Publication date: Jul 31, 2025

Since late 2019, COVID-19 has had a catastrophic impact on public health. Ensitrelvir, a new antiviral targeting the SARS-CoV-2 main protease, has reduced viral replication and disease severity. This meta-analysis and systematic review assessed Ensitrelvir’s efficacy and safety in patients with mild-to-moderate COVID-19 symptoms. A comprehensive search was conducted in PubMed (Medline), Scopus, Embase, and CENTRAL up to July 2024 to retrieve randomized controlled trials (RCTs) comparing Ensitrelvir to placebo in adults with mild to moderate, RT-PCR-confirmed COVID-19. Outcomes were assessed at standardized time points, with viral RNA measured at day 4. Mean differences (MD) for continuous outcomes and risk ratios (RR) for binary outcomes, both with 95% confidence intervals (CIs), were calculated using the Mantel-Haenszel random-effects model. Efficacy outcomes included SARS-CoV-2 viral RNA, while safety outcomes included HDL, triglycerides, bilirubin, AST, headache, diarrhea, TEAEs, TRAEs, serious TEAEs, and treatment discontinuation. The quality of the included RCTs was assessed with the Cochrane Risk of Bias 2 (ROB2) tool. The analysis included six RCTs with 2,793 participants: 1,860 received Ensitrelvir and 933 were given a placebo. Ensitrelvir gave significant results for reduced viral RNA levels of SARS-CoV-2 [MD: - 1. 35; 95% CI - 1. 58 to - 1. 13; p 

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