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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Cirrhosis
• Intervention / Treatment: Drug: Simvastatin 40mg; Drug: Placebo Oral Tablet

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.

• Study Type: Interventional
• Enrollment (Actual): 142
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Rajni L Mehta, MPH; Phone Number: 2228 (203) 668-5760; Email: rajni.mehta@va.gov
• Study Contact Backup: Name: David E Kaplan, MD MSc; Phone Number: (215) 823-5800; Email: David.Kaplan2@va.gov

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94121
      • San Francisco VA Medical Center, San Francisco, CA
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • VA Connecticut Healthcare System West Haven Campus, West Haven, CT
  • Kentucky
    • Louisville, Kentucky, United States, 40206
      • Robley Rex VA Medical Center, Louisville, KY
  • Massachusetts
    • Boston, Massachusetts, United States, 02130
      • VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
  • New York
    • Bronx, New York, United States, 10468
      • James J. Peters VA Medical Center, Bronx, NY
    • Brooklyn, New York, United States, 11209
      • Brooklyn Campus of the VA NY Harbor Healthcare System, Brooklyn, NY
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19106
      • Philadelphia MultiService Center, Philadelphia, PA
    • Philadelphia, Pennsylvania, United States, 19104-4551
      • Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
  • Texas
    • Houston, Texas, United States, 77030
      • Michael E. DeBakey VA Medical Center, Houston, TX
  • Virginia
    • Richmond, Virginia, United States, 23249
      • Hunter Holmes McGuire VA Medical Center, Richmond, VA
  • Washington
    • Seattle, Washington, United States, 98108
      • VA Puget Sound Health Care System Seattle Division, Seattle, WA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Simvastatin 40mg; Simvastatin 40mg taken once nightly at bed time.; Other Names: Simvastatin
Placebo Comparator: 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.	Drug: Placebo Oral Tablet; Placebo taken once nightly at bed time.; Other Names: Placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: David E. Kaplan, MD MSc, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2020
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: August 28, 2018
• First Submitted That Met QC Criteria: August 29, 2018
• First Posted (Actual): August 31, 2018

Study Record Updates

• Last Update Posted (Actual): January 17, 2024
• Last Update Submitted That Met QC Criteria: January 12, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: hepatocellular carcinoma; clinical trial; Human; cirrhosis; hepatic decompensation; HMG-coA reductase
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Liver Diseases; Fibrosis; Liver Cirrhosis; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: GAST-010-19F; VOCAL-001 (Other Identifier: Department of Veterans Affairs)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes