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Summary: Background: The use of histological inclusion criteria for clinical trials of at‐risk metabolic dysfunction‐associated steatohepatitis (MASH) is often associated with high screen failure rates. Aims: To describe the design of a trial investigating tirzepatide treatment of MASH and to examine the effect of new inclusion criteria incorporating the use of the FibroScan‐AST (FAST) score on the proportion of patients meeting histological criteria. Methods: SYNERGY‐NASH is a Phase 2b, multicentre, randomised, double‐blinded, placebo‐controlled trial in patients with biopsy‐confirmed MASH, F2–F3 fibrosis and NAFLD Activity Score ≥4. New inclusion criteria (FAST score >0.35 and an increase in AST inclusion criterion from >20 to >23 U/L) were adopted during the trial, allowing us to examine its impact on the qualification rate. Results: 1583 participants were screened, 651 participants proceeded to liver biopsy and 190 participants were randomised with an overall screen fail rate of 87%. Following the protocol amendment, the overall qualification rate for per‐protocol biopsies was minimally changed from 27.5% to 28.9% with considerable variation among different investigator medical speciality types: endocrinology: from 37.5% to 39.3%; gastroenterology/hepatology: from 26.0% to 23.3%; other specialities: from 21.3% to 29.7%. At 29 sites that performed per‐protocol biopsies before and after the amendment, qualification rates changed as follows: all: 26.1% to 29.1%; endocrinology: from 35.0% to 40.9%; gastroenterology/hepatology: 25.6% to 20.0%; other specialities: from 16.1% to 27.8%. Conclusions: For at‐risk MASH trials based on liver histology, the implementation of inclusion criteria with the proposed FAST score and AST cut‐offs in this trial was most effective at non‐specialist sites. [ABSTRACT FROM AUTHOR]