Back to resultsMulti-Center Study of the Effects of Simvastatin on Hepatic Decompensation and Death in Subjects Presenting With High-Risk Compensated Cirrhosis (SACRED)
Primary Purpose
Cirrhosis
Status
Recruiting
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Placebo Oral Tablet
Simvastatin 40mg
Sponsored by
About this trial
This is an interventional treatment trial for Cirrhosis focused on measuring cirrhosis, hepatic decompensation, HMG-coA reductase, hepatocellular carcinoma, clinical trial, Human
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
Sites / Locations
- San Francisco VA Medical Center, San Francisco, CARecruiting
- VA Connecticut Healthcare System West Haven Campus, West Haven, CTRecruiting
- Robley Rex VA Medical Center, Louisville, KYRecruiting
- VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MARecruiting
- Kansas City VA Medical Center, Kansas City, MO
- James J. Peters VA Medical Center, Bronx, NYRecruiting
- Brooklyn Campus of the VA NY Harbor Healthcare System, Brooklyn, NYRecruiting
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PARecruiting
- Philadelphia MultiService Center, Philadelphia, PARecruiting
- Michael E. DeBakey VA Medical Center, Houston, TXRecruiting
- Hunter Holmes McGuire VA Medical Center, Richmond, VARecruiting
- VA Puget Sound Health Care System Seattle Division, Seattle, WARecruiting
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Simvastatin
Placebo
Arm 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.
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
Liver-related death
Occurrence of death after hepatic decompensation, or hepatocellular carcinoma or transplantation
Survival free from major cardiac events
Occurrence of acute myocardial infarction, or unstable angina, or acute ischemic stroke, or coronary revascularization.
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
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)
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)
Rhabdomyolysis
Occurrence of rhabdomyolysis defined as Grade 3 (symptomatic, urgent intervention indicated)
Hepatotoxicity
Liver enzyme testing (AST, ALT, alkaline phosphatase, total bilirubin) at each study visit.
Full Information
NCT ID
NCT03654053
First Posted
August 28, 2018
Last Updated
May 18, 2023
Sponsor
VA Office of Research and Development
1. Study Identification
Unique Protocol Identification Number
NCT03654053
Brief Title
Multi-Center Study of the Effects of Simvastatin on Hepatic Decompensation and Death in Subjects Presenting With High-Risk Compensated Cirrhosis
Acronym
SACRED
Official Title
Effect of Simvastatin on Hepatic Decompensation and Death in Subjects With High-risk Compensated Cirrhosis
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
October 2, 2020 (Actual)
Primary Completion Date
December 31, 2025 (Anticipated)
Study Completion Date
December 31, 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
VA Office of Research and Development
4. Oversight
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
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cirrhosis
Keywords
cirrhosis, hepatic decompensation, HMG-coA reductase, hepatocellular carcinoma, clinical trial, Human
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Masking Description
Double-blind, placebo-controlled
Allocation
Randomized
Enrollment
500 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Simvastatin
Arm Type
Experimental
Arm 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 Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo Oral Tablet
Other Intervention Name(s)
Placebo
Intervention Description
Placebo taken once nightly at bed time.
Intervention Type
Drug
Intervention Name(s)
Simvastatin 40mg
Other Intervention Name(s)
Simvastatin
Intervention Description
Simvastatin 40mg taken once nightly at bed time.
Primary Outcome Measure Information:
Title
Survival free from hepatic decompensation
Description
Occurrence of hepatic decompensation measured by first variceal hemorrhage, or development of ascites, or onset of hepatic encephalopathy, or hepatocellular carcinoma.
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Liver-related death
Description
Occurrence of death after hepatic decompensation, or hepatocellular carcinoma or transplantation
Time Frame
24 months
Title
Survival free from major cardiac events
Description
Occurrence of acute myocardial infarction, or unstable angina, or acute ischemic stroke, or coronary revascularization.
Time Frame
24 months
Title
Change in patient health-related quality of life
Description
Clinically significant change in score from baseline to month 12 as assessed by the PROMIS-29 questionnaire
Time Frame
12 months
Title
Statin-related hepatotoxicity
Description
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)
Time Frame
24 months
Title
Myositis
Description
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)
Time Frame
24 months
Title
Rhabdomyolysis
Description
Occurrence of rhabdomyolysis defined as Grade 3 (symptomatic, urgent intervention indicated)
Time Frame
24 months
Title
Hepatotoxicity
Description
Liver enzyme testing (AST, ALT, alkaline phosphatase, total bilirubin) at each study visit.
