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

NCT ID: NCT03654053

Last Updated: 2025-11-14

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 142 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-10-02
• Study Completion Date: 2025-12-31

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.

Conditions

Cirrhosis

Keywords

cirrhosis; hepatic decompensation; HMG-coA reductase; hepatocellular carcinoma; clinical trial; Human

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Simvastatin

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.

Group Type: EXPERIMENTAL

Simvastatin 40mg

Intervention Type: DRUG

Simvastatin 40mg taken once nightly at bed time.

Placebo

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.

Group Type: PLACEBO_COMPARATOR

Placebo Oral Tablet

Intervention Type: DRUG

Placebo taken once nightly at bed time.

Interventions

Placebo Oral Tablet

Placebo taken once nightly at bed time.

Intervention Type: DRUG

Simvastatin 40mg

Simvastatin 40mg taken once nightly at bed time.

Intervention Type: DRUG

Other Intervention Names

Placebo; Simvastatin

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

VA Office of Research and Development

FED

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David E. Kaplan, MD MSc

Role: PRINCIPAL_INVESTIGATOR

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

Locations

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

VA Puget Sound Health Care System Seattle Division, Seattle, WA

Seattle, Washington, United States

Countries

United States

References

Kaplan DE, Mehta R, Garcia-Tsao G, Albrecht J, Aytaman A, Baffy G, Bajaj J, Hernaez R, Hunt K, Ioannou G, Johnson K, Kanwal F, Lee TH, Monto A, Pandya P, Schaubel D, Taddei TH. SACRED: Effect of simvastatin on hepatic decompensation and death in subjects with high-risk compensated cirrhosis: Statins and Cirrhosis: Reducing Events of Decompensation. Contemp Clin Trials. 2021 May;104:106367. doi: 10.1016/j.cct.2021.106367. Epub 2021 Mar 24.

Reference Type: BACKGROUND

PMID: 33771685 (View on PubMed)

Provided Documents

Document Type: Informed Consent Form

View Document

Other Identifiers

VOCAL-001

Identifier Type: OTHER

Identifier Source: secondary_id

GAST-010-19F

Identifier Type: -

Identifier Source: org_study_id