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

Cirrhosis Clinical Trial

— SACRED  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03654053
• Other study ID #: GAST-010-19F
• Secondary ID: VOCAL-001
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 2, 2020
• Est. completion date: December 31, 2025

Study information

• Verified date: January 2024
• Source: VA Office of Research and Development
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Active, not recruiting
• Enrollment: 142
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Cirrhosis
• Fibrosis
• Liver Cirrhosis

Intervention

Drug:
• Placebo Oral Tablet
Placebo taken once nightly at bed time.
• Simvastatin 40mg
Simvastatin 40mg taken once nightly at bed time.

Locations

Country	Name	City	State
United States	VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA	Boston	Massachusetts
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	Michael E. DeBakey VA Medical Center, Houston, TX	Houston	Texas
United States	Robley Rex VA Medical Center, Louisville, KY	Louisville	Kentucky
United States	Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA	Philadelphia	Pennsylvania
United States	Philadelphia MultiService Center, Philadelphia, PA	Philadelphia	Pennsylvania
United States	Hunter Holmes McGuire VA Medical Center, Richmond, VA	Richmond	Virginia
United States	San Francisco VA Medical Center, San Francisco, CA	San Francisco	California
United States	VA Puget Sound Health Care System Seattle Division, Seattle, WA	Seattle	Washington
United States	VA Connecticut Healthcare System West Haven Campus, West Haven, CT	West Haven	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
VA Office of Research and Development

Country where clinical trial is conducted

United States, 

References & Publications (1)

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. — View Citation

Outcome

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