A Phase I Single- and Multiple- Ascending Dose and Food Effect Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of HRS-7535 in Healthy Subjects

Study Overview
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Brief Summary
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This is a randomized, double-blinded, placebo-controlled study to evaluate the safety, tolerability, Pharmacokinetics and Pharmacodynamics of single ascending dose (Part A) and multiple ascending dose (Part B) of HRS-7535 in healthy subjects.

Official Title
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A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of HRS-7535 in Healthy Subjects

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: HRS-7535
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must be 18 to 55 years of age (inclusive) healthy male or female of nonchildbearing potential; Body weight of at least 50 kg for male, and 45 kg for female; and Body Mass Index (BMI) within the range of 19 to 28 kg/m2 (inclusive); Subjects (including partners) of childbearing potential are willing to use protocol specified effective methods of contraception from screening to at least 6 months after the final dose of study drug; Able and willing to provide written informed consent and to comply with the study protocol; Physical examination, vital signs are normal or are judged not clinically significant by the investigator; Exclusion Criteria: Participants with any abnormal results and judged clinically significant by the investigator; HbA1c ≥6.2%, fasting blood-glucose ≤3.9mmol/L (70mg/dL) or ≥6.1mmol/L(110mg/dL) at screening ; Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2 x ULN; total bilirubin ≥1.5 x ULN at screening; Abnormal ECG that is clinically significant, or QTcF >450 msec; Positive test result of any of the following at screening: hepatitis B surface antigen (HBsAg), hepatitis C antibody, syphilis, or human immunodeficiency virus (HIV) antibody; Any malignancy (except basal cell carcinoma and squamous cell carcinoma of the skin) in the previous 5 years; Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, history of pancreatitis or symptomatic gallbladder disease; History of gastric emptying anomalies (gastric outlet obstruction), severe chronic gastrointestinal diseases (such as inflammatory bowel disease, active ulcer) ; Subject with major medical history of heart, liver, kidney, endocrine, digestive, blood, respiratory and genitourinary system or existing diseases of the above systems; Use any prescription drugs, non-prescription drugs, food supplements, vitamins and Chinese herbal medicines within 2 weeks before administration; Subject who received bariatric surgery or procedures, or use of weight-reducing drugs within 3 months prior to administration, or body weight change of more than ±10% within 3 months prior to administration; Use any drugs that may affect glucose metabolism were used within 1 month before administration. Suspected allergy to any ingredient in the study drug; Participation in clinical trials of any drug or medical device within 3 months before screening; History of regular alcohol consumption exceeding 14 drinks per week within 6 months before screening; More than 5 cigarettes per day or cigarettes within 3 months before screening; Subjects who consume alcoholic beverages, Seville oranges, grapefruit or juices, or products containing caffeine or xanthine (such as coffee, tea, cola drinks and chocolate) from 2 days before the start of study treatment; Strenuous exercise in 48 hours before treatment; Subjects with a history of drug abuse, drug dependence, or a positive drugs of abuse test, or a positive alcohol breath test before study drug administration; Donation or loss of blood of ≥ 200 mL within 1 month or of ≥ 400 mL within 3 months prior to the first dose of study drug; Subjects can't tolerate venipuncture; Subjects have special dietary requirements and cannot comply with the unified diet; Other conditions judged by the investigator to be not suitable to participate in the trial;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: HRS-7535 tablet compared with placebo
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Drug: HRS-7535 | Drug: HRS-7535<br>* Drug: HRS-7535<br>|
| Placebo Comparator: Group B<br>Drug: Placebo | Drug: Placebo<br>* Drug: Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse Events | Number of adverse events per subject, including clinically relevant changes in physical examination, vital signs, laboratory tests and ECGs; | Day-2 to last follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) profile of HRS-7535 - AUC0-t | Area under the concentration-time curve from time zero to the last quantifiable time point t (AUC0-t); | pre-dose to 96 hours post-dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - AUC0-∞ | Area under the plasma concentration-time curve from time zero to infinity (AUC0-∞); | pre-dose to 96 hours post-dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - Cmax | Maximum observed concentration (Cmax); | pre-dose to 96 hours post-dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - Tmax | Time to maximum observed concentration (Tmax); | pre-dose to 96 hours post-dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - t1/2 | Terminal elimination half-life (t1/2) | pre-dose to 96 hours post-dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - CL/F | Apparent clearance (CL/F); | pre-dose to 96 hours post-dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - Vz/F | Apparent volume of distribution (Vz/F); | pre-dose to 96 hours post-dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - AUC0-τ,ss | Area under the plasma concentration-time curve from time zero to tau at steady state (AUC0-τ,ss) | pre-last dose to 96 hours post- last dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - AUC0-t,ss | AUC0-t at steady state (AUC0-t,ss) | pre- last dose to 96 hours post- last dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - AUC0-∞,ss | AUC0-∞ at steady state (AUC0-∞,ss) | pre- last dose to 96 hours post- last dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - Tmax,ss | Tmax at steady state (Tmax,ss) | pre- last dose to 96 hours post- last dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - Cmax,ss | Cmax at steady state (Cmax,ss) | pre- last doseto 96 hours post- last dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - Ctrough,ss | Ctrough at steady state (Ctrough,ss) | pre- last dose to 96 hours post- last dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - Cavg,ss | Cavg at steady state (Cavg,ss) | pre- last dose to 96 hours post- last dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - DF | Degree of fluctuation at steady state (DF) | pre- last dose to 96 hours post- last dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - Vz,ss/F | Vz/F at steady state (Vz,ss/F) | pre- last dose to 96 hours post- last dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - CLss/F | CL/F at steady state (CLss/F) | pre- last dose to 96 hours post- last dose | 
| Pharmacokinetic (PK) profile of HRS-7535 - t1/2,ss | t1/2 at steady state (t1/2,ss) | pre- last dose to 96 hours post- last dose | 
| Pharmacodynamic (PD) profile of doses of HRS-7535 - blood glucose |  | pre-dose to 24 hours post-dose | 
| Pharmacodynamic (PD) profile of doses of HRS-7535 - insulin |  | pre-dose to 24 hours post-dose | 
| Pharmacodynamic (PD) profile of doses of HRS-7535 - C-peptide |  | pre-dose to 24 hours post-dose | 
| Pharmacodynamic (PD) profile of doses of HRS-7535 - glucagon |  | pre-dose to 24 hours post-dose | 
| Pharmacodynamic (PD) profile of doses of HRS-7535 - fructosamine |  | pre-dose up to 96 hours after the last dose | 
| PD profile of multiple doses of HRS-7535 - HbA1c |  | pre-dose up to 96 hours after the last dose | 
| PD profile of multiple doses of HRS-7535 - 5-points glucose profile |  | pre-dose up to 24 hours after the last dose | 
| PD profile of multiple doses of HRS-7535 - weight |  | pre-dose up to 96 hours after the last dose |