A Clinical Trial Evaluating TQF3250 Capsules in Patients With Type 2 Diabetes Mellitus and Overweight/Obesity

Official title

A Phase 1b Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetic Profiles and Preliminary Efficacy of TQF3250 Capsules in Trial Participants With Type 2 Diabetes Mellitus Complicated With Overweight or Obesity

Overview

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

• Drug TQF3250 capsules
  An oral glucagon-like peptide-1 receptor agonist.
• Drug TQF3250 placebo
  TQF3250-matched placebo capsules.

Primary outcome measures

• Adverse Event [Time frame: Baseline up to 14 weeks]
• Abnormal clinical examination findings [Time frame: Baseline up to 14 weeks]

Secondary outcome measures (12)

• Area Under the Curve from 0 to 24 hours(AUC0-24h) [Time frame: 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 infinity(AUC0-∞) [Time frame: 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) [Time frame: 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.]
• Maximum Plasma Concentration(Cmax) [Time frame: 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.]
• Minimum Steady-State Concentration(Css-min) [Time frame: 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.]
• Maximum Steady-State Concentration(Css-max) [Time frame: 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.]
• Average Steady-State Concentration(Css-avg) [Time frame: 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.]
• Elimination Half-Life(t1/2) [Time frame: 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.]
• Time to Maximum Concentration(Tmax) [Time frame: 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.]
• Apparent Oral Clearance (CL/F) [Time frame: 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.]
• Apparent Volume of Distribution during Elimination Phase(Vz/F) [Time frame: 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.]
• Apparent Volume of Distribution at Steady State(Vss/F) [Time frame: 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.]

Eligibility criteria

Inclusion criteria

• 1.Aged between 18 and 70 years, inclusive.
• 2.Able to provide written informed consent, and meet the following requirements:

• Voluntarily participate in the study and capable of signing the informed consent form;
• 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

• Diagnosed with or suspected of type 1 diabetes mellitus, specific types of diabetes, or secondary diabetes mellitus;
• Occurrence of acute diabetic complications within 6 months prior to screening;
• Medical history of severe hypoglycemic coma; occurrence of severe hypoglycemic episodes or recurrent hypoglycemic events within 6 months prior to screening;
• 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;
• 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

• Any condition that may interfere with drug absorption;
• 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;
• 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;
• 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;
• 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;
• Any major surgery performed within 30 days prior to the first dose of study treatment, or any surgery planned during the study period;
• 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);
• Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN2), or subjects suspected of MTC per investigator judgment;
• 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.;
• Acute gallbladder disease;
• Severe blood loss (> 500 mL) or blood transfusion within 4 weeks prior to randomization;
• Inability to take oral medication;
• Inability to tolerate venipuncture and/or maintain an intravenous access line;
• History of uncontrolled psychotropic substance abuse or diagnosed psychiatric disorders;
• Any other medical, psychiatric and/or social reasons determined by medical judgment to preclude study participation;
• 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;
• Daily cigarette consumption exceeding 10 cigarettes within 3 months prior to screening, or inability to cease smoking during intensive pharmacokinetic blood sampling periods;
• 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

• Systemic glucocorticoids administered within 3 months prior to screening;
• Antihyperglycemic agents other than metformin administered within 3 months prior to screening;
• Weight-loss medications administered within 3 months prior to screening;
• Concomitant use of medications with direct effects on gastrointestinal peristalsis.
• 4.Serological viral testing criteria

• Positive hepatitis C virus (HCV) antibody, with HCV viral load exceeding the upper limit of normal (ULN);
• Positive hepatitis B surface antigen (HBsAg), with hepatitis B virus DNA (HBV DNA) exceeding the ULN;
• Positive human immunodeficiency virus (HIV) test;
• 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

• 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;
• 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;
• Any other marked laboratory abnormalities that may pose unacceptable risks to subjects during the study per medical judgment.
• 6.Additional exclusion criteria

• Use of strong or moderate CYP3A4 inhibitors or inducers within 28 days prior to screening, including but not limited to rifampicin, rifapentine, carbamazepine, phenytoin, phenobarbital, St. John's Wort, itraconazole, ketoconazole, voriconazole, ritonavir, cobicistat, clarithromycin, etc.;
• Subjects receiving simvastatin at screening who cannot discontinue simvastatin and switch to an alternative treatment regimen approved by the investigator. Subjects with prior simvastatin use shall discontinue simvastatin and switch to an investigator-approved alternative regimen at least 30 days prior to enrollment, with stable dosing of the alternative regimen maintained throughout this period;
• Any significant history of drug hypersensitivity (e.g., anaphylaxis or hepatotoxicity); known hypersensitivity to GLP-1 receptor agonists or any excipients of the study drug;
• Participation in any other clinical trial within 3 months prior to screening or within 5 half-lives of the investigational product (whichever is longer) (excluding subjects who failed screening or never received the investigational product for other reasons);
• Inability to comply with the study protocol;
• Planned or prior allogeneic bone marrow transplantation or solid organ transplantation;
• Subjects with any other factors deemed unsuitable for participation in this clinical trial by the investigator, which may interfere with the evaluation of efficacy or safety of the study treatment (including but not limited to poor subject compliance per investigator judgment, or residence at an excessively remote location precluding scheduled follow-up visits).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 12 centers

• Fuzhou University Affiliated Provincial Hospital — Fuzhou
• Sun Yat-sen Memorial Hospital, Sun Yat-sen University — Guangzhou
• Hebei Petro China Central Hosptial — Langfang
• Luoyang First People's Hospital — Luoyang
• Zhongnan Hospital of Wuhan University — Wuhan
• Yichang Central People's Hospital — Yichang
• The Third Hospital of Changsha — Changsha
• Nanjing Drum Tower Hospital — Nanjing
• … and 4 more centers

Identifiers

NCT: NCT07747857 · TQF3250-Ib-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