Efficacy and Safety of CS0159 Combined With Semaglutide in MASH Patients With Obesity and T2DM

This is an exploratory study to evaluate the efficacy, safety, and tolerability of CS0159 in combination with Semaglutide in MASH patients with obesity and T2DM. A total of 60 patients will be recruited. BMI ≥35 kg/m2 will be used as a randomized stratification factor, and patients will be randomly assigned in a 1:1 ratio.

Inclusion criteria

• 1. Age≥18 and ≤65 years, male or female.
• 2. Patients with previous liver biopsy for MASH or MRI-PDFF ≥10% within 3 months prior to randomization.
• 3. Diagnosis of T2DM.
• 4. HbA1c: 7.0%-10.5%.
• 5. FPG: 7.0-13.3 mmol/L.
• 6. BMI: 30-45 kg/m2.
• 7. Subjects control blood glucose only by lifestyle intervention for at least 3 months before the screening period.
• 8. Willing to maintain consistent diet and exercise habits throughout the entire study, and adhere to the study protocol for timely administration of the study drug, and timely self-monitoring of blood glucose and recording.

Exclusion criteria

• 1. ALT≥2.5×ULN, AST≥2.5×ULN, TBil≥2×ULN, creatinine (Cr) ≥1.5×ULN and Serum creatinine clearance<60 mL/min, PLT<100×10^9/L, INR >1.3, ALB <3.5 g/dL.
• 2. Use of glucose-lowering medication in the 3 months prior to randomization.
• 3. Weight loss ≥ 5% in the 3 months prior to randomization or ≥10% in the 6 months prior to randomization or use of other weight-lowering drugs, corticosteroids, and etc.
• 4. History of allergy to glucagon-like peptide-1 receptor agonists (GLP-1RA) medications, currently in an allergic state, having allergic conditions, or history of allergies to ≥2 substances.
• 5. Subjects with T1DM, monogenic diabetes, diabetes caused by pancreatic damage, or other secondary diabetes.
• 6. Subjects with a history of severe pruritus.
• 7. Uncontrolled and potentially unstable diabetic retinopathy or maculopathy.
• 8. Thyroid C-cell tumour or family history, multiple endocrine neoplasia type 2 or family history.
• 9. History of acute or chronic pancreatitis.
• 10. Subjects with Child-Pugh class B or C grade cirrhosis.
• 11. HBsAg positive, HCV Ab positive, HIV Ab positive, TP Ab positive.
• 12. Arrhythmias, male QTc≥450 ms, or female QTc≥470 ms. Or cardiovascular disease for which the researcher has assessed that participation in the trial is not appropriate.
• 13. Diseases that interfere with the absorption, distribution, metabolism or excretion.
• 14. Gastrointestinal diseases that affect food digestion and absorption.
• 15. Use moderate or strong inhibitors or inducers of cytochrome P450 enzyme (CYP3A4 enzyme) within the first 14 days of randomization and throughout the entire trial period.
• 16. History of malignant tumors within the first 5 years of randomization.
• 17. Serious hypoglycemic events occurring ≥ 3 times within 12 weeks prior to administration, or acute and severe metabolic disorder occurred within 12 weeks prior to administration.
• 18. Drug abuse or alcohol abuse within the first 6 months of randomization.
• 19. Poor blood pressure control.
• 20. Mental illness, epilepsy.
• 21. Patients with uncontrollable severe infectious diseases before randomization.
• 22. Pregnant, planned pregnancy or breastfeeding.
• 23. Participated in other clinical trials in the first three months of randomization.
• 24. Any condition that in the judgement of the researcher precludes participation.