This study will determine the effect of oral 80 mg resmetirom administered once daily on participants with well-compensated non-alcoholic steatohepatitis (NASH) cirrhosis by measuring the time to experiencing a Composite Clinical Outcome event.

This is a multi-national, multicenter, double-blind, randomized, placebo-controlled study in participants with well-compensated NASH cirrhosis. Participants will be randomized 3:1 in a blinded manner to receive 80 mg resmetirom or matching placebo given orally once daily in the morning for the duration of the study (until the required number of Composite Clinical Outcome events are achieved). Composite Clinical Outcome events are defined as any of the following: all cause mortality, liver transplant, and significant hepatic events, including potential hepatic decompensation events (ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage), and confirmed increase of Model for End-stage Liver Disease (MELD) score from <12 to ≥15. The study comprises an up to 60-day screening period and an approximately 3-year treatment period.

Inclusion Criteria:

• A clinical diagnosis of NASH cirrhosis
• At least 3 metabolic risk factors
• Historical liver biopsy read as consistent with NASH cirrhosis.
• Historical biopsy consistent with NASH with significant fibrosis, now with progression to cirrhosis. Or, no historical biopsy, with a clinical picture of NASH cirrhosis.
• Well-compensated Child-Pugh A (score of 5-6) cirrhosis at Screening and Baseline
• No history of a hepatic decompensation event.
• MRE ≥4.2 obtained during the screening period (if MRE is <4.2 and ≥3.7, then an ELF ≥10.25 OR platelet counts <140K obtained during the screening period is required for eligibility)

Exclusion Criteria:

• Participants with a chronic liver diseases other than NASH cirrhosis, such as primary biliary cholangitis, primary sclerosing cholangitis, Hepatitis B positive, Hepatitis C, history or evidence of current active autoimmune hepatitis, history or evidence of Wilson's disease, history or evidence of alpha-1 -antitrypsin deficiency, history or evidence of genetic hemochromatosis (hereditary, primary), evidence of drug-induced liver disease, as defined on the basis of typical exposure and history, known bile duct obstruction, or suspected or confirmed liver cancer
• Participants with MELD score ≥12 due to liver disease are excluded.
• Participants with a history of hepatic decompensation or impairment are excluded
• Diagnosis of hepatocellular carcinoma (HCC) at Screening or historically
• Liver Imaging Reporting and Data System (LI-RADS) score ≥4 at Screening
• No history of alcohol-related liver disease or history (within 5 years) of excessive alcohol consumption
• Weight gain or loss ≥5% total body weight within 12 weeks prior to randomization
• PEth value of ≥20 ng/mL measured at Screening
• HbA1c >9.0%
• Platelet counts <70,000/mm3 at either screening or baseline
• Use of high dose vitamin E (>400 IU/day) unless stable for ≥6 months prior to randomization
• Use of pioglitazone >15 mg per day
• Glucagon-like peptide 1 (GLP-1) agonist therapy for diabetes treatment must be a stable dose for at least 12 weeks prior to randomization. GLP-1 agonists for weight loss must be at stable doses for at least 6 months (including body weight change ≥ 5% weight loss in the 12 weeks prior to randomization)