Multi-Center Study of the Effects of Simvastatin on Hepatic Decompensation and Death in Subjects Presenting With High-Risk Compensated Cirrhosis (SACRED)
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| ClinicalTrials.gov Identifier: NCT03654053 |
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Recruitment Status :
Recruiting
First Posted : August 31, 2018
Last Update Posted : August 20, 2021
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Sponsor:
VA Office of Research and Development
Information provided by (Responsible Party):
VA Office of Research and Development
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Cirrhosis | Drug: Placebo Oral Tablet Drug: Simvastatin 40mg | Phase 3 |
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 (Clinical Trial) |
| Estimated Enrollment : | 500 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Triple (Participant, Care Provider, Investigator) |
| Masking Description: | Double-blind, placebo-controlled |
| Primary Purpose: | Treatment |
| Official Title: | Effect of Simvastatin on Hepatic Decompensation and Death in Subjects With High-risk Compensated Cirrhosis |
| Actual Study Start Date : | October 2, 2020 |
| Estimated Primary Completion Date : | September 30, 2024 |
| Estimated Study Completion Date : | September 30, 2024 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
North American Indian childhood cirrhosis
MedlinePlus related topics:
End of Life Issues
Drug Information available for:
Simvastatin
| 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.
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Drug: Simvastatin 40mg
Simvastatin 40mg taken once nightly at bed time.
Other Name: Simvastatin |
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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.
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Drug: Placebo Oral Tablet
Placebo taken once nightly at bed time.
Other Name: Placebo |
Primary Outcome Measures :
- Survival free from hepatic decompensation [ Time Frame: 24 months ]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 [ Time Frame: 24 months ]Occurrence of death after hepatic decompensation, or hepatocellular carcinoma or transplantation
- Survival free from major cardiac events [ Time Frame: 24 months ]Occurrence of acute myocardial infarction, or unstable angina, or acute ischemic stroke, or coronary revascularization.
- Change in patient health-related quality of life [ Time Frame: 12 months ]Clinically significant change in score from baseline to month 12 as assessed by the PROMIS-29 questionnaire
- Statin-related hepatotoxicity [ Time Frame: 24 months ]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 [ Time Frame: 24 months ]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 [ Time Frame: 24 months ]Occurrence of rhabdomyolysis defined as Grade 3 (symptomatic, urgent intervention indicated)
- Hepatotoxicity [ Time Frame: 24 months ]Liver enzyme testing (AST, ALT, alkaline phosphatase, total bilirubin) at each study visit.
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| Ages Eligible for Study: | 18 Years to 80 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
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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 <= 110 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 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 < 16%
- 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)
- Prior TIPSS shunt
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03654053
Contacts
| Contact: Rajni L Mehta, MPH | (203) 668-5760 ext 2228 | rajni.mehta@va.gov | |
| Contact: David E Kaplan, MD MSc | (215) 823-5800 | David.Kaplan2@va.gov |
Locations
| United States, California | |
| San Francisco VA Medical Center, San Francisco, CA | Recruiting |
| San Francisco, California, United States, 94121 | |
| Contact: Alexander Monto, MD 415-221-4810 ext 2958 alexander.monto@va.gov | |
| Contact: Christina Haight 4157502150 Christina.Haight@va.gov | |
| United States, Connecticut | |
| VA Connecticut Healthcare System West Haven Campus, West Haven, CT | Recruiting |
| West Haven, Connecticut, United States, 06516 | |
| Contact: Tamar H Taddei, MD 203-932-5711 ext 2206 tamar.taddei@va.gov | |
| Contact: Rajni Mehta, BS 2036685760 rajni.mehta@va.gov | |
| United States, Massachusetts | |
| VA Boston Healthcare System Jamaica Plain Campus, Jamaica Plain, MA | Recruiting |
| Boston, Massachusetts, United States, 02130 | |
| Contact: Gyorgy Baffy, MD 857-364-4327 gyorgy.baffy@va.gov | |
| Contact: Yunren Bolortuya 8573646501 Yunren.Bolortuya@va.gov | |
| United States, Missouri | |
| Kansas City VA Medical Center, Kansas City, MO | Withdrawn |
| Kansas City, Missouri, United States, 64128 | |
| United States, New York | |
| James J. Peters VA Medical Center, Bronx, NY | Recruiting |
| Bronx, New York, United States, 10468 | |
| Contact: Kristel Hunt, MD 718-584-9000 ext 3600 kristel.hunt@va.gov | |
| Contact: Annabelle Perez 7185849000 ext 6627 Guerry.Perez@va.gov | |
| Brooklyn Campus of the VA NY Harbor Healthcare System, Brooklyn, NY | Recruiting |
| Brooklyn, New York, United States, 11209 | |
| Contact: Ayse Aytman, MD 718-836-6600 ext 3716 ayse.aytaman@va.gov | |
| Contact: Jennifer Yudkevich 7188366600 ext 4719 Jennifer.Yudkevich@va.gov | |
| United States, Pennsylvania | |
| Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA | Recruiting |
| Philadelphia, Pennsylvania, United States, 19104 | |
| Contact: Tamar H Taddei, MD 203-932-5711 ext 5335 tamar.taddei@va.gov | |
| Principal Investigator: David E. Kaplan, MD MSc | |
| Philadelphia MultiService Center, Philadelphia, PA | Recruiting |
| Philadelphia, Pennsylvania, United States, 19106 | |
| Contact: David E Kaplan, MD 215-823-5800 ext 206729 david.kaplan2@va.gov | |
| Contact: Alexander Burdzy 2154709960 alexander.burdzy@va.gov | |
| United States, Texas | |
| Michael E. DeBakey VA Medical Center, Houston, TX | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Ruben Hernaez, MD 713-791-1414 ext 25152 ruben.hernaez@va.gov | |
| Contact: Aisha Khan 7134404670 Aisha.Khan@va.gov | |
| United States, Virginia | |
| Hunter Holmes McGuire VA Medical Center, Richmond, VA | Recruiting |
| Richmond, Virginia, United States, 23249 | |
| Contact: Jasmohan Bajaj, MD 804-675-5802 jasmohan.bajaj@va.gov | |
| Contact: Donna McMillion 8046755000 ext 4330 Donna.McMillion2@va.gov | |
| United States, Washington | |
| VA Puget Sound Health Care System Seattle Division, Seattle, WA | Recruiting |
| Seattle, Washington, United States, 98108 | |
| Contact: George Ioannou, MD 206-277-3136 george.ioannou@va.gov | |
| Contact: LYnn Edmondson 2062773597 Lynn.Edmondson@va.gov | |
Sponsors and Collaborators
VA Office of Research and Development
Investigators
| Principal Investigator: | David E. Kaplan, MD MSc | Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | VA Office of Research and Development |
| ClinicalTrials.gov Identifier: | NCT03654053 |
| Other Study ID Numbers: |
GAST-010-19F VOCAL-001 ( Other Identifier: Department of Veterans Affairs ) |
| First Posted: | August 31, 2018 Key Record Dates |
| Last Update Posted: | August 20, 2021 |
| Last Verified: | August 2021 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| 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 |
Keywords provided by VA Office of Research and Development:
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cirrhosis hepatic decompensation HMG-coA reductase |
hepatocellular carcinoma clinical trial Human |
Additional relevant MeSH terms:
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Liver Cirrhosis Fibrosis Pathologic Processes Liver Diseases Digestive System Diseases Simvastatin Anticholesteremic Agents |
Hypolipidemic Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Lipid Regulating Agents Hydroxymethylglutaryl-CoA Reductase Inhibitors Enzyme Inhibitors |