Pre-hepatectomy Rehabilitation in Obese MASLD-Complicated Living Liver Donors With Mazdutide (PRIME)

Prior treatment

• Unstable weight, defined as self-reported weight change \> 5% within 90 days prior to screening up to the time of screening.
• Presence of other clearly defined etiologies causing chronic liver disease (non-NAFLD), including positive HBsAg, positive anti-HIV, or positive HCV RNA at screening, or a known history of HCV RNA or HBsAg positivity within 2 years prior to screening.
• History of acute pancreatitis within 180 days prior to screening, or a history of chronic pancreatitis.
• Presence or history of gastroparesis, severe gastroesophageal reflux disease, or prior bariatric surgery at screening and randomization.
• Occurrence of myocardial infarction, stroke, NYHA class IV heart failure, hospitalization due to unstable angina, or transient ischemic attack within 90 days prior to screening or during the screening-to-randomization window.
• Participation in any approved or unapproved investigational drug clinical trial within 180 days prior to screening (defined as exposure to the investigational drug and inclusive of any post-treatment follow-up period).
• Prior participation in this trial (defined as having already undergone randomization).
• Use of any GLP-1 receptor agonist (GLP-1RA) within 90 days prior to screening.

Other illness

• Failure to diagnose overweight or MASLD by non-invasive means, including BMI \< 24 kg/m² and/or CAP \< 268 dB/m.
• Presence or history of ascites, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis, hepatocellular carcinoma, or liver transplantation at screening and randomization.
• Presence or history of malignant tumors within 5 years (except basal cell carcinoma, squamous cell skin cancer, and any carcinoma in situ).
• Personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN2).
• History or presence of type 1 diabetes.
• Type 2 diabetes accompanied by uncontrolled and potentially unstable diabetic retinopathy or maculopathy.
• History of severe depression, suicidal ideation, or recent suicide attempts.
• Known or suspected allergy to the active ingredients or any excipients of the study drug.
• Any condition considered by the investigator to render the participant unsuitable for liver donation, or diseases/conditions that may compromise participant safety, pose safety hazards from substantial weight loss, or affect compliance with the protocol.

Lab values

• Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) \> 5 × upper limit of normal (ULN) at screening, and/or ALT or AST levels increase by more than 1 fold compared to baseline during screening, which is considered clinically significant by the investigator.
• Total bilirubin (TBil) \> 25.6 μmol/L (1.5 mg/dL), and/or alkaline phosphatase (ALP) \> 2 × ULN, and/or International Normalized Ratio (INR) \> 1.35 at screening.
• Platelet count \< 150,000/μL at screening, unless considered by the investigator to reflect the patient's daily baseline level and portal hypertension is absent.
• Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73m² based on the CKD-EPI formula at screening.
• Glycated hemoglobin (HbA1c) \> 9.5% at screening.
• Receipt of glucose-lowering drugs (except GLP-1RA), lipid-lowering drugs, or weight-loss drugs considered by the investigator to be at unstable doses within 90 days prior to screening.

Other

• Liver biopsy indicates complication with any degree of liver fibrosis.
• Histological evaluation shows a total NAS \< 3 and/or a steatosis subscore \< 2.
• Females who are pregnant, lactating, planning a pregnancy, or of childbearing potential but not utilizing highly effective contraceptive methods.
• Known or suspected excessive alcohol consumption (females \> 20g/day, males \> 30g/day) or presence of alcohol dependence.
• The recipient designated to receive the liver graft is not a spouse or a direct or collateral blood relative within three generations, or the donation violates ethical, moral, legal, or regulatory codes.

• Age between 18 and 60 years old at the time of signing the informed consent form.
• Overweight, defined as Body Mass Index (BMI) ≥ 24 kg/m².
• Diagnosed with MASLD by non-invasive means (conventional ultrasound, FibroScan®, or MRI), with a Controlled Attenuation Parameter (CAP) ≥ 268 dB/m via FibroScan®.
• Histologically confirmed MASLD without any liver fibrosis, presenting a NAS ≥ 3, including a steatosis subscore ≥ 2 (subscores for hepatocyte ballooning and lobular inflammation are not limited).
• Meets ethical and legal regulations, voluntarily donates a portion of the liver, and the corresponding potential liver transplant recipient must be a spouse or a direct or collateral blood relative within three generations.
• Understands all procedures and follow-up requirements of the study, participates voluntarily, and signs the written informed consent form in person.