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

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

Sponsors

Lead sponsor: VA Office of Research and Development

Collaborator: VA Connecticut Healthcare System

Source 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.

Overall Status Not yet recruiting
Start Date October 1, 2020
Completion Date September 30, 2024
Primary Completion Date September 30, 2024
Phase Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Survival free from hepatic decompensation 24 months
Secondary Outcome
Measure Time Frame
Liver-related death 24 months
Survival free from major cardiac events 24 months
Change in patient health-related quality of life 12 months
Statin-related hepatotoxicity 24 months
Myositis 24 months
Rhabdomyolysis 24 months
Hepatotoxicity 24 months
Enrollment 500
Condition
Intervention

Intervention type: Drug

Intervention name: Placebo Oral Tablet

Description: Placebo taken once nightly at bed time.

Arm group label: Placebo

Other name: Placebo

Intervention type: Drug

Intervention name: Simvastatin 40mg

Description: Simvastatin 40mg taken once nightly at bed time.

Arm group label: Simvastatin

Other name: 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 25kPa

- Platelet count 70 K/mm

- 60 total points (~67% of clinically significant portal hypertension using the ANTICIPATE Nomogram)

- Competent to provide informed consent

Exclusion Criteria:

- Prior exposure to any statin within 2 years

- Prior allergy or sensitivity to simvastatin

- History of variceal hemorrhage confirmed endoscopically within the previous 2 years

- Presence of overt ascites or treatment with diuretics for ascites

- History of chronic, recurrent or episodic overt hepatic encephalopathy with asterixis

- 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 of 70-189 mg/dl

- Patients without diabetes, age 40-75 years, with an estimated 10-year ASCVD risk 7.5%

- 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, verapamil, diltiazem, dronedarone, amiodarone, renolazine, lomitapide, and cobicistat)

Gender: All

Minimum age: 18 Years

Maximum age: 80 Years

Healthy volunteers: No

Overall Official
Last Name Role Affiliation
David E. Kaplan, MD MSc Principal Investigator Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
Overall Contact

Last name: Rajni Mehta

Phone: (203) 932-5711

Phone ext: 2228

Email: [email protected]

Location
facility contact investigator Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA Rajni Mehta 203-932-5711 2228 [email protected] David E. Kaplan, MD MSc Principal Investigator
Location Countries

United States

Verification Date

April 2020

Responsible Party

Responsible party type: Sponsor

Keywords
Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Arm group label: Simvastatin

Arm group type: Experimental

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.

Arm group label: Placebo

Arm group type: Placebo Comparator

Description: Placebo 40mg PO once at bedtime for up to 24 months.

Acronym SACRED
Patient Data Yes
Study Design Info

Allocation: Randomized

Intervention model: Parallel Assignment

Primary purpose: Treatment

Masking: Triple (Participant, Care Provider, Investigator)

Source: ClinicalTrials.gov