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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 : May 14, 2020
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE November 18, 2016
First Posted Date  ICMJE November 21, 2016
Last Update Posted Date May 14, 2020
Actual Study Start Date  ICMJE June 21, 2017
Estimated Primary Completion Date April 14, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 18, 2016)
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 2, 2018)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 18, 2016)
  • Change in 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 t
  • 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 t
  • Change in 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 t
  • 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 ris
  • 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 t
  • 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 t
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Simvastatin in Preventing Liver Cancer in Patients With Liver Cirrhosis
Official Title  ICMJE Statin Therapy to Reduce Disease Progression From Liver Cirrhosis to Cancer
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Condition  ICMJE Cirrhosis
Intervention  ICMJE
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Other: Placebo Administration
    Given PO
  • Other: Questionnaire Administration
    Ancillary studies
  • Drug: Simvastatin
    Given PO
    Other Names:
    • MK 733
    • Synvinolin
    • Zocor
Study Arms  ICMJE
  • 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.
    Interventions:
    • Other: Laboratory Biomarker Analysis
    • Other: Questionnaire Administration
    • Drug: Simvastatin
  • 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.
    Interventions:
    • Other: Laboratory Biomarker Analysis
    • Other: Placebo Administration
    • Other: Questionnaire Administration
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 18, 2016)
80
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 14, 2021
Estimated Primary Completion Date April 14, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE Puerto Rico,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02968810
Other Study ID Numbers  ICMJE 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 )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Marc T Goodman Northwestern University
PRS Account National Cancer Institute (NCI)
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP