Short-term Mazdutide Plus Lifestyle Intervention Versus Placebo for Pre-hepatectomy Prehabilitation in Living Liver Donors With MASLD: A Multicenter, Randomized, Double-blind, Placebo-controlled Trial
Trial Snapshot
- Phase
- Phase 4
- Status
- Recruiting
- Sponsor
- West China Hospital
- Enrollment
- 60
- Locations
- 4
- Primary Endpoint
- Proportion of Participants Achieving Resolution of MASLD Without Worsening of Liver Fibrosis (ROM)
Study Overview
Brief Summary
The purpose of this study is to evaluate the efficacy and safety of a short-term (12-week) prehabilitation strategy combining mazdutide (a novel GLP-1/GCG receptor dual agonist) with lifestyle optimization, compared to lifestyle optimization alone, in potential living liver transplantation donors with metabolic dysfunction-associated steatohepatitis (MASLD).
Overweight or obese individuals who intend to donate a portion of their liver but are temporarily disqualified due to hepatic steatosis will be recruited across multiple clinical centers. Participants will be randomly assigned in a 1:1 ratio to either the experimental group (mazdutide subcutaneous injection once weekly plus standardized lifestyle counseling) or the control group (placebo subcutaneous injection once weekly plus standardized lifestyle counseling).
The primary objective is to determine whether the short-term addition of mazdutide can significantly increase the proportion of donors achieving histological resolution of hepatic steatosis without the worsening of fibrosis within 12 weeks. The study ultimately aims to provide high-quality evidence for a rapid, safe, and effective surgical prehabilitation protocol to expand the living donor pool and optimize perioperative outcomes for both donors and recipients.
Detailed Description
Background and Rationale:
Hepatic steatosis significantly elevates perioperative complications in major abdominal surgeries. In living donor liver transplantation (LDLT), macrovesicular steatosis exceeding 30% renders potential donors ineligible due to severe ischemia-reperfusion injury risks in recipients and impaired remnant liver regeneration in donors. Traditional prehabilitation strategies relying solely on lifestyle changes or low-calorie diets often fail to achieve satisfactory histological reversal within the critical, time-sensitive pre-operative window. Mazdutide, a dual agonist of GLP-1 and glucagon (GCG) receptors, has demonstrated powerful synergistic effects in rapid weight reduction and rapid hepatic fat clearance by simultaneously suppressing appetite and activating hepatic lipolysis. This trial aims to validate whether short-term mazdutide intervention can serve as an aggressive prehabilitation tool to accelerate donor downstaging.
Study Design and Procedures:
This is a prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial conducted in major transplant centers. The study consists of two parts: Part 1 spans from screening to the liver procurement surgery (up to 24 weeks), and Part 2 covers post-operative follow-up up to 1 year.
Potential donors will undergo a rigorous two-step screening process:
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
Mazdutide and placebo pens are identical in appearance and handling. Participants and investigators involved in treatment, clinical care and follow-up remain unaware of allocation. Histopathological, MRI and ultrasonographic assessments are performed independently by clinicians outside the trial team who are not provided allocation information. Trial statisticians are unblinded but have no role in recruitment, treatment delivery or outcome assessment. Emergency unblinding is permitted only when essential for immediate clinical management and must be documented.
Because gastrointestinal symptoms and weight loss may lead to functional unblinding, treatment perceptions are assessed during follow-up and at the primary endpoint visit. Identical visit schedules, lifestyle counselling and mirrored dose-escalation procedures are used to minimize bias.
Eligibility Criteria
- Ages
- 18 Years to 60 Years (Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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.
Exclusion Criteria
- •Liver biopsy indicates complication with any degree of liver fibrosis.
- •Failure to diagnose overweight or MASLD by non-invasive means, including BMI < 24 kg/m² and/or CAP < 268 dB/m.
- •Histological evaluation shows a total NAS < 3 and/or a steatosis subscore <
- •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.
- •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.
- •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 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.
- •History or presence of type 1 diabetes.
- •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.
- •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.
- •Females who are pregnant, lactating, planning a pregnancy, or of childbearing potential but not utilizing highly effective contraceptive methods.
- •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).
- •Known or suspected excessive alcohol consumption (females > 20g/day, males > 30g/day) or presence of alcohol dependence.
- •Use of any GLP-1 receptor agonist (GLP-1RA) within 90 days prior to 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.
- •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.
- •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.
Arms & Interventions
Lifestyle optimization only (LL group)
Subcutaneous injection of a matching placebo once weekly with identical appearance, volume, and injection device for 12 weeks. Standardized lifestyle optimization is identical to the experimental group, consisting of an energy-restricted diet (deficit of 500-750 kcal/day, total daily intake <=1500 kcal/day) and structured physical exercise (>=150 minutes/week of moderate-to-high intensity exercise). A matching 1-week placebo washout period is enforced prior to surgery to maintain blinding.
