Placebo-associated changes in MRI-PDFF and metabolic parameters in MASLD patients from phase Ib/IIa clinical trials: implications for early-phase trial design and translational endpoint interpretation

Background The placebo effect in early-phase metabolic dysfunction–associated steatotic liver disease (MASLD) trials is poorly defined but may substantially influence endpoint interpretation and proof-of-concept decisions. A ≥30% relative reduction in magnetic resonance imaging–proton density fat fraction (MRI-PDFF) is an established noninvasive surrogate of histologic improvement. This study aimed to evaluate short-term placebo responses and 1-year longitudinal changes in hepatic fat content and metabolic parameters in phase Ib/IIa MASLD trials. Methods A total of 41 MASLD participants from the placebo arms of five phase Ib/IIa clinical trials (2020–2024) were prospectively enrolled, with 18 completed the 1-year follow-up. Hepatic fat content (MRI-PDFF), body weight, liver enzymes, and lipid parameters were assessed from baseline to week 56. Results After 4–5 weeks of placebo treatment, 20% of participants achieved ≥30% hepatic fat reduction, with mean absolute and relative decreases of 2.48% (SD: 2.88) and 16.47% (SD: 23.46), respectively. Body weight decreased by 2.5 kg (SD: 1.8), corresponding to a relative reduction of 2.73% (SD: 1.97). Additionally, liver enzymes and most lipid parameters declined, whereas triglycerides showed a modest increase. During 1-year follow-up, hepatic fat content and body weight rebounded from end-of-treatment levels but remained below baseline. Liver enzymes partially rebounded but stayed below baseline, while lipid parameters exceeded baseline values. Conclusion Early-phase MASLD trials show a measurable, heterogeneous placebo effect with partial rebound after treatment cessation. These findings underscore the importance of explicitly accounting for short-term placebo-associated changes when designing early-phase trials, selecting surrogate endpoints and interpreting preliminary efficacy signals.