A Study of CS060380 Tablets in Patients With MASH and Obesity

A Randomized, Double-blind, Placebo-controlled, Parallel-group Phase II Study to Evaluate the Efficacy and Safety of CS060380 Tablets in Patients With Metabolic Dysfunction-associated Steatohepatitis (MASH) and Obesity.

this study is looking at a new investigational medicine called CS060380, when used together with semaglutide, in adults who have both metabolic dysfunction-associated steatohepatitis (MASH) and obesity. MASH is a condition where too much fat builds up in the liver, leading to inflammation and damage. Obesity is a major risk factor for this condition.

This is a Phase II clinical trial, which means we are testing the medicine to see if it works and is safe. The study will last up to 54 weeks, which is a little over a year. It includes:

• A screening period of up to 2 weeks to check if you are eligible to take part.
• A 36-week double-blind treatment period, where you will be randomly assigned (like flipping a coin) to receive either the study drug CS060380 or a placebo (an inactive pill that looks like the study drug). Both groups will also receive semaglutide, which is an approved medicine for weight management. Neither you nor your doctor will know which treatment you are receiving.
• A 16-week open-label period, where all participants will receive CS060380. The main goal of this study is to see how the study drug affects the amount of fat in the liver, measured by a special MRI scan, and body weight. We will also monitor your overall health and safety throughout the study by checking your vital signs, doing blood and urine tests, and asking about any side effects you might experience.

About 120 participants will take part in this study at almost 15 different hospitals across China, with Ruijin Hospital in Shanghai as the main study site.

The total study duration will not exceed 54 weeks, consisting of: screening period (up to 2 weeks), 36-week double-blind treatment period, and 16-week open-label period.

1. The double-blind treatment period will employ a randomized, double-blind, placebo-controlled, parallel-group design.
2. During the open-label period, all participants will receive CS060380.
3. This study will enroll participants with MASH and obesity. About 120 participants are planned for enrollment.
4. Eligible participants will be randomized in a 1:1 ratio to Control Group A (60 participants) and Experimental Group B (60 participants).
5. Both groups will receive semaglutide 1.7 mg as background therapy. Control Group A will receive placebo, while Experimental Group B will receive CS060380 1.0 mg.
6. Interim analyses will be conducted when approximately 80% of participants complete Week 16 and Week 24 visits.
7. The sponsor will decide whether to continue the open-label study based on safety and efficacy data.

Inclusion Criteria:

• Age 18 to 65 years (inclusive), male or female.
• Liver fat content ≥10% as measured by MRI-PDFF at screening.
• BMI ≥30 kg/m².
• Body weight change ≤5% during the 3 months prior to screening with only diet and exercise control (self-reported). The weight change is calculated as: (Maximum weight - Minimum weight within 3 months before screening) / Maximum weight × 100%.
• Glycated hemoglobin (HbA1c) <6.5% at screening.
• Fasting venous blood glucose <7 mmol/L at screening.
• All participants with reproductive capacity agreed to take effective contraceptive measures for themselves and their partners from the screening period until the end of the trial (physical contraception was used before and during the trial, and only drug contraception was used when necessary after or during the trial), and there were no recent plans for sperm donation, egg donation, or childbearing.
• Voluntary consent to participate in this clinical trial and provide written informed consent.

Exclusion Criteria:

Diagnosis of type 2 diabetes mellitus, type 1 diabetes mellitus, monogenic diabetes, diabetes due to pancreatic injury (e.g., post-pancreatitis diabetes), or other secondary diabetes prior to randomization.

