Drug Interaction Study Between Dorzagliatin and Sitagliptin

Study Overview
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Brief Summary
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This is a Phase 1, open-label, sequential, multiple-dose, drug interaction study of glucokinase activator dorzagliatin and sitagliptin in subjects with T2DM. Pharmacokinetics and pharmacodynamics when dorzagliatin and sitagliptin given alone and in combination will be studied.

Official Title
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A Phase 1, Open-Label, Sequential, Multiple-Dose, Drug-Drug Interaction Study of Dorzagliatin and Sitagliptin in Subjects With Type 2 Diabetes Mellitus

Conditions
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Patients

Intervention / Treatment
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* Drug: Sitagliptin
* Drug: Dorzagliatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects diagnosed with T2DM within at least 3 months prior to screening Male and/or female subjects between the ages of 30 and 65 years, inclusive; Body Mass Index (BMI) of 19 to 38 kg/m2, inclusive; Fasting C-peptide test result >0.3 nmol/L (>0.90 ng/mL); HbA1c ≥7% and ≤10.5%; Exclusion Criteria: Fasting blood glucose at screening or Day -1 ≤110 or ≥270 mg/dL; Type 1 diabetes mellitus; Reported incidence of severe or serious hypoglycemia within 3 months prior to screening; Known contraindications to sitagliptin; Clinically significant gastrointestinal disorder; History or symptoms of clinically significant cardiovascular disease within one year prior to screening; History of more than three urinary tract infections and/or more than three genital fungal infections in the last 12 months; Reported history of clinically significant central nervous system disease; Reported history of liver disease; Reported history of clinically significant renal disease; Estimated glomerular filtration rate (eGFR) ≤60 mL/min/1.73m2; Acute or chronic metabolic acidosis, including diabetic ketoacidosis; Known or suspected malignancy; Any reported hypersensitivity or intolerance to sitagliptin; Antidiabetic treatment with insulin, sulfonylureas, thiazolidinediones or GLP-1 agonist within 3 months prior to screening; Systolic blood pressure <90 or >160 mmHg or diastolic blood pressure <60 or >100 mmHg at screening; A hospital admission or major surgery within 90 days prior to screening; Uncontrolled hypertriglyceridemia >500 mg/dL; Positive blood screen for HIV, hHBsAg, or hepatitis C antibody; Positive pregnancy test result; Female is breast-feeding or planning to become pregnant; Treated with any investigational drugs within 6 weeks prior to screening; Reported history of prescription drug abuse; Reported history of alcohol abuse; Reported history of donation or or acute loss of blood during the 90 days prior to screening;

Ages Eligible for Study
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Minimum Age: 30 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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequential arm ABC<br>A: Sitagliptin 100 mg QD in the morning on Days 1-5; B: Sitagliptin 100 mg QD in the morning and dorzagliatin 75 mg BID (morning and evening) on Days 6-10, with only the morning dose on Day 10; C: Dorzagliatin 75 mg BID (morning and evening) on Days 11-15, with only the morning dose on Day 15. | Drug: Sitagliptin<br>* Sitagliptin (Januvia® 100 mg tablets for oral administration)<br>* Other names: Januvia;Drug: Dorzagliatin<br>* Glucokinase activator currently under development<br>* Other names: HMS5552;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric mean ratio (GMR) for Cmax of sitagliptin | GMR between combination and sitagliptin monotherapy for Cmax of sitagliptin | up to 10 days | 
| GMR for AUC0-24h of sitagliptin | GMR between combination and sitagliptin monotherapy for AUC0-24h of sitagliptin | up to 10 days | 
| GMR for Cmax of dorzagliatin | GMR between combination and dorzagliatin monotherapy for Cmax of dorzagliatin | up to 15 days | 
| GMR for AUC0-24h of dorzagliatin | GMR between combination and dorzagliatin monotherapy for AUC0-24h of dorzagliatin | up to 15 days | 
| Adverse events | Number of participants with AEs | up to 15 days | 
| Abnormal vital signs | Number of participants with abnormal vital signs (blood pressure, pulse rate, respiratory rate and oral temperature) | up to 15 days | 
| Abnormal clinical laboratory findings | Number of participants with abnormal clinical laboratory findings | up to 15 days | 
| 12-lead ECG | Number of participants with abnormal ECG VR,, PR, QRS and QT | up to 15 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| iCmax of glucose | The incremental peak plasma concentration of glucose post OGTT | up to 15 days | 
| iAUC0-4h of glucose | The incremental area under the concentration-time curve of glucose in 4 hours post OGTT | up to 15 days | 
| iCmax of C-peptide | The incremental peak plasma concentration of C-peptide post OGTT | up to 15 days | 
| iAUC0-4h of C-peptide | The incremental area under the concentration-time curve of C-peptide in 4 hours post OGTT | up to 15 days | 
| iCmax of GLP-1 | The incremental peak plasma concentration of GLP-1 post OGTT | up to 15 days | 
| iAUC0-4h of GLP-1 | The incremental area under the concentration-time curve of GLP-1 in 4 hours post OGTT | up to 15 days |