Time Frame
24 months
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Rajni L Mehta, MPH
Phone
(203) 668-5760
Ext
2228
Email
rajni.mehta@va.gov
First Name & Middle Initial & Last Name or Official Title & Degree
David E Kaplan, MD MSc
Phone
(215) 823-5800
Email
David.Kaplan2@va.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David E. Kaplan, MD MSc
Organizational Affiliation
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
Official's Role
Principal Investigator
Facility Information:
Facility Name
San Francisco VA Medical Center, San Francisco, CA
City
San Francisco
State/Province
California
ZIP/Postal Code
94121
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alexander Monto, MD
Phone
415-221-4810
Ext
2958
Email
alexander.monto@va.gov
First Name & Middle Initial & Last Name & Degree
Christina Haight
Phone
4157502150
Email
Christina.Haight@va.gov
Facility Name
VA Connecticut Healthcare System West Haven Campus, West Haven, CT
City
West Haven
State/Province
Connecticut
ZIP/Postal Code
06516
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Tamar H Taddei, MD
Phone
203-932-5711
Ext
2206
Email
tamar.taddei@va.gov
First Name & Middle Initial & Last Name & Degree
Rajni Mehta, BS
Phone
2036685760
Email
rajni.mehta@va.gov
Facility Name
Robley Rex VA Medical Center, Louisville, KY
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40206
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Craig McClain, MD
Phone
502-852-6189
Email
craig.mcclain@va.gov
Facility Name
VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02130
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gyorgy Baffy, MD
Phone
857-364-4327
Email
gyorgy.baffy@va.gov
First Name & Middle Initial & Last Name & Degree
Yunren Bolortuya
Phone
8573646501
Email
Yunren.Bolortuya@va.gov
Facility Name
Kansas City VA Medical Center, Kansas City, MO
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64128
Country
United States
Individual Site Status
Withdrawn
Facility Name
James J. Peters VA Medical Center, Bronx, NY
City
Bronx
State/Province
New York
ZIP/Postal Code
10468
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kristel Hunt, MD
Phone
718-584-9000
Ext
3600
Email
kristel.hunt@va.gov
First Name & Middle Initial & Last Name & Degree
Annabelle Perez
Phone
7185849000
Ext
6627
Email
Guerry.Perez@va.gov
Facility Name
Brooklyn Campus of the VA NY Harbor Healthcare System, Brooklyn, NY
City
Brooklyn
State/Province
New York
ZIP/Postal Code
11209
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ayse Aytman, MD
Phone
718-836-6600
Ext
3716
Email
ayse.aytaman@va.gov
First Name & Middle Initial & Last Name & Degree
Jennifer Yudkevich
Phone
7188366600
Ext
4719
Email
Jennifer.Yudkevich@va.gov
Facility Name
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104-4551
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rajni L Mehta, MPH
Phone
203-668-5760
Ext
2228
Email
rajni.mehta@va.gov
First Name & Middle Initial & Last Name & Degree
David E. Kaplan, MD MSc
Facility Name
Philadelphia MultiService Center, Philadelphia, PA
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19106
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
David E Kaplan, MD
Phone
215-823-5800
Ext
206729
Email
david.kaplan2@va.gov
First Name & Middle Initial & Last Name & Degree
Alexander Burdzy
Phone
2154709960
Email
alexander.burdzy@va.gov
Facility Name
Michael E. DeBakey VA Medical Center, Houston, TX
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ruben Hernaez, MD
Phone
713-791-1414
Ext
25152
Email
ruben.hernaez@va.gov
First Name & Middle Initial & Last Name & Degree
Aisha Khan
Phone
7134404670
Email
Aisha.Khan@va.gov
Facility Name
Hunter Holmes McGuire VA Medical Center, Richmond, VA
City
Richmond
State/Province
Virginia
ZIP/Postal Code
23249
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jasmohan Bajaj, MD
Phone
804-675-5802
Email
jasmohan.bajaj@va.gov
First Name & Middle Initial & Last Name & Degree
Donna McMillion
Phone
8046755000
Ext
4330
Email
Donna.McMillion2@va.gov
Facility Name
VA Puget Sound Health Care System Seattle Division, Seattle, WA
City
Seattle
State/Province
Washington
ZIP/Postal Code
98108
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
George Ioannou, MD
Phone
206-277-3136
Email
george.ioannou@va.gov
First Name & Middle Initial & Last Name & Degree
LYnn Edmondson
Phone
2062773597
Email
Lynn.Edmondson@va.gov
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
33771685
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.
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Multi-Center Study of the Effects of Simvastatin on Hepatic Decompensation and Death in Subjects Presenting With High-Risk Compensated Cirrhosis
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