Liver Cirrhosis Network Rosuvastatin Efficacy and Safety for Cirrhosis in the United States

Inclusion Criteria:

1. Age 18-75 years

2. Cirrhosis due to nonalcoholic steatohepatitis, alcohol-associated liver disease, orchronic viral hepatitis (treated hepatitis B virus or hepatitis C virus)

3. Clinical diagnosis of cirrhosis as defined investigator confirmation and thefollowing:

4. At least one liver biopsy within 5 years prior to consent showing either:Metavir stage 4 fibrosis; Ishak Stage 5-6 fibrosis, OR

5. At least 2 of the following: i. Evidence on imaging: Nodular liver with either splenomegaly or recanalizedumbilical vein within the past 48 weeks ii. Liver stiffness: vibration-controlledtransient elastography within 48 weeks prior to consent or during Screening ≥15kilopascal or magnetic resonance elastography within 48 weeks prior to consent orduring Screening ≥5 kilopascal iii. Evidence of varices demonstrated on imaging orendoscopy within 3 years prior to consent or during Screening iv. Either:Fibrosis-4>2.67 or platelets <150/mL within 6 months prior to consentor during Screening

6. Two measures of vibration-controlled transient elastography: one at screening andone at the randomization study visit, meeting the following criteria:

7. The first measure must be ≥ 15 kilopascal.

8. The two measures must be at least 2 hours apart and no more than 60 days apartfrom one another.

9. The mean of two measurements must be ≥ 15 kilopascal.

10. Additionally, both screening and open-label dispense liver stiffness measuresmust be ≤50 kPa

11. Compensated defined by:

12. Absence of ascites/hydrothorax, hepatic encephalopathy or variceal bleedingcurrently or in the last 48 weeks, as determined clinically by investigator.

13. If prior history of decompensation, must be without current symptoms ofdecompensation and no longer requiring treatment of complications for the last 48 weeks, including the use of diuretics for the treatment of ascites, and/orrifaximin or lactulose for the treatment of hepatic encephalopathy. Use ofnon-selective beta blockers will be allowed.

14. Child-Pugh score <8

15. Provision of written informed consent.

Exclusion Criteria:

1. Currently on a statin or any statin exposure within 24 weeks prior to consent.

2. Known indication for statin therapy, defined as:

3. Prior peripheral vascular, cardiovascular or cerebrovascular event for whichstatins are indicated for secondary prevention, OR

4. Documented familial hypercholesterolemia, heterozygous familialhypercholesterolemia, OR

5. Fasting LDL-C ≥ 190 mg/dL

6. Myocardial infarction, Unstable angina, transient ischemic events, or stroke within 24 weeks of screening.

7. Alcohol Use Disorder Identification Test (AUDIT) total score of ≥8 at screening.

8. Patients with limitations in attending study visits.

9. Prisoners.

10. Known prior or current hepatocellular carcinoma (HCC) or cholangiocarcinoma.

11. Known transjugular intrahepatic portosystemic shunt (TIPS), balloon retrogradetransvenous obliteration (BRTO) or porto-systemic shunt surgery regardless of timeof occurrence.

12. Current (in past 24 weeks prior to consenting) use of medications known to causehepatic fibrogenesis or confound endpoint assessment, defined as:

13. amiodarone

14. methotrexate

15. warfarin

16. Current (in past 24 weeks prior to consenting) use of medications which may increaserisk for rosuvastatin-related myositis or DILI, defined as:

17. fenofibrate

18. erythromycin

19. gemfibrozil

20. niacin (500 mg or more)

21. HIV protease inhibitors (darunivar, indinavir, nelfinavir, amprenavir) inpatients of East Asian descent

22. colchicine

23. cyclosporin

24. Additional medications that will be excluded: atazanavir/ritonavir capmatinib darolutamidedasabuvir/ombitasvir/paritaprevir/ritonavir ledipasvir/sofosbuvirelbasvir/grazoprevir erythromycin glecaprevir/pibrentasvir lopinavir/ritonavirregorafenib ritonavir, in any combination simeprevirsofbuvir/velpatasvir/voxilaprevir sofosbuvir/velpatasvir tafamidis teriflunomide

*If exposure was for 7 or less days for one of these medications can considerenrollment after 28 days from final dose.

11. Presence of portal or hepatic vein thrombosis

12. Diagnosis of untreated hypothyroidism or on unstable treatment regimen forhypothyroidism

13. Receiving an elemental diet or parenteral nutrition

14. Chronic pancreatitis or pancreatic insufficiency

15. Etiology of cirrhosis other than ALD, NAFLD, or viral hepatitis (excluded diagnosesinclude cryptogenic immune-mediated such as AIH, PSC and PBC, cardiac cirrhosis orFontan-associated liver disease, A1AT, Wilson's disease, etc.)

16. Conditions which may confound study outcome:

17. Unstable or active inflammatory bowel disease

18. Active infection

19. Any malignant disease (other than squamous or basal cell carcinoma of the skin)within previous 3 years

20. Prior solid organ or hematopoietic cell transplant

21. Bariatric surgery in the last 24 weeks prior to consent or planned bariatricsurgery within the next 96 weeks

22. Current liver-unrelated end-stage organ failures such as end-stage renaldisease on dialysis, stage 3-4 congestive heart failure (CHF), current chronicobstructive pulmonary disease (COPD) on home oxygen.

23. Known current medical or psychiatric conditions which, in the opinion of theinvestigator, would make the participant unsuitable for the study for safety reasonsor interfere with or prevent adherence to the protocol.

24. The following laboratory abnormalities within 90 days of screening:

25. Hemoglobin <10 g/dL

26. Albumin <3.0 g/dL

27. Prolonged international normalized ratio (INR) >1.5

28. Total bilirubin ≥ 2.0 mg/dl (unless due to Gilbert's syndrome or hemolysis asdenoted by normal direct bilirubin fraction)

29. Direct bilirubin ≥ 0.9

30. Uncontrolled diabetes (HbA1c ≥ 9.5%) within past 90 days.

31. Kidney function abnormalities including:

32. Dialysis

33. Baseline eGFR < 30 cc/min with CKD-Epi equation

34. Known nephrotic proteinuria, defined as 3g or greater of protein in 24-hoururine collection

35. Recent (within 48 weeks) or present hepatic decompensation with ascites/hydrothorax,hepatic encephalopathy or variceal bleeding

36. Untreated chronic hepatitis B or C infection

37. HCV eligible for enrollment if HCV RNA negative at baseline or documentation ofprior SVR12

38. HBV eligible if an HBV DNA <100 IU/mL within the last 48 weeks and on treatment

39. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 200 U/L,or alkaline phosphatase (ALP) ≥ 300 within the past 24 weeks.

40. Documented history of intolerance to statins

41. Serious comorbid medical disease which in the investigator's opinion renders alife-expectancy less than 96 weeks

42. Active illicit substance use (other than THC), including inhaled or injected drugs,in the 24 weeks prior to screening

43. Pregnancy, planned pregnancy or breastfeeding

44. Current participation in active medication treatment trials (within 24 weeks priorto randomization) or planned participation in active medication treatment trialssimultaneous to participation in present trial.

45. Significant existing muscle pain or tenderness or prior history of myasthenia gravisas determined by a site physician.

46. Failure or inability to provide informed consent.