Placebo Rates in Metabolic Dysfunction-associated Steatohepatitis Clinical Trials: A Systematic Review and Meta-analysis.

Abstract

Background: High placebo response rates complicate drug development in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials. We performed a meta-analysis to quantify placebo response and assess influencing factors.

Methods: MEDLINE, Embase, and CENTRAL were searched from inception to May 7, 2025 for placebo-controlled trials of pharmacological interventions for MASH. Placebo response rates were pooled by random-effects model and meta-regression was used to evaluate the effects of patient and trial design factors on the primary outcomes.

Results: One-hundred and twenty-seven studies (6,880 participants) were included. For the primary outcome, the pooled proportion of non-cirrhotic placebo patients achieving MASH resolution without worsening of fibrosis was 11% (95% CI: 8% to 14%). Meta-regression did not identify any significant patient or trial characteristics associated with placebo response. For the second primary outcome, the proportion of cirrhotic placebo patients whose Model for End-stage Liver Disease score increased from below 12 to ≥15 was 4% (95% CI 1% to 13%). Regarding secondary outcomes, 12% (95% CI: 8% to 18%) of placebo patients achieved normal alanine aminotransferase levels, and 22% (95% CI: 18% to 27%) showed an absolute reduction of 5% in hepatic fat content. Additionally, 19% of placebo patients (95% CI: 16% to 22%) achieved a relative reduction of 30% in fat content, while 2% (95% CI: 0.7% to 3%) progressed to cirrhosis.

Conclusion: Placebo response rates among patients with MASH are generally elevated yet vary considerably depending on the outcome measured. This study provides valuable insights to enhance the design of future MASH trials.