Clinical trial NCT03654053: Multi-Center Study of the Effects of Simvastatin on Hepatic Decompensation and Death in Subjects Presenting With High-Risk Compensated Cirrhosis
Official title: Effect of Simvastatin on Hepatic Decompensation and Death in Subjects With High-risk Compensated Cirrhosis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Cirrhosis
Keywords: cirrhosis
hepatic decompensation
HMG-coA reductase
hepatocellular carcinoma
clinical trial
Human
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2018-08-31
Enrollment: 142
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Survival free from hepatic decompensation
timeFrame: 24 months
Secondary outcomes:
measure: Liver-related death
timeFrame: 24 months
measure: Survival free from major cardiac events
timeFrame: 24 months
measure: Change in patient health-related quality of life
timeFrame: 12 months
measure: Statin-related hepatotoxicity
timeFrame: 24 months
measure: Myositis
timeFrame: 24 months
measure: Rhabdomyolysis
timeFrame: 24 months
measure: Hepatotoxicity
timeFrame: 24 months
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: San Francisco VA Medical Center, San Francisco, CA
state: California
city: West Haven
country: United States
facility: VA Connecticut Healthcare System West Haven Campus, West Haven, CT
state: Connecticut
city: Louisville
country: United States
facility: Robley Rex VA Medical Center, Louisville, KY
state: Kentucky
city: Boston
country: United States
facility: VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
state: Massachusetts
city: Bronx
country: United States
facility: James J. Peters VA Medical Center, Bronx, NY
state: New York
city: Brooklyn
country: United States
facility: Brooklyn Campus of the VA NY Harbor Healthcare System, Brooklyn, NY
state: New York
city: Philadelphia
country: United States
facility: Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
state: Pennsylvania
city: Philadelphia
country: United States
facility: Philadelphia MultiService Center, Philadelphia, PA
state: Pennsylvania
city: Houston
country: United States
facility: Michael E. DeBakey VA Medical Center, Houston, TX
state: Texas
city: Richmond
country: United States
facility: Hunter Holmes McGuire VA Medical Center, Richmond, VA
state: Virginia
city: Seattle
country: United States
facility: VA Puget Sound Health Care System Seattle Division, Seattle, WA
state: Washington
Study officials:
affiliation: Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
name: David E. Kaplan, MD MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.