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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Effect of Simvastatin on Hepatic Decompensation and Death in Subjects With High-risk Compensated Cirrhosis

Conditions
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Cirrhosis

Intervention / Treatment
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* Drug: Placebo Oral Tablet
* Drug: Simvastatin 40mg


Participation Criteria
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Eligibility Criteria
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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 44 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 Hemodialysis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Simvastatin<br>Simvastatin 40mg PO once at bedtime for up to 24 months. Note: all enrolled subjects will trial 20mg once at bedtime for two weeks as lead-in to determine tolerability prior to randomization. | Drug: Simvastatin 40mg<br>* Simvastatin 40mg taken once nightly at bed time.<br>* Other names: Simvastatin;|
| Placebo Comparator: Placebo<br>Placebo 40mg PO once at bedtime for up to 24 months. Note: all enrolled subjects will trial 20mg once at bedtime for two weeks as lead-in to determine tolerability prior to randomization. | Drug: Placebo Oral Tablet<br>* Placebo taken once nightly at bed time.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver-related death | Occurrence of death after hepatic decompensation, or hepatocellular carcinoma or transplantation | 24 months | 
| Survival free from major cardiac events | Occurrence of acute myocardial infarction, or unstable angina, or acute ischemic stroke, or coronary revascularization. | 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 | 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) | 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) | 24 months | 
| Rhabdomyolysis | Occurrence of rhabdomyolysis defined as Grade 3 (symptomatic, urgent intervention indicated) | 24 months | 
| Hepatotoxicity | Liver enzyme testing (AST, ALT, alkaline phosphatase, total bilirubin) at each study visit. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cirrhosis, hepatic decompensation, HMG-coA reductase, hepatocellular carcinoma, clinical trial, Human