• ≥2 episodes of hypoglycemia (blood glucose ≤2.8 mmol/L in non-diabetic patients) within 6 months before screening.
• Impaired gastrointestinal function or gastrointestinal disease that may affect the absorption of oral medications, such as severe gastrointestinal diseases (peptic ulcer, erosive or atrophic gastritis), partial gastrectomy, or grade >1 gastrointestinal symptoms (e.g., nausea, vomiting, or diarrhea) at screening.
• Thyroid diseases including hyperthyroidism and hypothyroidism [participants with benign thyroid lesions (e.g., thyroid nodules) may participate in this study] or pituitary diseases, or long-term use of thyroid hormone replacement therapy, antithyroid drugs, or drugs that may affect thyroid hormone production and/or interfere with thyroid function (including but not limited to methimazole, propylthiouracil, tyrosine kinase inhibitors, lithium, iodides, and glucocorticoids, etc.).
• Previous diagnosis of obesity caused by endocrine diseases or single-gene mutations, including but not limited to hypothalamic obesity, pituitary obesity, hypothyroid obesity, Cushing's syndrome, insulinoma, acromegaly, and hypogonadism.
• Previous bariatric surgery (including sleeve gastrectomy, Roux-en-Y gastric bypass, or combined procedures, etc.) or use of medical devices for obesity treatment, or planned such procedures during the trial; except for liposuction or abdominal lipectomy performed more than 1 year before screening; adjustable gastric banding with band removal more than 1 year before screening; intragastric balloon removal more than 1 year before screening.
• Any contraindication to MRI scanning (including but not limited to severe claustrophobia, coronary artery stents, coronary implant devices, waist circumference exceeding scanner capacity making MRI-PDFF examination impossible). If coronary stents or other devices do not interfere with the function of the MRI machine, the investigator may decide at their discretion whether to allow inclusion.
• Blood donation within 3 months before screening, or total blood loss (excluding female physiological bleeding) due to blood donation or other reasons reaching or exceeding 400 mL within 6 months.
• Use of glucagon-like peptide-1 receptor agonists (GLP-1 RA) or compound preparations containing GLP-1 RA components within 3 months before randomization.
• Use of any approved or unapproved weight-loss drugs (e.g., orlistat, lorcaserin, phentermine/topiramate, naltrexone/bupropion, etc.) or drugs affecting body weight (including Chinese herbal medicines), health products, meal replacements, or weight-loss acupuncture treatments within 3 months before randomization.
• Use of drugs that may cause significant weight gain: systemic glucocorticoid therapy for more than 1 week; tricyclic antidepressants; antipsychotic or antiepileptic drugs (e.g., imipramine, amitriptyline, mirtazapine, paroxetine, phenelzine, chlorpromazine hydrochloride, clozapine, olanzapine, valproic acid and its derivatives, lithium preparations, thioridazine), etc., within 3 months before randomization.
• History of treatment for more than 1 week such as total parenteral nutrition (TPN), amiodarone, methotrexate, tetracycline, tamoxifen, estrogens in excess of hormone replacement doses, anabolic steroids, valproic acid, anticholinergic drugs, or other known hepatotoxic drugs within 3 months before randomization.
• Use of vitamin E (≥800-1000 IU/day), polyunsaturated fatty acids, ursodeoxycholic acid, fibrates, statins within 3 months before randomization, unless the participant had a stable dose for 3 months before screening, continued taking until the screening visit, and will continue the same medication regimen throughout the study participation period.
• Use of metformin, SGLT2 inhibitors, and other hypoglycemic agents within 3 months before randomization.
• Use of strong inhibitors of CYP3A enzymes, strong inducers of CYP3A enzymes, or inhibitors of P-gp or BCRP transporters that may affect the metabolism or absorption of the study drug within 14 days before randomization or at least 5 half-lives (whichever is longer), see Appendix 1.
• Use of hepatoprotective drugs not permitted by the protocol within 4 weeks before randomization or planned use during the clinical study, including silymarin, bicyclol, glycyrrhizin preparations (magnesium isoglycyrrhizinate, compound glycyrrhizin, diammonium glycyrrhizinate), except for ursodeoxycholic acid, polyene phosphatidylcholine, and reduced glutathione that have been stably used for ≥3 months before randomization.
• Anticoagulant therapy within 2 weeks before randomization: drugs that increase INR (e.g., FXa inhibitors, warfarin, heparin, etc.).
