Type 2 Diabetes Mellitus Combined With Overweight or Obesity
Conditions
Brief summary
This is a multicenter, randomized, double-blind, placebo-controlled Phase 1b clinical study designed to evaluate the safety, tolerability, pharmacokinetic profiles and preliminary efficacy of multiple oral doses of TQF3250 capsules in trial subjects with type 2 diabetes mellitus complicated with overweight or obesity. A total of 72 eligible subjects are planned to be enrolled in this study. Six treatment dose groups are established, including 4 mg, 8 mg, 12 mg, 24 mg, 32 mg and 40 mg, with a dose-escalation titration design. Each dose group will consist of 12 subjects. Eligible screened subjects will be randomized at a ratio of 10:2 (10 subjects receiving investigational drug and 2 subjects receiving placebo) to receive treatment with either TQF3250 capsules or matching placebo.
Interventions
DRUGTQF3250 capsules
An oral glucagon-like peptide-1 receptor agonist.
DRUGTQF3250 placebo
TQF3250-matched placebo capsules.
Sponsors
Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* 1.Aged between 18 and 70 years, inclusive. * 2.Able to provide written informed consent, and meet the following requirements: 1. Voluntarily participate in the study and capable of signing the informed consent form; 2. Willing and able to complete all study-specified procedures and study visits. Subjects who fail to comply with the treatment regimen, diabetic diet, and exercise program formulated by the investigator, or who are unwilling or unable to perform self-monitoring of blood glucose, shall be excluded. * 3.Diagnosed with type 2 diabetes mellitus combined with overweight or obesity at screening, in accordance with the 1999 WHO diagnostic criteria. * 4.Females of childbearing potential must agree to use effective contraceptive measures throughout the study period and for 6 months after study completion (Note: Oral hormonal contraceptives shall not be relied upon as the sole contraceptive method), and have a negative serum pregnancy test result within 7 days prior to study enrollment. Male subjects must agree to use effective contraceptive measures throughout the study period and for 6 months after study completion.
Exclusion criteria
* 1.Other diabetic conditions besides type 2 diabetes mellitus 1. Diagnosed with or suspected of type 1 diabetes mellitus, specific types of diabetes, or secondary diabetes mellitus; 2. Occurrence of acute diabetic complications within 6 months prior to screening; 3. Medical history of severe hypoglycemic coma; occurrence of severe hypoglycemic episodes or recurrent hypoglycemic events within 6 months prior to screening; 4. Presence of proliferative retinopathy or macular lesions requiring acute treatment, painful diabetic neuropathy, diabetic foot or intermittent claudication confirmed by ophthalmic examination or medical records within 90 days prior to randomization; 5. Presence of diseases judged by the investigator to be clinically significant and likely to compromise subject safety, interfere with study drug metabolism, or confound evaluation of study outcomes, including but not limited to diseases of the nervous, psychiatric, cardiovascular, endocrine, gastrointestinal, respiratory, urinary, hematological and immune systems (excluding complications related to type 2 diabetes mellitus). * 2.Other medical conditions and medical history 1. Any condition that may interfere with drug absorption; 2. Concurrent hyperthyroidism, Cushing's syndrome, diabetic gastroparesis or other diseases associated with gastric emptying disorders, gastrointestinal diseases assessed by the investigator to increase postdosing risks, anorexia nervosa, alcohol dependence, drug abuse, substance dependence, epilepsy, psychiatric