 1. 18. Received the last dose of a study drug (or treatment with a medical device) within 30 days or 5 T1/2 (whichever is longer) of the study drug of Day 1 or are currently participating in another study of a study drug (or medical device). 19. Any other medical or psychological condition, which in the opinion of the Investigator, might create undue risk to the subject or interfere with the subject's ability to comply with the protocol requirements or to 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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Male

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SHR4640 2.5mg<br>6 subjects assigned to 2.5mg SHR4640 and 2 subjects assigned to placebo | Drug: SHR4640<br>* SHR4640 or placebo once daily for a week<br>|
| Experimental: SHR4640 10mg<br>6 subjects assigned to 10mg SHR4640 and 2 subjects assigned to placebo | Drug: SHR4640<br>* SHR4640 or placebo once daily for a week<br>|
| Experimental: SHR4640 20mg<br>6 subjects assigned to 20mg SHR4640 and 2 subjects assigned to placebo | Drug: SHR4640<br>* SHR4640 or placebo once daily for a week<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse events in terms of changes in Hematology | Hemoglobin Hematocrit Erythrocytes count Mean cell volume, Mean cell hemoglobin concentration, Leukocytes count, Neutrophils count, Lymphocytes count, Monocytes count, Eosinophils count, Basophils count, Platelets count | Up to Day 14 | 
| Incidence of Adverse events in terms of changes in Urinalysis | Urobilinogen Dipstick urinalysis, including: pH, Specific gravity, Protein, Blood, Leukocytes, Glucose, Ketones, Bilirubin, Nitrites | Up to Day 14 | 
| Incidence of Adverse events in terms of changes in Biochemistry (fasting) | Including Serum creatinine, Urea, Alanine aminotransferase, Aspartate aminotransferase, Gamma glutamyl transferase, Total bilirubin, Total protein, Albumin, Alkaline phosphatase, Serum uric acid, Glucose, Triglycerides, Total cholesterol, High-density lipoprotein cholesterol, Low-density lipoprotein cholesterol | Up to Day 14 | 
| Incidence of Adverse events in terms of changes in Physical examinations | Review of body weight and height; general appearance; head; eyes; ears/nose/throat; neck; lymph nodes; neurological and musculoskeletal systems; heart; lungs; abdomen; skin; and extremities | Up to Day 14 | 
| Incidence of Adverse events in terms of changes in Vital signs | Oral temperature, respiratory rate, blood pressure, and pulse rate | Up to Day 14 | 
| Incidence of Adverse events in terms of changes in 12-lead ECGs | The 12-lead ECGs must be recorded after the subjects have rested in the supine position for 5 minutes to ensure a stable baseline. | Up to Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Plasma Concentration (Cmax) (of single dose and at stable status) |  | Up to Day 10 | 
| Area under the plasma concentration versus time curve (AUC) (of single dose and at stable status) |  | Up to Day 10 | 
| Half-time (T1/2) (of single dose and at stable status) |  | Up to Day 10 | 
| Time to the peak plasma concentration (Tmax) (of single dose and at stable status) |  | Up to Day 10 | 
| Changes in serum uric acid concentration from baseline |  | Up to Day 10 | 
| Changes in urinary uric acid excretion from baseline |  | Up to Day 10 |