• History of heavy alcohol consumption for more than 3 consecutive months within 1 year before screening. Note: Heavy alcohol consumption is defined as an average weekly alcohol intake of more than approximately 7 standard drinks for women and more than approximately 14 standard drinks for men. One standard drink is defined as any beverage containing 14g of pure alcohol, such as 12 oz/360 ml of beer (5% alcohol), 8 oz/240 ml of malt liquor (7% alcohol), 5 oz/150 ml of wine (12% alcohol), 1.5 oz/45 ml of spirits (40% alcohol).
• Hemoglobin ≤90 g/L at screening.
• ALT ≥2.5×ULN at screening.
• AST ≥2.5×ULN at screening.
• Serum albumin (ALB) <35 g/L at screening.
• International normalized ratio (INR) >1.2 at screening.
• Total bilirubin (TBil) >1.2×ULN at screening (except for Gilbert's syndrome).
• Serum amylase or lipase ≥3×ULN at screening.
• Calcitonin ≥50 ng/L at screening.
• Estimated glomerular filtration rate (eGFR) <50 mL/min/1.73m² at screening.
• Clinically relevant abnormalities on 12-lead ECG that, in the investigator's judgment, may affect participant safety or the interpretation of study results, such as: at screening, QTcF interval corrected by Fridericia >450 ms (males) or >470 ms (females) [Fridericia formula: QTcF = QT/(RR^0.33)].
• Uncontrolled hypertension: sitting systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg.
• Previous history of acute or chronic pancreatitis, or acute or chronic pancreatitis at screening.
• History of liver cirrhosis (e.g., the participant has undergone liver histopathological examination showing cirrhosis, or endoscopic examination suggesting esophageal and gastric varices).
• Including other liver diseases or liver disease history, such as: PBC, PSC, alcoholic liver disease, definite autoimmune liver disease or coexisting hepatitis, drug-induced liver injury, suspected or confirmed Gilbert syndrome or Wilson disease; homozygous α-1-antitrypsin deficiency; all primary iron overload diseases (including but not limited to hereditary hemochromatosis, non-hemochromatosis primary iron overload such as ceruloplasminemia, congenital transferrin deficiency syndrome, etc.) or some secondary iron overload diseases (including but not limited to transfusion-dependent iron overload, ineffective hematopoiesis-related iron overload such as MDS and sideroblastic anemia, copper-induced Parkinsonism secondary iron overload, long-term excessive iron metabolism intake, etc.), but MASH metabolism-related iron overload is excluded; drug-induced liver disease; known biliary obstruction; suspected or confirmed liver cancer or any other form of liver disease except alcoholic liver steatosis and MASH (except for those related to alcohol), known biliary obstruction, suspected or confirmed liver cancer.
• Patients with multiple endocrine neoplasia type 2 or medullary thyroid carcinoma, or a family history of multiple endocrine neoplasia type 2 or medullary thyroid carcinoma.
• History of the following cardiovascular and cerebrovascular diseases within 6 months before screening: decompensated cardiac insufficiency (NYHA class III or IV), arrhythmia requiring treatment, unstable angina or myocardial infarction, coronary artery bypass grafting or percutaneous coronary intervention, stroke (ischemic or hemorrhagic) or transient ischemic attack.
• History of malignant tumor within 5 years (excluding clinically cured cervical epithelial carcinoma, squamous cell carcinoma, or basal cell carcinoma of the skin).
• History of major depression or anxiety disorder within 2 years before screening, or current diagnosis of other mental illnesses (e.g., schizophrenia, bipolar disorder) that, in the investigator's assessment, are not suitable for participation in this trial.
• PHQ-9 questionnaire (Depression Screening Scale) score ≥15 at screening.
• Previous suicide attempt or suicidal behavior.
• Known hypersensitivity to any ingredient in semaglutide injection or to other GLP-1 RA drugs or drugs with GLP-1 receptor agonist mechanism.
• History of human immunodeficiency virus (HIV) infection at screening; history of Treponema pallidum (TP) infection (except those with stable conditions judged by the investigator as suitable for inclusion in this trial); positive for hepatitis B surface antigen (HBsAg) [except those with HBV-DNA results below the lower limit of detection], positive for hepatitis C virus antibody.
• Unwilling to cooperate, or unable to cooperate, or incapable of completing the clinical trial.
• Suspected or confirmed history of drug or substance abuse.
• Pregnant or lactating women; female participants of childbearing potential or those with menopause less than 12 months must have a negative pregnancy test during the screening period.
• Participation in other drug clinical trials within the last 3 months.
• In the investigator's judgment, the participant is not suitable to participate in this clinical trial.