Single Ascending Dose and Multiple Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SHR-1816 in Healthy Subjects

Study Overview
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Brief Summary
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This is a randomized, double-blind, placebo-controlled study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of SHR-1816 after single and multiple injection with different dose regimens in healthy subjects.

Official Title
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A Phase 1, Randomized, Double-blind, Placebo-controlled, Single Ascending Dose and Multiple Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of SHR-1816 in Healthy Subjects

Conditions
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Diabetes

Intervention / Treatment
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* Drug: SHR-1816
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and infertility females aged between 18 years and 55 years at screening. Male subjects weight ≥50kg, female subjects weight ≥45kg. Body mass index (BMI) in the range of 19-26kg /m2. HbA1c<6.2% at screening. FPG>3.9mmol/L (70mg/dL) and <6.1mmol/L (110mg/dL) at screening Agree to take effective contraceptive methods. Able and willing to provide a written informed consent. Exclusion Criteria: The following clinical laboratory tests or examination abnormalities exist during the screening period: 1) Any clinically significant lab tests abnormal with one-time retest. 2) ALT and AST were higher than the upper limit of normal value. 3) Subject who has fatty liver disease diagnosed by ultrasound examination. 4) Subject who has abnormal thyroid function. 5) The 12-lead electrocardiogram (ECG) is abnormal and clinically significant, or shows QTcF>450 ms in male and 470 ms in female. 6) Positive infectious diseases screening tests: HBsAg, HCV-Ab, TP-Ig G, HIV-Ab 2. Having any of the following diseases or history: Subject with a history of hypertension or with abnormal vital signs and clinical significance. Subject with a history of life-threatening diseases within the previous 5 years prior to screening. Subject with severe systemic infectious diseases within 1 month prior to screening. Subject with medical history or family history of medullary thyroid cancer, multiple endocrine adenomatosis type 2, and previous history of pancreatitis. Subject with major medical history of heart, liver, kidney, endocrine, digestive, blood, respiratory and genitourinary system or existing diseases of the above systems. 3. Use of any other medicine or other non-drug operations: 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. Drugs that may affect glucose metabolism were used within 1 month before administration. Subject who undergone other gastrointestinal surgery that could lead to malabsorption, or long-term use of drugs that had a direct impact on gastrointestinal motility prior to screening. 4. Any of the following conditions exists: History of allergy to the study drug or any component of it. Treatment with an investigational drug or device within 3 months (or 5 half-lives, whichever is longer) prior to screening. History of regular alcohol consumption in the past week exceeding an average 15g per day and positive alcohol test. More than 5 cigarettes per day or cigarettes in 48 hours before treatment and positive nicotine test. Long time or in 48 hours before treatment drinking for tea, cola, coffee or any other soft drinking within 48 hours. Strenuous exercise in 48 hours before treatment. Subject with known or suspected history of drug abuse or positive urine drug screening test during screening. Unwillingness to comply with lifestyle requirements during the trial. Donate blood within 1 month before screening, or screening trauma or major surgical operation patients who donated blood ≥400 mL or lost blood ≥400 mL within 3 months before the screening. Mentally incapacitated or language impaired subject cannot fully understand or participate in the test process. The investigator assessed the subject's poor compliance or inability to draw blood due to arm vein conditions, or history of needle and blood sickness. 5. Other conditions or laboratory abnormality that may affect trial evaluations associated with study participation reviewed by the investigators.

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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: SHR-1816 injection compared with placebo
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br> | Drug: SHR-1816<br>* SHR-1816<br>|
| Placebo Comparator: Group B<br> | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse Events |  | Day-2 to Day29/Day50 | 
| Incidence of hypoglycemic events |  | Day1 to Day8/Day29 | 
| Incidence of reaction of the injection sites |  | Day1 to Day8/Day29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) profile of SHR-1816 - AUC0-t | AUC0-t, area under the concentration-time curve from time 0 to the time of last quantifiable concentration; | pre-dose, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, 336 hours post-dose | 
| Pharmacokinetic (PK) profile of SHR-1816 - AUC0-inf | AUC0-inf, area under the concentration-time curve from time 0 to infinity; | pre-dose, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, 336 hours post-dose | 
| Pharmacokinetic (PK) profile of SHR-1816 - Cmax | Cmax, observed maximum concentration; | pre-dose, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, 336 hours post-dose | 
| Pharmacokinetic (PK) profile of SHR-1816 - Tmax | Tmax, time of occurrence of Cmax; | pre-dose, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, 336 hours post-dose | 
| Pharmacokinetic (PK) profile of SHR-1816 - Vz/F | Vz/F, apparent volume of distribution; | pre-dose, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, 336 hours post-dose | 
| Pharmacokinetic (PK) profile of SHR-1816 - CL/F | CL/F, apparent clearance; | pre-dose, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, 336 hours post-dose | 
| Pharmacokinetic (PK) profile of SHR-1816 - t1/2 | t1/2, terminal half-life; | pre-dose, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, 336 hours post-dose | 
| Pharmacokinetic (PK) profile of SHR-1816 - MRTinf | MRTinf, mean residence time from time 0 to infinity. | pre-dose, 4, 8, 12, 24, 48, 72, 96, 120, 144, 168, 336 hours post-dose | 
| Pharmacodynamic (PD) profile of doses of SHR-1816 - fasting blood glucose |  | Day-1 to Day15/Day29 | 
| Pharmacodynamic (PD) profile of doses of SHR-1816 - insulin |  | Day-1 to Day15/Day29 | 
| Pharmacodynamic (PD) profile of doses of SHR-1816 - C-peptide |  | Day-1 to Day15/Day29 | 
| Pharmacodynamic (PD) profile of doses of SHR-1816 - glucagon |  | Day-1 to Day15/Day29 | 
| Pharmacodynamic (PD) profile of doses of SHR-1816 - total GLP-1 |  | Day-1 to Day15/Day29 | 
| Pharmacodynamic (PD) profile of doses of SHR-1816 - active GLP-1 |  | Day-1 to Day15/Day29 | 
| Pharmacodynamic (PD) profile of doses of SHR-1816 - fructosamine |  | Day-1 to Day15/Day29 | 
| PD profile of multiple doses of SHR-1816 - HbA1c |  | Day-1, Day29 | 
| PD profile of multiple doses of SHR-1816 - 7-points glucose profile |  | Day-1 to Day15/Day29 | 
| PD profile of multiple doses of SHR-1816 - weight |  | Day-1 to Day15/Day29 | 
| Immunogenicity | Incidence of SHR-1816 antibody formation. | Day1 to Day29/Day50 |