Clinical trial endpoints for metabolic dysfunction and alcohol associated steatotic liver disease.

BACKGROUND

Metabolic dysfunction and alcohol-associated steatotic liver disease (MetALD) has emerged as a new subtype of steatotic liver disease, and presents a substantial challenge in clinical trial design due to a lack of data and consensus on endpoint selection.

OBJECTIVE

This review proposes patient selection, stratification, and optimization in Phase II and III clinical trial designs for MetALD and provides reasonable stage-specific clinical trial endpoints. It provides a comprehensive review of data on non-invasive tests (NITs) and trial endpoints in metabolic dysfunction-associated steatotic liver disease and alcohol-associated liver disease, and extrapolates these data to MetALD.

RESULTS

The design of effective MetALD trials necessitates rigorous stratification by fibrosis stage and drinking patterns. In pre-cirrhotic MetALD, NITs, including vibration-controlled transient elastography, magnetic resonance elastography, and magnetic resonance imaging-proton density fat fraction, are reliable surrogate endpoints, with each modality-specific cut-off set to meet clinical improvement targets. For patients with compensated or decompensated cirrhosis, the emphasis shifts to hard clinical outcomes, such as transplant-free survival, overall survival, and prevention of major adverse liver events in phase III clinical trials. Additionally, integrating alcohol-reduction endpoints and comprehensive cardiometabolic endpoints is essential to capture the full impact of interventions in clinical trials.

CONCLUSION

The MetALD clinical trials require strategic design, the adoption of the NITs shift concept, and stage- and phase-specific endpoints.