A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study of the Effects of Simvastatin on Hepatic Decompensation and Death in Subjects Presenting With High-Risk Compensated Cirrhosis
Statins And Cirrhosis: Reducing Events of Decompensation
Sponsors
Source
VA Connecticut Healthcare System
Oversight Info
Has Dmc
Yes
Is Fda Regulated Drug
No
Is Fda Regulated Device
No
Is Us Export
No
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
2020-03-01
Completion Date
2024-03-01
Primary Completion Date
2024-03-01
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
Description
Placebo taken once nightly at bed time.
Arm Group Label
Placebo
Other Name
Placebo
Intervention Type
Drug
Intervention Name
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 |
|
Tamar Taddei, MD |
Principal Investigator |
VACHS, Yale University School of Medicine |
Overall Contact
Verification Date
2019-10-01
Lastchanged Date
N/A
Firstreceived Date
N/A
Responsible Party
Responsible Party Type
Sponsor-Investigator
Investigator Affiliation
VA Connecticut Healthcare System
Investigator Full Name
Tamar Taddei
Investigator Title
Associate Professor
Keywords
Has Expanded Access
No
Condition Browse
Number Of Arms
2
Intervention Browse
Mesh Term
Simvastatin
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.
Firstreceived Results Date
N/A
Overall Contact Backup
Acronym
SACRED
Firstreceived Results Disposition Date
N/A
Study Design Info
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
Triple (Participant, Care Provider, Investigator)
Study First Submitted
August 28, 2018
Study First Submitted Qc
August 29, 2018
Study First Posted
August 31, 2018
Last Update Submitted
October 7, 2019
Last Update Submitted Qc
October 7, 2019
Last Update Posted
October 10, 2019
ClinicalTrials.gov processed this data on December 06, 2019
Conditions
Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov,
conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions
Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied.
Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase
Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions
that study is seeking to answer:
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.
In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.
In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.
These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.