A Single-dose and Multiple-dose Study to Evaluate the Pharmacokinetics and Pharmacodynamics of DBPR108 Tablets in Type 2 Diabetes Mellitus Patients

Study Overview
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Brief Summary
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This is a phase I study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single-dose and multiple-dose of DBPR108 tablets in Type 2 Diabetes Mellitus Patients.

Detailed Description
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This study aims to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics characteristics, single-dose and multiple-dose of DBPR108 tablets in Chinese Type 2 Diabetes Mellitus Patients. The 30 eligible patients will be randomized to receive 50 mg, 100 mg, or 200 mg DBPR108 tablets.

Official Title
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A Randomized, Open-Label, Parallel-Cohort, Single-dose and Multiple-dose Phase I Study of DBPR108 Tablets in Type 2 Diabetes Mellitus Patients

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: DBPR108 tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients who meet the World Health Organization (WHO) (1999) criteria for the diagnosis and classification criteria for type 2 diabetes mellitus; 18 ≤ age ≤ 75 years old, male or female; Body mass index (BMI) within the range of 19-35 kg/m^2 (inclusive), BMI = weight (kg) / height^2 (m^2); 7.0% ≤Hemoglobin A1c (HbA1c) ≤ 9.5%; Patients who voluntarily participate in the study and sign the informed consent form; Patients who agree to use contraception from the signing of the informed consent form until 1 month after the end of the last medication. Exclusion Criteria: Fasting plasma glucose (FPG) > 13.9 mmol/L; The investigator determines that the patients need to use insulin therapy; Patients with acute or serious complications of diabetes (including diabetic ketoacidosis, hyperosmotic nonketotic diabetic coma, lactic acidosis and hypoglycemia coma); History of severe hypoglycemia (hypoglycemia with severe cognitive impairment and requiring other measures to help recover); History of acute or chronic pancreatitis, or related diseases that are most common cause of acute pancreatitis (such as recurrent cholelithiasis, etc.); History of allergy to DPP-4 inhibitors or the investigator determines that the patients may be allergic to investigational drug; Patients with untreated hyperthyroidism and other diseases, which may affect blood glucose; Patients who have used other hypoglycemic drugs within 14 days before the first dose; or patients who are not suitable for this study as determined by the investigator due to taking other hypoglycemic drugs; Patients with inflammatory bowel disease, partial intestinal obstruction or chronic bowel disease related to obvious digestive and absorption disorders; Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) > 3 * upper limit of normal (ULN), or total bilirubin > 1.5 *ULN; Abnormal renal function: serum creatinine>1.5 * ULN; or eGFR< 45 mL/min/1.73m^2; White blood cells (WBC) < 3.0 *10^9/L and neutrophil count of peripheral blood < 1.5 * 10^9/L; hemoglobin < 100 g / L; triglyceride > 5.7 mmol/L; Patients who have the second or third degree atrioventricular block, long Q-T syndrome, or QTc>500 ms without cardiac pacemaker; Patients with any one of HBsAg, hepatitis C antibody, anti-HIV antibody and antibody of treponema pallidum positive; Female patients of childbearing age with pregnant test positive or lactating women; History of alcohol or drug abuse within 3 months before screening, alcohol abuse is average alcohol intake more than 14 units alcohol (1 unit=12 ounces or 360 mL of beer,1.5 ounces or 45 mL spirits with 40% alc/vol, 5 ounces or 150 mL grape wine); or intake any other products containing alcohol within 2 days before the first administration of investigational product; Patients who smoke more than 5 cigarettes per day within 3 months prior to screening; Patients with consumption of grapefruit juice, methylxanthine-rich food or beverage (such as coffee, tea, cola, chocolate, energy drinks) within 2 days before the first administration in treatment period , or patients who have strenuous exercise, or have other factors affecting drug absorption, distribution, metabolism, excretion, etc; Participation in other clinical trials or administration of any other investigational drugs or devices within 3 months before screening; Patients with the following diseases: Serious dysrhythmias, obvious left ventricular dysfunction, New York Heart Association (NYHA) functional class III or IV; History of unstable angina pectoris, myocardial infarction, or other high-risk coronary artery diseases; Uncontrolled hypertension, systolic pressure ≥160 mmHg or diastolic pressure ≥100 mmHg; History of cancer , organ transplantation; History of epilepsy, psychosis, severe depression, etc. Not suitable for this study as determined by the investigator due to other reasons.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 50 mg DBPR108 tablets<br>10 patients will be randomized to receive 50 mg DBPR108 tablets. | Drug: DBPR108 tablets<br>* DBPR108 tablets, oral, once daily on Day 1 and Day 3-9 for a total of 8 doses.<br>|
| Experimental: 100 mg DBPR108 tablets<br>10 patients will be randomized to receive 100 mg DBPR108 tablets. | Drug: DBPR108 tablets<br>* DBPR108 tablets, oral, once daily on Day 1 and Day 3-9 for a total of 8 doses.<br>|
