Randomised clinical trial: Design of the SYNERGY-NASH phase 2b trial to evaluate tirzepatide as a treatment for metabolic dysfunction-associated steatohepatitis and modification of screening strategy to reduce screen failures.

ABSTRACT

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.