BALANCE-DM2 Study of Bofanglutide in Adults With Type 2 Diabetes

Inclusion criteria

• Adults aged 18 years and older who agree to participate in the study by voluntarily signing the Informed Consent Form.
• Adult participants of either male or female sex.
• Diagnosis of type 2 diabetes mellitus (T2DM) with a duration greater than 6 months, established according to the diagnostic and classification criteria for diabetes mellitus of the World Health Organization (WHO) in 1999, as well as the supplementary WHO diagnostic criteria of 2011, and in accordance with the widely accepted clinical criteria of the American Diabetes Association.
• Background treatment with metformin monotherapy, at a stable dose for at least 90 days prior to screening, at a dose ≥1500 mg/day or at the maximum tolerated dose (MTD; ≥1000 mg/day), with no planned changes during the study.
• HbA1c determined by central laboratory during the screening period ≥7.0% and ≤10.5%.
• Fasting plasma glucose (FPG) during screening <270 mg/dL.
• Body mass index (BMI) ≥27 kg/m².
• Stable body weight prior to screening, defined as a change ≤5% in body weight during the previous 3 months.
• Women of childbearing potential must have a negative pregnancy test during screening and at the baseline visit; must not be breastfeeding; must have no plans for pregnancy from signing the ICF until 6 months after the last dose of study treatment; and must agree to use effective contraceptive methods during this period.

Men must have no plans for sperm donation during the same period.

Exclusion criteria

• Known or suspected hypersensitivity to GLP-1 type drugs or any of their excipients; or presence of contraindications for this type of medication.
• Participation in clinical trials of other drugs or devices and having received treatment within the 3 months prior to the screening period.
• Conditions that may cause significant instability in body weight or glycemic control within the 3 months prior to screening, including, but not limited to:

• Major surgery or surgical procedures with the potential to significantly alter body weight, intake, absorption, gastric emptying, mobility, or metabolic recovery.
• Current use of non-antidiabetic medications that affect body weight.
• Participation in weight loss programs that are not in the maintenance phase.
• Use, initiation, discontinuation, or relevant dose change of concomitant medications that, in the investigator's judgment, may significantly affect glycemic control or body weight, including, but not limited to, chronic systemic glucocorticoids, antipsychotics, antiepileptics, or other drugs with relevant metabolic effects, within the 12 weeks prior to the screening period, or plans to initiate or modify such treatments during the study.
• History of alcohol or drug abuse, including, but not limited to, amphetamines, benzodiazepines, marijuana, cocaine, methadone, and morphine-like drugs, within the 6 months prior to screening, determined by medical history or positive substance abuse screening test results (urine).
• Previous antidiabetic treatment with:

• Insulin for more than 14 consecutive days within the year prior to screening (insulin treatment for gestational diabetes mellitus is not considered under this criterion).
• GLP-1 receptor agonists within the 6 months prior to screening.
• DPP-4 inhibitors ≤3 months prior to screening.
• Use of medications such as growth hormone, or others that, in the investigator's judgment, may affect insulin levels, within the 3 months prior to screening.
• History of diabetic ketoacidosis, diabetic lactic acidosis, or hyperosmolar non-ketotic coma within the 6 months prior to screening.
• T2DM complications such as proliferative retinopathy or maculopathy that is unstable or has required treatment; severe diabetic neuropathy, intermittent claudication, or diabetic foot within the 6 months prior to screening.
• Severe hypoglycemia (Grade 3) within the 6 months prior to screening; or ≥3 episodes of hypoglycemia (blood glucose ≤70 mg/dL) within the month prior to screening; or recurrent symptoms related to hypoglycemia.
• Severe trauma, serious infection, or major surgery that, in the investigator's judgment, may affect glycemic control, within the month prior to screening.
• Serum calcitonin ≥50 pg/mL during screening.
• Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2A or 2B (MEN 2A/2B), or diagnosis of other malignant neoplasms within the last 5 years.
• Uncontrolled hyperthyroidism or hypothyroidism. Subjects who have received stable thyroxine replacement treatment for ≥3 months prior to screening and whose TSH, FT3, and FT4 levels are within normal ranges are exempt from this criterion.
• History of acute or chronic hepatitis, acute or chronic pancreatitis, symptomatic gallbladder disease (for example, multiple gallstones), pancreatic injury, or other high-risk factors that may predispose to the development of pancreatitis.
• Uncontrolled arterial hypertension, defined as systolic blood pressure (SBP) ≥160 mmHg and/or diastolic blood pressure (DBP) ≥100 mmHg at screening.
• History of hospitalization for severe cardiovascular disease (including, among others, acute myocardial infarction, unstable angina, cerebrovascular disease, or peripheral vascular disease) or sequelae of cerebrovascular disease within the 6 months prior to screening; presence of a cardiac pacemaker, second/third-degree atrioventricular block, long QT syndrome, QTc ≥450 ms on 12-lead ECG without pacemaker; NYHA class III or IV heart failure; or any other clinically significant cardiac abnormality that, in the investigator's judgment, makes the subject unsuitable for the study.
• Clinically significant hematologic disorders or any condition that may affect erythrocyte half-life or stability, and therefore interfere with interpretation of glycated hemoglobin (HbA1c), including, but not limited to, aplastic anemia, myelodysplastic syndrome, thalassemia, sickle cell anemia, hemolytic anemia, or any disease causing hemolysis or erythrocyte instability (including malaria or Henoch-Schönlein purpura). Likewise, blood donation or blood loss >400 mL or blood transfusion within the 3 months prior to screening.
• Clinically significant gastric emptying abnormalities (for example, gastric outlet obstruction), severe chronic gastrointestinal disorders (for example, active ulcers within the last 6 months), prolonged use of drugs that directly affect gastrointestinal motility (including, but not limited to, domperidone, mosapride, cisapride), or gastrointestinal surgery within the 6 months prior to screening, which, in the investigator's judgment, make the subject unsuitable to participate in the study.
• Clinically significant laboratory abnormalities, including:

• ALT or AST ≥2.5 times the upper limit of normal (ULN).
• Fasting triglycerides >500 mg/dL.
• Amylase and/or lipase ≥1.5 times the ULN.
• Fasting blood glucose >270 mg/dL.
• Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m².
• Evidence of clinically relevant active infection at screening, defined as:

• Hepatitis B virus (HBV): positive surface antigen (HBsAg) accompanied by detectable viral load (HBV DNA above the laboratory lower limit of detection).
• Hepatitis C virus (HCV): positive antibodies with detectable viral load (HCV RNA above the laboratory lower limit of detection). Subjects with resolved infection (documented negative RNA) may be included.
• Human immunodeficiency virus (HIV): confirmed infection with clinical impact or unstable treatment that, in the investigator's judgment, may interfere with subject safety or study participation.
• Treponema pallidum: positive serology confirmed as active infection by confirmatory tests.
• History of organ transplantation, or acquired or congenital immune system disorders.
• Previous history of psychiatric disorders such as schizophrenia, bipolar disorder, previous suicidal tendency, etc., or use of psychiatric medications that, in the investigator's judgment, may interfere with subject participation in the study or protocol compliance.
• Any clinical condition or circumstance that, in the investigator's judgment, may compromise subject safety, protocol compliance, or the validity and interpretability of study data.