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

Official title

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

Overview

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:

1. Non-invasive screening: Assessment of body mass index (BMI \>= 24 kg/m²) and controlled attenuation parameter via FibroScan (CAP \>= 268 dB/m). 2. Histological confirmation: A baseline liver biopsy (Liver Biopsy 1) demonstrating MASLD with a NAFLD Activity Score (NAS) \>= 3 and a steatosis subscore \>= 2, strictly excluding any degree of liver fibrosis.

Eligible participants will be randomized (1:1) into:

* Experimental Group (GG Group): Mazdutide subcutaneous injections once weekly, following a dose-escalation regimen: 2mg for Weeks 1-2, 4mg for Weeks 3-4, and a target dose of 6mg from Week 5 to Week 12. * Control Group (LL Group): Matching placebo injections once weekly. Both groups will receive identical, standardized counseling on an energy-restricted diet (deficit of 500-750 kcal/day, total intake \<= 1500 kcal/day) and structured physical exercise (\>= 150 minutes/week of moderate-to-high intensity sport). Compliance will be monitored via electronic diaries and smart wearable fitness trackers.

Efficacy and Safety Endpoints:

At Week 12 (or earlier if triggered by regular FibroScan text assessments indicating steatosis resolution), a second liver biopsy (Liver Biopsy 2) and abdominal magnetic resonance imaging proton density fat fraction (MRI-PDFF) will be completed to evaluate the primary endpoint: resolution of hepatic steatosis without worsening of MASLD.

For donors successfully meeting the transplantation criteria, a mandatory 1-week drug washout period will be enforced before surgery to mitigate potential anesthesia risks associated with delayed gastric emptying. On the day of surgery, an ultrasound assessment of gastric volume will be performed prior to anesthesia induction.

Exploratory analysis in Part 2 will dynamically track the remnant liver regeneration rate in donors (via CT volumetry) and early graft function (AST/ALT peaks, TBil, and INR recovery profiles) as well as long-term quality of life (SF-36) in recipients up to 1 year post-transplantation.

Interventions

• Drug Mazdutide
  Active drug intervention consisting of a novel GLP-1/GCG receptor dual agonist solution (Mazdutide) administered via subcutaneous injection once weekly using a single-use prefilled automatic injection pen. The dosing schedule follows a 12-week step-up titration regimen starting at 2 mg q1w for Weeks 1-2, increasing to 4 mg q1w for Weeks 3-4 if gastrointestinal tolerated, and reaching a target dose of 6 mg q1w from Week 5 to Week 12 if gastrointestinal tolerated. For participants with intolerable
• Drug Placebo (Normal Saline)
  Inactive comparator intervention consisting of a matching placebo (normal saline) solution administered via subcutaneous injection once weekly. To strictly maintain the double-blind design, the placebo features an identical appearance, volume, and automatic prefilled injection pen delivery device. The administration schedule, dose escalation simulation steps, and the mandatory 1-week pre-operative drug washout period mirror the experimental mazdutide group exactly to maintain the blinding integr
• Behavioral Lifestyle Optimization
  Standardized lifestyle optimization provided to both groups, consisting of an calorie-restricted diet (CRD) and structured physical exercise. The CRD targets a daily calorie deficit of 500 to 750 kcal, with a total daily intake not exceeding 1500 kcal (1000-1200 kcal for females; 1200-1500 kcal for males). The structured exercise requires at least 5 days per week, totaling \>=150 minutes of moderate-to-high intensity aerobic training with a daily energy expenditure \>=150 kcal. Adherence is trac

Primary outcome measures

• Proportion of Participants Achieving Resolution of MASLD Without Worsening of Liver Fibrosis (ROM) [Time frame: From randomization (Week 0) to Week 12]

Secondary outcome measures (12)

• Proportion of Participants Achieving Ultrasound-Assessed Improvement of Hepatic Steatosis (uIOS) [Time frame: From randomization (Week 0) up to Week 12]
• Proportion of Participants Achieving Imaging-Assessed Improvement of Hepatic Steatosis (iIOS) [Time frame: From randomization (Week 0) up to Week 12]
• Proportion of Participants Achieving Improvement of MASLD Without Worsening of Liver Fibrosis (IOM) [Time frame: From randomization (Week 0) up to Week 12]
• Proportion of Participants Achieving Improvement of Hepatic Steatosis Without Worsening of MASLD (IOS) [Time frame: From randomization (Week 0) up to Week 12]
• Proportion of Participants Successfully Completing Liver Donation (SCD) [Time frame: From randomization (Week 0) up to Week 24]
• Percentage Change from Baseline in Body Weight [Time frame: From randomization (Week 0) up to Week 12]
• Percentage Change from Baseline in Body Mass Index (BMI) [Time frame: From randomization (Week 0) up to Week 12]
• Percentage Change from Baseline in Body Fat Percentage [Time frame: From randomization (Week 0) up to Week 12]
• Percentage Change from Baseline in Visceral Fat Content [Time frame: From randomization (Week 0) up to Week 12]
• Daily Net Energy Intake During the Treatment Period [Time frame: From randomization (Week 0) up to Week 12]
• Time to Ultrasound-Assessed Hepatic Steatosis Improvement [Time frame: From randomization (Week 0) up to Week 12]
• Time to Successful Liver Donation [Time frame: From randomization (Week 0) up to Week 24]

Eligibility criteria

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 < 2.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

China · 3 centers

• Anhui Provincial Hospital (The First Affiliated Hospital of USTC) — Hefei
• Beijing Friendship Hospital, Capital Medical University — Beijing
• West China Hospital, Sichuan University — Chengdu

Identifiers

NCT: NCT07718126 · 2026-1206

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