disorders, or conditions requiring systemic antiinfective treatment. Subjects with subclinical hypothyroidism or well-controlled hypothyroidism under stable medication are eligible for enrollment; 3. Medical history of myocardial infarction, unstable angina, arterial revascularization, stroke, New York Heart Association (NYHA) Class II-IV heart failure, or transient ischemic attack within 6 months prior to screening; or medical history of clinically significant ventricular arrhythmia or arrhythmia requiring continuous antiarrhythmic medication; 4. Clinically significant abnormal electrocardiogram (ECG) results at screening or randomization, such as supraventricular tachycardia, atrial fibrillation, atrial flutter, second or third-degree atrioventricular block, and deemed unsuitable for study participation by the investigator; 5. Resting blood pressure: systolic blood pressure (SBP) ≥160 mmHg or \<90 mmHg, and/or diastolic blood pressure (DBP) ≥100 mmHg; or initiation, modification or dose adjustment of antihypertensive drugs within 4 weeks prior to screening; 6. Any major surgery performed within 30 days prior to the first dose of study treatment, or any surgery planned during the study period; 7. Current malignancy or medical history of cancer or lymphoproliferative disease within the past 5 years (except fully treated basal cell carcinoma or squamous cell carcinoma of the skin with no evidence of recurrence); 8. Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN2), or subjects suspected of MTC per investigator judgment; 9. Medical history of acute or chronic pancreatitis or pancreatic surgery, or presence of high-risk factors for pancreatitis per investigator judgment, including symptomatic cholelithiasis, biliary tract infection, pancreatic trauma, etc.; 10. Acute gallbladder disease; 11. Severe blood loss (\> 500 mL) or blood transfusion within 4 weeks prior to randomization; 12. Inability to take oral medication; 13. Inability to tolerate venipuncture and/or maintain an intravenous access line; 14. History of uncontrolled psychotropic substance abuse or diagnosed psychiatric disorders; 15. Any other medical, psychiatric and/or social reasons determined by medical judgment to preclude study participation; 16. Regular heavy alcohol consumption within 3 months prior to screening, defined as more than 14 alcohol units per week; clinically significant abnormal blood alcohol test results at screening; or inability to comply with the alcohol prohibition specified in the study protocol; 17. Daily cigarette consumption exceeding 10 cigarettes within 3 months prior to screening, or inability to cease smoking during intensive pharmacokinetic blood sampling periods; 18. History of substance abuse, drug dependence or illicit drug use within 1 year prior to screening, or positive urine drug screen prior to study dosing. * 3.Concomitant and prior medications 1. Systemic glucocorticoids administered within 3 months prior to screening; 2. Antihyperglycemic agents other than metformin administered within 3 months prior to screening; 3. Weight-loss medications administered within 3 months prior to screening; 4. Concomitant use of medications with direct effects on gastrointestinal peristalsis. * 4.Serological viral testing criteria 1. Positive hepatitis C virus (HCV) antibody, with HCV viral load exceeding the upper limit of normal (ULN); 2. Positive hepatitis B surface antigen (HBsAg), with hepatitis B virus DNA (HBV DNA) exceeding the ULN; 3. Positive human immunodeficiency virus (HIV) test; 4. Active syphilis: positive treponemal antibody test and positive nontreponemal serological test (rapid plasma reagin \[RPR\] or toluidine red unheated serum test \[TRUST\]) at screening. * 5.Abnormal physical or