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Simvastatin in Preventing Liver Cancer in Patients With Liver Cirrhosis

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ClinicalTrials.gov Identifier: NCT02968810
Recruitment Status : Recruiting
First Posted : November 21, 2016
Last Update Posted : July 11, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This randomized phase II trial studies how well simvastatin works in preventing liver cancer in patients with liver cirrhosis. Simvastatin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Cirrhosis Other: Laboratory Biomarker Analysis Other: Placebo Other: Questionnaire Administration Drug: Simvastatin Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the effect of a simvastatin intervention versus placebo on the change in serum AFP-L3% from baseline to 6 months following treatment initiation in patients with liver cirrhosis who have a current model for end-stage liver disease (MELD) =< 20.

SECONDARY OBJECTIVES:

I. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from baseline on the change in serum AFP.

II. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from baseline on the change in serum IL-6.

III. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from baseline on the change in serum bile acid levels.

IV. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from baseline on the change in liver stiffness.

V. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from baseline on the change in fibrosis 4 index (FIB-4) score.

VI. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from baseline on the change in MELD score.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive simvastatin orally (PO) once daily (QD).

GROUP II: Patients receive placebo PO QD.

In both groups, treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30, 60, and 90 days.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: Statin Therapy to Reduce Disease Progression From Liver Cirrhosis to Cancer
Actual Study Start Date : June 21, 2017
Estimated Primary Completion Date : January 1, 2020
Estimated Study Completion Date : January 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cirrhosis
Drug Information available for: Simvastatin

Arm Intervention/treatment
Experimental: Group I (simvastatin)
Patients receive simvastatin PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Other: Questionnaire Administration
Ancillary studies

Drug: Simvastatin
Given PO
Other Names:
  • MK 733
  • Synvinolin
  • Zocor

Placebo Comparator: Group II (placebo)
Patients receive placebo PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Other: Placebo
Given PO
Other Names:
  • placebo therapy
  • PLCB
  • sham therapy

Other: Questionnaire Administration
Ancillary studies




Primary Outcome Measures :
  1. Change in serum AFP-L3% assessed by liquid-phase binding assay [ Time Frame: Baseline to 6 months ]
    A non-parametric two-sample Wilcoxon-Mann-Whitney test will be used to address the hypothesis.


Secondary Outcome Measures :
  1. Change in serum AFP assessed by liquid-phase binding assay [ Time Frame: Baseline to 6 months ]
    Will use descriptive statistics and graphics at baseline and 6 months, as well as study random effects regression trends from baseline to 6 months for further hypotheses generation. Results from routine clinical tests into these regression analyses, specifically those that have been shown to be strongly predictive of hepatocellular carcinoma (HCC) diagnosis in prospective cohorts of cirrhosis including higher alkaline phosphatase, lower platelets, lower albumin, and lower prothrombin activity will be incorporated. Incorporated into these models will be variables representing important HCC risk factors captured through the epidemiological questionnaire, including body mass index, current alcohol use, and current dietary fat, carbohydrate, fiber, coffee, and antioxidants. Analyses will begin with univariate cross-sectional statistics for profiling the study population and bivariate tabulations as a preliminary step to possible model building.

  2. Change in serum IL-6 assessed by enzyme-linked immunosorbent assay [ Time Frame: Baseline to 6 months ]
    Will use descriptive statistics and graphics at baseline and 6 months, as well as study random effects regression trends from baseline to 6 months for further hypotheses generation. Results from routine clinical tests into these regression analyses, specifically those that have been shown to be strongly predictive of HCC diagnosis in prospective cohorts of cirrhosis including higher alkaline phosphatase, lower platelets, lower albumin, and lower prothrombin activity will be incorporated. Incorporated into these models will be variables representing important HCC risk factors captured through the epidemiological questionnaire, including body mass index, current alcohol use, and current dietary fat, carbohydrate, fiber, coffee, and antioxidants. Analyses will begin with univariate cross-sectional statistics for profiling the study population and bivariate tabulations as a preliminary step to possible model building.

  3. Change in serum bile acid levels assessed by liquid chromatography-tandem mass spectrometry [ Time Frame: Baseline to 6 months ]
    Will use descriptive statistics and graphics at baseline and 6 months, as well as study random effects regression trends from baseline to 6 months for further hypotheses generation. Results from routine clinical tests into these regression analyses, specifically those that have been shown to be strongly predictive of HCC diagnosis in prospective cohorts of cirrhosis including higher alkaline phosphatase, lower platelets, lower albumin, and lower prothrombin activity will be incorporated. Incorporated into these models will be variables representing important HCC risk factors captured through the epidemiological questionnaire, including body mass index, current alcohol use, and current dietary fat, carbohydrate, fiber, coffee, and antioxidants. Analyses will begin with univariate cross-sectional statistics for profiling the study population and bivariate tabulations as a preliminary step to possible model building.

  4. Change in liver stiffness assessed by liver elastography [ Time Frame: Baseline to 6 months ]
    Will use descriptive statistics and graphics at baseline and 6 months, as well as study random effects regression trends from baseline to 6 months for further hypotheses generation. Results from routine clinical tests into these regression analyses, specifically those that have been shown to be strongly predictive of HCC diagnosis in prospective cohorts of cirrhosis including higher alkaline phosphatase, lower platelets, lower albumin, and lower prothrombin activity will be incorporated. Incorporated into these models will be variables representing important HCC risk factors captured through the epidemiological questionnaire, including body mass index, current alcohol use, and current dietary fat, carbohydrate, fiber, coffee, and antioxidants. Analyses will begin with univariate cross-sectional statistics for profiling the study population and bivariate tabulations as a preliminary step to possible model building.

