Primary, Secondary and Exploratory Endpoints in Phase 2 and 3 Clinical Trials with Novel Therapies in MASH Cirrhosis:...

Background/Objectives: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease and a major driver of cirrhosis, liver failure, and mortality worldwide. Despite the urgent need for effective therapies, clinical trials in MASH cirrhosis face substantial challenges due to the heterogeneity and the lack of standardization in study endpoints. A clear understanding of how endpoints are defined and applied across trials is critical for interpreting efficacy, comparing results, and guiding regulatory decisions. The objective of this systematic review was to classify and critically evaluate the primary, secondary, and exploratory endpoints used in phase 2 and 3 clinical trials of novel therapies for MASH cirrhosis, and to assess their consistency, strengths, and limitations. Methods: PubMed, Embase, and Cochrane Library databases were searched to identify Phase 2 and 3 trials of novel therapies for MASH-related cirrhosis. Studies of adults with biopsy-confirmed MASH cirrhosis in which clinical, histological, hemodynamic, imaging, and laboratory outcomes being assessed were included. Results: Nine eligible trials were included. Histological measures, most commonly improvement in fibrosis stage without worsening of MASH, were generally considered key efficacy outcomes. Biochemical (e.g., ALT, AST, Pro-C3, composite fibrosis scores) and imaging-based markers (e.g., liver stiffness) were widely used as secondary or exploratory endpoints and more frequently demonstrated treatment-related changes than histology. Hepatic venous pressure gradient (HVPG) was selected as a primary endpoint in some studies and as an exploratory outcome in others. Patient-centered outcomes, when incorporated, were typically exploratory. Conclusions: Phase 2 and 3 trials in MASH cirrhosis employ diverse and inconsistently defined endpoints, with limited standardization across studies. Establishing consensus on endpoint classification, definitions and clinical relevance is critical to advancing therapeutic development and ensuring regulatory acceptance in this high-risk patient population.