laboratory examination findings 1. Clinically significant abnormal chest X-ray/chest computed tomography (CT) or ECG findings, including Fridericia-corrected QT interval (QTcF) \> 450 milliseconds (ms) for male subjects and \> 470 ms for female subjects; 2. Laboratory abnormalities judged clinically significant by the investigator, including: a) Serum alanine aminotransferase (ALT) ≥2.0 × ULN; b) Serum aspartate aminotransferase (AST) ≥2.0 × ULN; c) Total serum bilirubin ≥1.5 × ULN; d) Estimated glomerular filtration rate (eGFR) \< 60 mL/min/1.73 m², calculated via the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation; e) Calcitonin ≥20 ng/L; f) Triglycerides (TG) ≥5.65 mmol/L. If the subject is receiving lipid-lowering therapy, the type and dose of lipid-lowering medications shall remain stable for at least 30 days prior to screening and shall be maintained unchanged in principle throughout the study period; g) Serum lipase and/or amylase \> 1.5 × ULN; 3. Any other marked laboratory abnormalities that may pose unacceptable risks to subjects during the study per medical judgment. * 6.Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adverse Event | Baseline up to 14 weeks | Incidence and Severity of All Adverse Events (AEs), Serious Adverse Events (SAEs) and Treatment-Emergent Adverse Events (TEAEs). |
| Abnormal clinical examination findings | Baseline up to 14 weeks | Incidence of abnormal clinical laboratory examination, vital signs, physical examination, 12-lead electrocardiogram,etc. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin | Week 4, Week 8, and Week 12 | Change from baseline in insulin. |
| Area Under the Curve from 0 to 24 hours(AUC0-24h) | Prior to dose on Day 1,8,15,22,29,36,50,64,78; 4-6 hours post-dose on Day 36,50,64,78. At target dose: Prior to 1st dose and 1,2,4,6,8,12,24 hours after. Prior to last dose and 1,2,4,6,8,12,24,48,96 hours after. | AUC0-24h following the first administration at target dose, and AUC0-24h after multiple administrations. |
| Area Under the Curve from time zero to infinity(AUC0-∞) | Prior to dose on Day 1,8,15,22,29,36,50,64,78; 4-6 hours post-dose on Day 36,50,64,78. At target dose: Prior to 1st dose and 1,2,4,6,8,12,24 hours after. Prior to last dose and 1,2,4,6,8,12,24,48,96 hours after. | AUC0-∞ following the first administration at target dose, and AUC0-∞ after multiple administrations. |
| Area Under the Curve from time zero to the last quantifiable time point(AUC0-t) | Prior to dose on Day 1,8,15,22,29,36,50,64,78; 4-6 hours post-dose on Day 36,50,64,78. At target dose: Prior to 1st dose and 1,2,4,6,8,12,24 hours after. Prior to last dose and 1,2,4,6,8,12,24,48,96 hours after. | Area Under the Curve from time zero to the last quantifiable time point(AUC0-t). |
| Maximum Plasma Concentration(Cmax) | Prior to dose on Day 1,8,15,22,29,36,50,64,78; 4-6 hours post-dose on Day 36,50,64,78. At target dose: Prior to 1st dose and 1,2,4,6,8,12,24 hours after. Prior to last dose and 1,2,4,6,8,12,24,48,96 hours after. | Cmax following the first administration at target dose. |
| Minimum Steady-State Concentration(Css-min) | Prior to dose on Day 1,8,15,22,29,36,50,64,78; 4-6 hours post-dose on Day 36,50,64,78. At target dose: Prior to 1st dose and 1,2,4,6,8,12,24 hours after. Prior to last dose and 1,2,4,6,8,12,24,48,96 hours after. | Css-min after multiple administrations. |
| Maximum Steady-State Concentration(Css-max) | Prior to dose on Day 1,8,15,22,29,36,50,64,78; 4-6 hours post-dose on Day 36,50,64,78. At target dose: Prior to 1st dose and 1,2,4,6,8,12,24 hours after. Prior to last dose and 1,2,4,6,8,12,24,48,96 hours after. | Css-max after multiple administrations. |