Intervention: Placebo (Normal Saline) (Drug)
Lifestyle optimization only (LL group)
Subcutaneous injection of a matching placebo once weekly with identical appearance, volume, and injection device for 12 weeks. Standardized lifestyle optimization is identical to the experimental group, consisting of an energy-restricted diet (deficit of 500-750 kcal/day, total daily intake <=1500 kcal/day) and structured physical exercise (>=150 minutes/week of moderate-to-high intensity exercise). A matching 1-week placebo washout period is enforced prior to surgery to maintain blinding.
Intervention: Lifestyle Optimization (Behavioral)
GLP-1/GCG receptor dual agonist plus lifestyle optimization (GG Group)
Subcutaneous injection of mazdutide once weekly following a 12-week dose-escalation regimen: 2 mg q1w for Weeks 1-2, 4 mg q1w for Weeks 3-4 (if gastrointestinal tolerated), and a target dose of 6 mg q1w from Week 5 to Week 12 (if gastrointestinal tolerated). Standardized lifestyle optimization consists of an energy-restricted diet (deficit of 500-750 kcal/day, total daily intake <=1500 kcal/day) and structured physical exercise (>=150 minutes/week of moderate-to-high intensity exercise). A mandatory 1-week drug washout period is enforced prior to surgery.
Intervention: Mazdutide (Drug)
GLP-1/GCG receptor dual agonist plus lifestyle optimization (GG Group)
Subcutaneous injection of mazdutide once weekly following a 12-week dose-escalation regimen: 2 mg q1w for Weeks 1-2, 4 mg q1w for Weeks 3-4 (if gastrointestinal tolerated), and a target dose of 6 mg q1w from Week 5 to Week 12 (if gastrointestinal tolerated). Standardized lifestyle optimization consists of an energy-restricted diet (deficit of 500-750 kcal/day, total daily intake <=1500 kcal/day) and structured physical exercise (>=150 minutes/week of moderate-to-high intensity exercise). A mandatory 1-week drug washout period is enforced prior to surgery.
Intervention: Lifestyle Optimization (Behavioral)
Outcomes
Primary Outcomes
Proportion of Participants Achieving Resolution of MASLD Without Worsening of Liver Fibrosis (ROM)
Time Frame: From randomization (Week 0) to Week 12
Percentage of participants who achieve histological resolution of MASLD. Resolution is defined based on the second liver biopsy as a NAFLD Activity Score (NAS) steatosis subscore \<= 1, a hepatocyte ballooning subscore = 0, and a lobular inflammation subscore \<= 1. Additionally, to meet the criteria for resolution, there must be no increase in the total NAS, hepatocyte ballooning, or lobular inflammation subscores, and no worsening of liver fibrosis compared to the baseline liver biopsy.
Secondary Outcomes
- Proportion of Participants Achieving Ultrasound-Assessed Improvement of Hepatic Steatosis (uIOS)(From randomization (Week 0) up to Week 12)
- Percentage Change from Baseline in Body Mass Index (BMI)(From randomization (Week 0) up to Week 12)
- Proportion of Participants Achieving Imaging-Assessed Improvement of Hepatic Steatosis (iIOS)(From randomization (Week 0) up to Week 12)
- Proportion of Participants Achieving Improvement of MASLD Without Worsening of Liver Fibrosis (IOM)(From randomization (Week 0) up to Week 12)
- Proportion of Participants Achieving Improvement of Hepatic Steatosis Without Worsening of MASLD (IOS)(From randomization (Week 0) up to Week 12)
- Proportion of Participants Successfully Completing Liver Donation (SCD)(From randomization (Week 0) up to Week 24)
- Percentage Change from Baseline in Body Weight(From randomization (Week 0) up to Week 12)
- Percentage Change from Baseline in Body Fat Percentage(From randomization (Week 0) up to Week 12)
- Percentage Change from Baseline in Visceral Fat Content(From randomization (Week 0) up to Week 12)
- Daily Net Energy Intake During the Treatment Period(From randomization (Week 0) up to Week 12)
- Time to Ultrasound-Assessed Hepatic Steatosis Improvement(From randomization (Week 0) up to Week 12)
- Time to Successful Liver Donation(From randomization (Week 0) up to Week 24)
- Change from Baseline in Health-Related Quality of Life (HRQoL) Score(From randomization (Week 0) up to Week 12)
Investigators
Kunlin Xie
Associate professor
West China Hospital