  5. Change in fibrosis 4 index (FIB-4) score [ Time Frame: Baseline to 6 months ]
    Will use descriptive statistics and graphics at baseline and 6 months, as well as study random effects regression trends from baseline to 6 months for further hypotheses generation. Results from routine clinical tests into these regression analyses, specifically those that have been shown to be strongly predictive of HCC diagnosis in prospective cohorts of cirrhosis including higher alkaline phosphatase, lower platelets, lower albumin, and lower prothrombin activity will be incorporated. Incorporated into these models will be variables representing important HCC risk factors captured through the epidemiological questionnaire, including body mass index, current alcohol use, and current dietary fat, carbohydrate, fiber, coffee, and antioxidants. Analyses will begin with univariate cross-sectional statistics for profiling the study population and bivariate tabulations as a preliminary step to possible model building.

  6. Change in Model for End-Stage Liver Disease (MELD) score [ Time Frame: Baseline to 6 months ]
    Will use descriptive statistics and graphics at baseline and 6 months, as well as study random effects regression trends from baseline to 6 months for further hypotheses generation. Results from routine clinical tests into these regression analyses, specifically those that have been shown to be strongly predictive of HCC diagnosis in prospective cohorts of cirrhosis including higher alkaline phosphatase, lower platelets, lower albumin, and lower prothrombin activity will be incorporated. Incorporated into these models will be variables representing important HCC risk factors captured through the epidemiological questionnaire, including body mass index, current alcohol use, and current dietary fat, carbohydrate, fiber, coffee, and antioxidants. Analyses will begin with univariate cross-sectional statistics for profiling the study population and bivariate tabulations as a preliminary step to possible model building.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmed diagnosis of liver cirrhosis assessed by the presence of clinical signs, symptoms, body imaging (ultrasound, computed tomography [CT], or magnetic resonance imaging [MRI]), or liver biopsy
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
  • Leukocytes >= 2,500/microliter
  • Absolute neutrophil count >= 1,500/microliter
  • Platelets >= 50,000/microliter
  • Hemoglobin >= 10 g/dL
  • Total bilirubin =< 3 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional ULN
  • Creatinine =< 1.5 x institutional ULN
  • Women who are able to become pregnant must have a confirmed negative pregnancy test result prior to enrollment; women >= 50 years of age who have not had a menstrual period in the past year; and women who have had a hysterectomy, both ovaries removed, or a tubal ligation; will not be required to have a pregnancy test
  • Women who are able to become pregnant must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
  • Ability to understand and the willingness to sign a written informed consent document and medical release
  • Willing and able to comply with trial protocol and follow-up
  • Have had an abdominal imaging test (CT, MRI, or ultrasound) within the past 7 months

Exclusion Criteria:

  • Prior or current use of statin medication
  • Current systemic use of medications known to interact with statins and potentially increase toxicity, including gemfibrozil, cyclosporine, danazol, lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine, ranolazine, strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, human immunodeficiency virus [HIV] protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, or cobicistat-containing products), or strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort, bosentan, efavirenz, etravirine, modafinil, nafcillin)
  • History of adverse effects, intolerance, or allergic reactions attributed to compounds of similar chemical or biologic composition to simvastatin (i.e., other statin medications)
  • Current use of any other investigational agents
  • Women who are pregnant or breastfeeding; breastfeeding should be discontinued if the mother is treated with simvastatin
  • Prior liver transplant
  • Prior known or suspected hepatocellular carcinoma
  • Prior cholangiocarcinoma
  • Model for end-stage liver disease (MELD) > 20
  • Any lab results that do not meet inclusion criteria after the Screen 1 blood tests
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • History of chronic myopathy
  • Prior germ cell cancer
  • History of active malignancy within the past 5 years (excluding basal/squamous cell skin cancer or prostate cancer with a Gleason score 6 or less)
  • Known active infection with HIV
  • Medical contraindications to blood draw (e.g., hemophilia)
  • Concurrent illness which in the opinion of the investigators would compromise either the patient or the integrity of the data
  • Current excessive alcohol consumption (average alcohol consumption of more than 5 drinks per day)

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): NCT02968810


Locations
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United States, California
Cedars Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Contact: Marc T. Goodman    310-423-6188    marc.goodman@cshs.org   
Principal Investigator: Marc T. Goodman         
United States, District of Columbia
MedStar Georgetown University Hospital Recruiting
Washington, District of Columbia, United States, 20007
Contact: Aiwu R. He    202-444-8642    arh29@georgetown.edu   
Principal Investigator: Aiwu R. He         
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Seema A. Khan    312-503-4236    skhan@nm.org   
Principal Investigator: Seema A. Khan         
Puerto Rico
University of Puerto Rico Recruiting
San Juan, Puerto Rico, 00936
Contact: Marcia R. Cruz-Correa       marcia.cruz1@upr.edu   
Principal Investigator: Marcia R. Cruz-Correa         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Marc T Goodman Northwestern University

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02968810     History of Changes
Other Study ID Numbers: NCI-2016-01719
NCI-2016-01719 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
N01-CN-2012-00035
NCI2015-06-03 ( Other Identifier: Northwestern University )
NWU2015-06-03 ( Other Identifier: DCP )
N01CN00035 ( U.S. NIH Grant/Contract )
P30CA060553 ( U.S. NIH Grant/Contract )
First Posted: November 21, 2016    Key Record Dates
Last Update Posted: July 11, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
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