Project Summary Alcoholic cirrhosis is a leading cause of morbidity and mortality in the US. One of the key drivers in its pathogenesis is the reduction in hepatic methionine adenosyltransferase 1A (MAT1A) expression resulting in the reduction in hepatic S-adenosylmethionine (SAMe) levels. The reduction in SAMe level leads to several adverse intracellular consequences, which include promoting the inflammatory cascades in immune cells such as macrophages by lipopolysaccharides (LPS), oxidative stress and endoplasmic reticulum (ER) stress. This project involves two academic centers in the United States (Cedars-Sinai Medical Center in Los Angeles and Indiana University Hospital), a research institute in Spain (CIC bioGUNE), and NIAAA intramural liver research scientist (Dr. Bin Gao) to examine SAMe in humans with alcoholic cirrhosis. We proposed a randomized double-blind placebo controlled trial to determine the efficacy of SAMe (1,200 mg/day given in two divided dose) and its mechanistic effects in patients with alcoholic cirrhosis (Child class A and B) in the real world setting. The primary endpoint will be the mortality of any causes between groups. The target enrollment of our clinical trial is 196 participants (176 patients with alcohol-associated cirrhosis and 20 controls). The approval for funding of our study started on September 20, 2019. However, our study was significantly impacted by the COVID-19 pandemic in 2020 and 2021. The administrative hold on research activities due to the pandemic prohibited us to enroll patients as we anticipated. To date, 112 participants (~57%) were enrolled. Our enrollment continues to improve and meet the monthly target enrollment starting around the beginning of Yr 3 of the project (~September 2021, the time when the overall COVID-19 pandemic was improving). Given the trajectory of the enrollment, we anticipated that we should be able to complete our enrollment around August 2026. Our current funding ends on 8/31/24. This supplemental application is to allow us to complete the clinical trial, currently being funded by 1U01AA02681.