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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
142
Placebo taken once nightly at bed time.
Simvastatin 40mg taken once nightly at bed time.
San Francisco VA Medical Center, San Francisco, CA
San Francisco, California, United States
VA Connecticut Healthcare System West Haven Campus, West Haven, CT
West Haven, Connecticut, United States
Robley Rex VA Medical Center, Louisville, KY
Louisville, Kentucky, United States
VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
Boston, Massachusetts, United States
Brooklyn Campus of the VA NY Harbor Healthcare System, Brooklyn, NY
Brooklyn, New York, United States
James J. Peters VA Medical Center, Bronx, NY
The Bronx, New York, United States
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
Philadelphia, Pennsylvania, United States
Philadelphia MultiService Center, Philadelphia, PA
Philadelphia, Pennsylvania, United States
Michael E. DeBakey VA Medical Center, Houston, TX
Houston, Texas, United States
Hunter Holmes McGuire VA Medical Center, Richmond, VA
Richmond, Virginia, United States
...and 1 more locations
Survival free from hepatic decompensation
Occurrence of hepatic decompensation measured by first variceal hemorrhage, or development of ascites, or onset of hepatic encephalopathy, or hepatocellular carcinoma.
Time frame: 24 months
Liver-related death
Occurrence of death after hepatic decompensation, or hepatocellular carcinoma or transplantation
Time frame: 24 months
Survival free from major cardiac events
Occurrence of acute myocardial infarction, or unstable angina, or acute ischemic stroke, or coronary revascularization.
Time frame: 24 months
Change in patient health-related quality of life
Clinically significant change in score from baseline to month 12 as assessed by the PROMIS-29 questionnaire
Time frame: 12 months
Statin-related hepatotoxicity
Occurrence of hepatotoxicity defined as Grade 3 liver toxicity per CTCAE 5.0 ( 5 times upper limit of normal as defined by local laboratory- transaminases)
Time frame: 24 months
Myositis
Occurrence of myositis defined as either Grade 3 myositis (pain associated with severe weakness; limiting self care Activities Daily Living {ADL}) OR Grade 4 creatine phosphokinase by CTCAE 5.0 ( 10x upper limit of normal)
Time frame: 24 months
Rhabdomyolysis
Occurrence of rhabdomyolysis defined as Grade 3 (symptomatic, urgent intervention indicated)
Time frame: 24 months
Hepatotoxicity
Liver enzyme testing (AST, ALT, alkaline phosphatase, total bilirubin) at each study visit.
Time frame: 24 months
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