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

VA Office of Research and Development

Status and phase: Active, not recruiting; Phase 3

Conditions: Cirrhosis

Treatments: Drug: Simvastatin 40mg; Drug: Placebo Oral Tablet

Study type: Interventional

Funder types: Other U.S. Federal agency

Identifiers

NCT03654053

VOCAL-001 (Other Identifier)

GAST-010-19F

Details and patient eligibility

About

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.

Full 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.

Enrollment: 142 patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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142 participants in 2 patient groups, including a placebo group

Simvastatin

Experimental group

Description:

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.

Treatment:

Drug: Simvastatin 40mg

Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo Oral Tablet