Phase III Study of UBT251 Injection in Patients With Type 2 Diabetes With Inadequate Glycemic Control on Metformin ± Sulfonylurea/SGLT2 Inhibitor Therapy (UNIGUIDE-2)

A Multicenter, Randomized, Open-Label, Semaglutide Injection-Controlled Phase III Clinical Study to Evaluate the Efficacy and Safety of UBT251 Injection in Participants With Type 2 Diabetes Mellitus With Inadequate Glycemic Control Despite Treatment With Metformin Alone or in Combination With Sulfonylurea/Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor Therapy (UNIGUIDE-2)

This study is a multicenter, randomized, open-label, parallel-group, semaglutide injection-controlled clinical trial. It aims to evaluate the non-inferiority of UBT251 Injection in glycemic control compared with Semaglutide Injection after 36 weeks of continuous administration in study participants with Type 2 Diabetes Mellitus (T2DM) and inadequate glycemic control on oral antidiabetic medications.A total of 956 participants are planned to be enrolled, including the UBT251 Injection 2 mg group, 4 mg group, 6 mg group, and Semaglutide group，with an approximate study duration of 58 weeks per participant.

Inclusion Criteria:

• Aged 18 to 75 years (inclusive) at the time of signing informed consent, with no restriction on gender;
• Diagnosed with Type 2 Diabetes Mellitus (T2DM) according to the 2019 World Health Organization (WHO) criteria (Appendix 1), with glycated hemoglobin (HbA1c) ≥7.5% and ≤11.0%;
• Participants with inadequate glycemic control despite stable treatment for 3 months prior to screening with 1) metformin; or 2) metformin in combination with sulfonylurea; or 3) metformin in combination with sodium-glucose cotransporter 2 (SGLT2) inhibitor, with the following dosage requirements:

Metformin: ≥1500 mg/day or maximum tolerated dose (at least ≥1000 mg/day); Sulfonylurea: half of the maximum daily dose as specified in the package insert or maximum tolerated dose (see Appendix 2 for details); SGLT2 inhibitor: daily dose approved in the package insert (see Appendix 2 for specific products and dosage requirements).

• Body mass index (BMI) ≥23.0 kg/m² at screening, with stable body weight for 3 months prior to screening (change <5%, based on participant's report);
• Participants (including their partners) with no plan for pregnancy from screening until 6 months after completion of the study, willing to use contraceptive measures, and with no plan to donate sperm or ova within 6 months after study completion;
• Participants who have been fully informed about the study and have voluntarily signed written informed consent.

Exclusion Criteria:

• Known history of hypersensitivity to the investigational medicinal product or its excipients or other similar active drugs;

• Treatment with any of the following medications within 3 months prior to screening:

  1. Other antidiabetic medications except background therapy (short-term insulin use ≤14 days for acute conditions is allowed, e.g., perioperative period or hospitalization);
  2. Medications that may affect glucose metabolism, such as systemic glucocorticoids, growth hormone, etc. (excluded if cumulative use <7 days and the end of treatment is >7 half-lives prior to the first day of screening);
  3. Weight-loss medications (including but not limited to orlistat, semaglutide, or other similar prescription or over-the-counter drugs for weight loss).

• History or evidence of any of the following diseases:

  1. Diagnosis of other types of diabetes: such as Type 1 diabetes mellitus, special types of diabetes (e.g., genetic defects in β-cell function, genetic defects in insulin action, diseases of the exocrine pancreas, etc.);

  2. History of acute or chronic pancreatitis, or pancreatic surgery;

  3. History of symptomatic gallbladder disease within 1 year prior to screening (participants who have undergone cholecystectomy [completed at least 3 months prior to screening] without long-term complications are excluded); or abdominal ultrasound at screening indicating large gallbladder stones (diameter ≥2 cm), gallbladder polyps (diameter ≥1 cm), or other gallbladder lesions that the investigator comprehensively determines may affect participant safety;

  4. Personal or family history (first-degree relatives, i.e., parents, children, or siblings) of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN2);

  5. History of hematological disorders that may affect HbA1c test results or increase participant risk (e.g., aplastic anemia, myelodysplastic syndrome, etc.), or any disease causing hemolysis or red blood cell instability (e.g., sickle cell disease, thalassemia, etc.);

  6. History of moderate to severe depression or history of severe psychiatric disorders (including but not limited to suicidal ideation or suicide attempt, schizophrenia, bipolar disorder, etc.);

  7. History of clinically significant cardiovascular or cerebrovascular disease within 6 months prior to screening, defined as:

     1. Myocardial infarction (MI) or unstable angina;
     2. Cardiac-related surgery (including coronary artery bypass grafting, percutaneous coronary intervention);
     3. Congestive heart failure (New York Heart Association [NYHA] Class III-IV) (see Appendix 3 for details);
     4. Cerebrovascular accident (excluding old lacunar infarction), including but not limited to hemorrhagic or ischemic stroke or transient ischemic attack;
     5. Other cardiovascular or cerebrovascular diseases assessed by the investigator as unsuitable for participation in this study;

  8. Severe retinal or macular lesions at screening (including but not limited to proliferative retinopathy, macular edema, retinal detachment, etc.), and the investigator determines that further urgent treatment is required;

  9. Severe hypoglycemia (hypoglycemia with severe cognitive impairment requiring other therapeutic measures to assist recovery) or recurrent symptomatic hypoglycemia (≥2 times within 6 months) within 6 months prior to screening;

  10. History of acute metabolic complications of diabetes (including but not limited to diabetic ketoacidosis, hyperosmolar hyperglycemic state requiring hospitalization, hyperosmolar coma, lactic acidosis, etc.) or diabetic foot within 6 months prior to screening;

  11. Concurrent gastrointestinal emptying disorders (e.g., gastroparesis, pyloric obstruction, intestinal obstruction, etc.) at screening, gastrointestinal diseases assessed by the investigator as increasing risk after administration (e.g., severe active ulcer, inflammatory bowel disease, acute gastroenteritis, uncontrolled gastroesophageal reflux disease, etc.), or history of major gastrointestinal surgery (gastrointestinal polypectomy, appendectomy, cholecystectomy, etc. that have completely recovered and are assessed by the investigator as not affecting study safety are excluded);

  12. Major surgery, severe trauma, or severe infection within 1 month prior to screening, assessed by the investigator as unsuitable for participation in this study;

  13. History of malignant tumors (excluding adequately treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, localized prostate cancer after radical surgery, ductal carcinoma in situ of the breast after radical surgery, and assessed by the investigator as currently stable);

  14. Concurrent other diseases, such as respiratory, urinary, neurological, hematological, immune system diseases, etc., and the investigator considers that they affect participant safety, efficacy evaluation, or compliance.

• Screening results showing any of the following abnormal findings:

  1. Hepatic or renal impairment: serum alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≥3× upper limit of normal (ULN); serum total bilirubin (TBIL) ≥1.5×ULN; estimated glomerular filtration rate (eGFR) <45 mL·min-¹·1.73m-² (calculated according to the CKD-EPI 2021 equation, see Appendix 4);

  2. Serum calcitonin ≥50 pg/mL (i.e., 50 ng/L);

  3. Thyroid dysfunction not controlled with stable drug dosage, or clinically significant abnormalities in thyroid function test results at screening requiring initiation of treatment, or thyroid ultrasound at screening indicating thyroid nodules ≥TI-RADS 4a (or ≥TR4 according to the US classification standard) or assessed by the investigator as possibly requiring biopsy and/or surgery during the study period;

  4. Fasting triglycerides ≥5.6 mmol/L;

  5. Serum amylase and/or lipase >2.0×ULN;

  6. International normalized ratio (INR) above the upper limit of the normal range;

  7. Hemoglobin <100 g/L;

  8. Untreated or poorly controlled hypertension (systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg, based on the mean of 3 blood pressure measurements during the screening period);

  9. Clinically significant electrocardiogram (ECG) abnormalities, such as:

     1. Second-degree or third-degree atrioventricular block;
     2. Long QT syndrome, or QT interval corrected using Fridericia's formula (QTcF) >470 ms for female participants or >450 ms for male participants (calculation formula see Appendix 5);
     3. Pre-excitation syndrome (Wolff-Parkinson-White syndrome);
     4. Heart rate <50 beats/min or >100 beats/min;
     5. Other serious arrhythmias requiring treatment;

  10. Positive hepatitis B surface antigen with hepatitis B virus deoxyribonucleic acid (HBV-DNA) exceeding the upper limit of the reference range, or positive hepatitis C virus antibody with hepatitis C virus ribonucleic acid (HCV-RNA) exceeding the upper limit of the reference range, or positive human immunodeficiency virus (HIV) antibody, or positive both specific and non-specific syphilis antibodies;

  11. Abnormalities in physical examination, vital signs, laboratory tests, etc. that are clinically significant and assessed by the investigator as potentially posing significant risk to participants or interfering with the evaluation of safety, PK, or PD results, making them unsuitable for participation in this study.

• Participation in other interventional clinical trials within 3 months prior to screening (excluding those who only participated in screening but were not enrolled, or those who were enrolled but did not receive treatment);

• Blood loss ≥400 mL (including trauma, blood draw, blood donation) within 3 months before screening, or receipt of blood or blood component transfusion;

• Lactating women or pregnant women;