Multi-Center Study of the Effects of Simvastatin on Hepatic Decompensation and Death in Subjects Presenting With High-Risk Compensated Cirrhosis
- Conditions
- Cirrhosis
- Interventions
- Drug: Placebo Oral Tablet
- Registration Number
- NCT03654053
- Lead Sponsor
- VA Office of Research and Development
- Brief 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.
- Detailed 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 142
-
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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Oral Tablet 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. Simvastatin Simvastatin 40mg 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.
- Primary Outcome Measures
Name Time Method Survival free from hepatic decompensation 24 months Occurrence of hepatic decompensation measured by first variceal hemorrhage, or development of ascites, or onset of hepatic encephalopathy, or hepatocellular carcinoma.
- Secondary Outcome Measures
Name Time Method Liver-related death 24 months Occurrence of death after hepatic decompensation, or hepatocellular carcinoma or transplantation
Change in patient health-related quality of life 12 months Clinically significant change in score from baseline to month 12 as assessed by the PROMIS-29 questionnaire
Statin-related hepatotoxicity 24 months 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)
Myositis 24 months 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)
Survival free from major cardiac events 24 months Occurrence of acute myocardial infarction, or unstable angina, or acute ischemic stroke, or coronary revascularization.
Rhabdomyolysis 24 months Occurrence of rhabdomyolysis defined as Grade 3 (symptomatic, urgent intervention indicated)
Hepatotoxicity 24 months Liver enzyme testing (AST, ALT, alkaline phosphatase, total bilirubin) at each study visit.
Trial Locations
- Locations (11)
VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
🇺🇸Boston, Massachusetts, United States
Philadelphia MultiService Center, Philadelphia, PA
🇺🇸Philadelphia, Pennsylvania, United States
San Francisco VA Medical Center, San Francisco, CA
🇺🇸San Francisco, California, United States
Robley Rex VA Medical Center, Louisville, KY
🇺🇸Louisville, Kentucky, United States
VA Connecticut Healthcare System West Haven Campus, West Haven, CT
🇺🇸West Haven, Connecticut, United States
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
🇺🇸Philadelphia, Pennsylvania, United States
James J. Peters VA Medical Center, Bronx, NY
🇺🇸Bronx, New York, United States
Brooklyn Campus of the VA NY Harbor Healthcare System, Brooklyn, NY
🇺🇸Brooklyn, New York, United States
VA Puget Sound Health Care System Seattle Division, Seattle, WA
🇺🇸Seattle, Washington, United States
Hunter Holmes McGuire VA Medical Center, Richmond, VA
🇺🇸Richmond, Virginia, United States
Michael E. DeBakey VA Medical Center, Houston, TX
🇺🇸Houston, Texas, United States