| Experimental: 200 mg DBPR108 tablets<br>10 patients will be randomized to receive 200 mg DBPR108 tablets. | Drug: DBPR108 tablets<br>* DBPR108 tablets, oral, once daily on Day 1 and Day 3-9 for a total of 8 doses.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak plasma concentration (Cmax) of DBPR108 tablets | Cmax of DBPR108 tablets will be assessed after single-dose and multiple-dose administration | Day 1-Day 11 | 
| Area under the plasma concentration versus time curve (AUC) of DBPR108 tablets in plasma | AUC of DBPR108 tablets will be assessed after single-dose and multiple-dose administration | Day 1-Day 11 | 
| Half-life(t1/2) of DBPR108 tablets | T1/2 of DBPR108 tablets will be assessed after single-dose and multiple-dose administration | Day 1-Day 11 | 
| Apparent volume of Distribution(Vz/F)of DBPR108 tablets | Vz/F of DBPR108 tablets will be assessed after single-dose and multiple-dose administration | Day 1-Day 11 | 
| CL/F of DBPR108 tablets | Apparent clearance(CL/F) of DBPR108 tablets will be assessed single-dose and multiple-dose administration | Day 1-Day 11 | 
| Change from baseline in dipeptidyl peptidase-IV inhibition rate | Change from baseline in dipeptidyl peptidase-IV inhibition rate will be assessed after single-dose and multiple-dose administration | Day 1-Day 11 | 
| Change from baseline in active glucagon-like peptide1 concentration | Change from baseline in active glucagon-like peptide1 concentration will be assessed after single-dose and multiple-dose administration | Day 1-Day 11 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of patients with adverse events | The number of patients with adverse events as a measure of safety and tolerability. | Throughout the study period, with an average of 1 months | 
| Clinically significant changes from baseline in 12-lead electrocardiogram (ECG) examination will be recorded as AEs at each visit time point | ECG monitoring includes P-R, QT and QTc intervals in ms. | Within screening period (Day-21 to Day-15), baseline period (Day-7 to Day-1), and before discharge (Day11). | 
| Clinically significant changes from baseline in vital signs examination will be recorded as AEs at each visit time point. | Vital signs monitoring includes respiratory rate and pulse in times per minute | Throughout the study period, with an average of 1 months | 
| Clinically significant changes from baseline in vital signs examination will be recorded as AEs at each visit time point. | Vital signs monitoring includes systolic blood pressure and diastolic blood pressure in mmHg. | Throughout the study period, with an average of 1 months | 
| Clinically significant changes from baseline in vital signs examination will be recorded as AEs at each visit time point. | Vital signs monitoring includes body temperature in degrees Celsius | Throughout the study period, with an average of 1 months | 
| Clinically significant changes from baseline in physical examination will be recorded as AEs at each visit time point. | Physical examination includes mucocutaneous, lymphonodus, head and neck,chest, abdomen, spinal column, musculoskeletal, nervous system | Within screening period (Day-21 to Day-15), baseline period (Day-7 to Day-1), and before discharge (Day11). | 
| Clinically significant changes from baseline in routine blood test will be recorded as AEs at each visit time point. | Routine blood test includes white blood cell count, platelet, neutrophilic granulocyte count, lymphocyte count and monocyte count in 10^9 /L. | Within screening period (Day-21 to Day-15), baseline period (Day-7 to Day-1), and before discharge (Day11) | 
| Clinically significant changes from baseline in blood biochemistry test will be recorded as AEs at each visit time point.recorded as AEs at each visit time point. | Blood biochemistry test includes total protein, albumin and albumin in g/L. | Within screening period (Day-21 to Day-15), baseline period (Day-7 to Day-1), and before discharge (Day11) | 
| Clinically significant changes from baseline in blood biochemistry test will be recorded as AEs at each visit time point.recorded as AEs at each visit time point. | Blood biochemistry test includes alanine aminotransferase, aspartate aminotransferase, amylase, alkaline phosphatase and in U/L. | Within screening period (Day-21 to Day-15), baseline period (Day-7 to Day-1), and before discharge (Day11) | 
| Clinically significant changes from baseline in blood biochemistry test will be recorded as AEs at each visit time point.recorded as AEs at each visit time point. | Blood biochemistry test includes ureophil, glucose, triglyceridein, total cholesterol, high-density lipoprotein, low-density lipoprotein, sodium, potassium, chlorine, calcium in mmol/L | Within screening period (Day-21 to Day-15), baseline period (Day-7 to Day-1), and before discharge (Day11) | 
| Clinically significant changes from baseline in blood biochemistry test will be recorded as AEs at each visit time point.recorded as AEs at each visit time point. | Blood biochemistry test includes total bilirubin and serum creatinine in umol/L. | Within screening period (Day-21 to Day-15), baseline period (Day-7 to Day-1), and before discharge (Day 11) | 
| Clinically significant changes from baseline in routine urine test will be recorded as AEs at each visit time point. | Routine urine test includes the count of leukocyte, and red blood cell in high-power field. | Within screening period (Day-21 to Day-15), baseline period (Day-7 to Day-1), and before discharge (Day11) | 
| Clinically significant changes from baseline in routine urine test will be recorded as AEs at each visit time point. | Routine urine test includes glucose, protein, ketonein in negative or positive. | Within screening period (Day-21 to Day-15), baseline period (Day-7 to Day-1), and before discharge (Day11) |