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Placebo-associated changes in MRI-PDFF and metabolic parameters in MASLD patients from phase Ib/IIa clinical trials:
Mengdi Lu1, Hong Zhang1, Xiaoxue Zhu1
1Phase I Clinical Research Center, First Hospital of Jilin University, Changchun, Jilin, China.
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.
Insights
Early-phase metabolic dysfunction-associated steatotic liver disease (MASLD) trials show a significant placebo effect on liver fat and weight. This effect partially rebounds after treatment, highlighting the need to account for it in trial design and interpretation.
Area of Science:
- Hepatology
- Clinical Trials
- Metabolic Disorders
Background:
- Placebo effect in early-phase metabolic dysfunction-associated steatotic liver disease (MASLD) trials is not well-defined.
- A ≥30% relative reduction in MRI-PDFF is a surrogate for histologic improvement in MASLD.
- Understanding placebo responses is crucial for interpreting trial endpoints and proof-of-concept decisions.
Purpose of the Study:
- To evaluate short-term placebo responses in early-phase MASLD trials.
- To assess 1-year longitudinal changes in hepatic fat and metabolic parameters under placebo.
- To inform the design and interpretation of MASLD clinical trials.
Main Methods:
- Prospective enrollment of 41 MASLD participants from placebo arms of five phase Ib/IIa trials.
- Assessment of hepatic fat (MRI-PDFF), body weight, liver enzymes, and lipids from baseline to 56 weeks.
- 18 participants completed the 1-year follow-up.
Main Results:
- After 4-5 weeks, 20% of participants achieved ≥30% hepatic fat reduction (mean 16.47% relative decrease).
- Placebo treatment led to decreased body weight, liver enzymes, and most lipids, with a slight triglyceride increase.
- One-year follow-up showed rebound in hepatic fat and weight, but they remained below baseline; liver enzymes partially rebounded, while lipids exceeded baseline.
Conclusions:
- Early-phase MASLD trials exhibit a measurable and heterogeneous placebo effect.
- A partial rebound in key parameters occurs after placebo treatment cessation.
- Findings emphasize accounting for placebo effects in trial design, endpoint selection, and efficacy signal interpretation.
