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

Background and Rationale:Hepatic steatosis significantly elevates perioperative complications in major abdominalsurgeries. In living donor liver transplantation (LDLT), macrovesicular steatosisexceeding 30% renders potential donors ineligible due to severe ischemia‐reperfusioninjury risks in recipients and impaired remnant liver regeneration in donors. Traditionalprehabilitation strategies relying solely on lifestyle changes or low‐calorie diets oftenfail to achieve satisfactory histological reversal within the critical, time‐sensitivepre‐operative window. Mazdutide, a dual agonist of GLP‐1 and glucagon (GCG) receptors,has demonstrated powerful synergistic effects in rapid weight reduction and rapid hepaticfat clearance by simultaneously suppressing appetite and activating hepatic lipolysis.This trial aims to validate whether short‐term mazdutide intervention can serve as anaggressive 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 twoparts: Part 1 spans from screening to the liver procurement surgery (up to 24 weeks), andPart 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) andcontrolled attenuation parameter via FibroScan (CAP >= 268 dB/m). 2. Histological confirmation: A baseline liver biopsy (Liver Biopsy 1) demonstratingMASLD with a NAFLD Activity Score (NAS) >= 3 and a steatosis subscore >= 2, strictlyexcluding 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 atarget dose of 6mg from Week 5 to Week 12. ‐ Control Group (LL Group): Matching placebo injections once weekly. Both groups willreceive identical, standardized counseling on an energy‐restricted diet (deficit of500‐750 kcal/day, total intake <= 1500 kcal/day) and structured physical exercise(>= 150 minutes/week of moderate‐to‐high intensity sport). Compliance will bemonitored via electronic diaries and smart wearable fitness trackers.Efficacy and Safety Endpoints:At Week 12 (or earlier if triggered by regular FibroScan text assessments indicatingsteatosis resolution), a second liver biopsy (Liver Biopsy 2) and abdominal magneticresonance imaging proton density fat fraction (MRI‐PDFF) will be completed to evaluatethe primary endpoint: resolution of hepatic steatosis without worsening of MASLD.For donors successfully meeting the transplantation criteria, a mandatory 1‐week drugwashout period will be enforced before surgery to mitigate potential anesthesia risksassociated with delayed gastric emptying. On the day of surgery, an ultrasound assessmentof gastric volume will be performed prior to anesthesia induction.Exploratory analysis in Part 2 will dynamically track the remnant liver regeneration ratein donors (via CT volumetry) and early graft function (AST/ALT peaks, TBil, and INRrecovery profiles) as well as long‐term quality of life (SF‐36) in recipients up to 1year post‐transplantation.