Multi-Center Study of the Effects of Simvastatin on Hepatic Decompensation and Death in Subjects Presenting With High-Risk Compensated Cirrhosis (SACRED)

  • STATUS
    Recruiting
  • End date
    Sep 30, 2024
  • participants needed
    500
  • sponsor
    VA Office of Research and Development
Updated on 7 July 2022
platelet count
hypertension
ascites
endoscopy
hepatitis
encephalopathy
cirrhosis
fatty liver
fibroscan
varices
esophageal varices
varicose veins

Summary

This phase III, randomized, double-blind, placebo-controlled, multi-center study seeks to test whether simvastatin, a statin usually used to lower cholesterol to prevent heart problems and strokes, can lower the risk of hepatic decompensation (developing symptoms of cirrhosis) in U.S. Veterans who have compensated cirrhosis (the liver is scarred and damaged but there are no symptoms). The study will also explore how changes or differences in genes effect the safety and effectiveness of using statins and how the use of statins affects quality of life.

Description

HMG-coA reductase inhibitors (statins), independent of cholesterol-lowering effects, are beneficial in liver diseases by reducing endothelial dysfunction, intrahepatic vasoconstriction, inflammation and fibrosis, and can reduce portal vein blood pressure. Clinically significant portal hypertension (hepatic vein wedge pressure greater than or equal to 10mmHg) is the most important predictor of decompensation and death in patients with cirrhosis.

This randomized, double-blind, placebo-controlled, multi-center Phase III interventional study seeks to demonstrate that statin therapy in patients with cirrhosis at high-risk for hepatic decompensation will reduce the incidence of hepatic decompensation, hepatocellular carcinoma or all-cause mortality.

Patients with compensated cirrhosis at high-risk for hepatic decompensation will be stratified based on the presence or absence of varices and randomized to simvastatin 40mg/day for up to 24 months. Patients will be observed for the development of hepatic decompensation (variceal hemorrhage, ascites, encephalopathy), hepatocellular carcinoma, liver-related death, death from any cause, and/or complications of statin therapy. Additionally, the interaction of SLCO1B1 and KIF6 polymorphisms on safety and clinical efficacy of statin therapy and the impact of statin exposure on health-related quality of life in patients with compensated cirrhosis will be examined.

Details
Condition Cirrhosis
Treatment simvastatin 40mg, Placebo Oral Tablet
Clinical Study IdentifierNCT03654053
SponsorVA Office of Research and Development
Last Modified on7 July 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

U.S. Veteran
Cirrhosis due to chronic viral hepatitis, or alcohol or non-alcoholic fatty liver
Compensated cirrhosis (history of endoscopically-confirmed variceal hemorrhage, absence of overt ascites, history of overt non-precipitated encephalopathy)
Age > 18 and <= 80
High risk of cirrhosis decompensation as defined by any of the following
Presence of esophageal varices on endoscopy
Presence of portosystemic collaterals on imaging as determined by a body radiologist
Fibroscan VCTE >= 20kPa
Platelet count <= 125 K/mm
total points (~50% of clinically significant portal hypertension using the ANTICIPATE Nomogram)
Competent to provide informed consent

Exclusion Criteria

Prior exposure to any statin within 6 months
Prior allergy or sensitivity to simvastatin
History of variceal hemorrhage confirmed endoscopically within the previous 3 years
Presence of overt ascites or treatment with diuretics for ascites with 6 months
History of chronic, recurrent or episodic overt hepatic encephalopathy with asterixis within 6 months
History of hepatocellular carcinoma
Child-Turcotte-Pugh C Stage (CTP Score > 9)
Prior receipt of organ transplant
Participation in another pharmacological clinical trial within 3 months of the current study
Pregnancy or anticipated pregnancy within 2 years
Breast Feeding
Patients with life expectancy < 3 years due to comorbid conditions
Independent indication for initiation of statin therapy
Patients with any form of clinical atherosclerotic cardiovascular disease (ASCVD)
Patients with primary LDL-C < 190 mg/dl
Patients with diabetes mellitus, age 40-75 years, with LDL-C levels >=130 mg/dl
Need for concomitant administration of potent inhibitors of CYP34A4 enzymes (medications or other supplements that should not be taken with simvastatin, including cyclosporine, danazol, gemfibrozil, fenofibrate, extended release niacin, itraconazole, ketoconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, macrolide antibiotics - erythromycin, clarithromycin, telithromycin, nefazadone, amlodipine, verapamil, diltiazem, dronedarone, amiodarone, renolazine, lomitapide, and cobicistat)
Prior TIPSS shunt
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