| Average Steady-State Concentration(Css-avg) | Prior to dose on Day 1,8,15,22,29,36,50,64,78; 4-6 hours post-dose on Day 36,50,64,78. At target dose: Prior to 1st dose and 1,2,4,6,8,12,24 hours after. Prior to last dose and 1,2,4,6,8,12,24,48,96 hours after. | Css-avg after multiple administrations. |
| Elimination Half-Life(t1/2) | Prior to dose on Day 1,8,15,22,29,36,50,64,78; 4-6 hours post-dose on Day 36,50,64,78. At target dose: Prior to 1st dose and 1,2,4,6,8,12,24 hours after. Prior to last dose and 1,2,4,6,8,12,24,48,96 hours after. | t1/2 following the first administration at target dose and t1/2 after multiple administrations. |
| Time to Maximum Concentration(Tmax) | Prior to dose on Day 1,8,15,22,29,36,50,64,78; 4-6 hours post-dose on Day 36,50,64,78. At target dose: Prior to 1st dose and 1,2,4,6,8,12,24 hours after. Prior to last dose and 1,2,4,6,8,12,24,48,96 hours after. | Tmax after multiple administrations |
| Apparent Oral Clearance (CL/F) | Prior to dose on Day 1,8,15,22,29,36,50,64,78; 4-6 hours post-dose on Day 36,50,64,78. At target dose: Prior to 1st dose and 1,2,4,6,8,12,24 hours after. Prior to last dose and 1,2,4,6,8,12,24,48,96 hours after. | CL/F following the first administration at target dose and CL/F after multiple administrations. |
| Apparent Volume of Distribution during Elimination Phase(Vz/F) | Prior to dose on Day 1,8,15,22,29,36,50,64,78; 4-6 hours post-dose on Day 36,50,64,78. At target dose: Prior to 1st dose and 1,2,4,6,8,12,24 hours after. Prior to last dose and 1,2,4,6,8,12,24,48,96 hours after. | Vz/F following the first administration at target dose. |
| Apparent Volume of Distribution at Steady State(Vss/F) | Prior to dose on Day 1,8,15,22,29,36,50,64,78; 4-6 hours post-dose on Day 36,50,64,78. At target dose: Prior to 1st dose and 1,2,4,6,8,12,24 hours after. Prior to last dose and 1,2,4,6,8,12,24,48,96 hours after. | Vss/F after multiple administrations. |
| Terminal elimination rate constant(λz) | Prior to dose on Day 1,8,15,22,29,36,50,64,78; 4-6 hours post-dose on Day 36,50,64,78. At target dose: Prior to 1st dose and 1,2,4,6,8,12,24 hours after. Prior to last dose and 1,2,4,6,8,12,24,48,96 hours after. | λz following the first administration at target dose and λz after multiple administrations. |
| Accumulation Ratio (Rac) | Prior to dose on Day 1,8,15,22,29,36,50,64,78; 4-6 hours post-dose on Day 36,50,64,78. At target dose: Prior to 1st dose and 1,2,4,6,8,12,24 hours after. Prior to last dose and 1,2,4,6,8,12,24,48,96 hours after. | Rac after multiple administrations. |
| Dose Fluctuation(DF) | Prior to dose on Day 1,8,15,22,29,36,50,64,78; 4-6 hours post-dose on Day 36,50,64,78. At target dose: Prior to 1st dose and 1,2,4,6,8,12,24 hours after. Prior to last dose and 1,2,4,6,8,12,24,48,96 hours after. | DF after multiple administrations. |
| Glycated hemoglobin(HbA1c) | Week 4, Week 8, and Week 12 | Change from baseline in HbA1c and Proportion of participants with HbA1c ≤7.0% and HbA1c ≤6.5%. |
| Oral Glucose Tolerance Test(OGTT) | Week 12 | Changes from baseline in C-peptide levels at each time point during the Oral Glucose Tolerance Test (OGTT), as well as changes from baseline in fasting plasma glucose (FPG) and 2-hour postprandial plasma glucose (2h-PPG). |
| Body Weight | Week 4, Week 8, and Week 12 | Changes and percent change from baseline in body weight. |
| Waist Circumference | Week 4, Week 8, and Week 12 | Change from baseline in waist circumference. |
| Fasting Plasma Glucose | Week 4, Week 8, and Week 12 | Change from baseline in(FPG) |
| Body Mass Index(BMI) | Week 4, Week 8, and Week 12 | Change from baseline in BMI. |
| C-peptide | Week 4, Week 8, and Week 12 | Change from baseline in C-peptide. |
Countries
China
Contacts
CONTACTDalong Zhu, Doctor
CONTACTJuan Li, Doctor
Outcome results
None listed