<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02968810</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2016-01719</org_study_id>
    <secondary_id>NCI-2016-01719</secondary_id>
    <secondary_id>N01-CN-2012-00035</secondary_id>
    <secondary_id>NCI2015-06-03</secondary_id>
    <secondary_id>NWU2015-06-03</secondary_id>
    <secondary_id>N01CN00035</secondary_id>
    <secondary_id>P30CA060553</secondary_id>
    <nct_id>NCT02968810</nct_id>
  </id_info>
  <brief_title>Simvastatin in Preventing Liver Cancer in Patients With Liver Cirrhosis</brief_title>
  <official_title>Statin Therapy to Reduce Disease Progression From Liver Cirrhosis to Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies how well simvastatin works in preventing liver cancer in patients&#xD;
      with liver cirrhosis. Simvastatin may stop the growth of cancer cells by blocking some of the&#xD;
      enzymes needed for cell growth.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. To evaluate the effect of a simvastatin intervention versus placebo on the change in serum&#xD;
      AFP-L3% from baseline to 6 months following treatment initiation in patients with liver&#xD;
      cirrhosis who have a current model for end-stage liver disease (MELD) =&lt; 20.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from&#xD;
      baseline on the change in:&#xD;
&#xD;
      Ia. Serum AFP; Ib. Serum IL-6; Ic. Serum deoxycholic acid; Id. Liver stiffness; Ie. Fibrosis&#xD;
      4 index (FIB-4) score; If. MELD score.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the effect of a simvastatin intervention versus placebo at 6 months from&#xD;
      baseline on the change in other:&#xD;
&#xD;
      Ia. serum bile acid levels; Ib. serum immune markers.&#xD;
&#xD;
      OUTLINE: Patients are randomized to 1 of 2 groups.&#xD;
&#xD;
      GROUP I: Patients receive simvastatin orally (PO) once daily (QD). Patients also undergo&#xD;
      collection of blood on study and computed tomography (CT) scans/magnetic resonance imaging&#xD;
      (MRI) throughout the trial.&#xD;
&#xD;
      GROUP II: Patients receive placebo PO QD. Patients also undergo collection of blood on study&#xD;
      and CT/MRI throughout the trial.&#xD;
&#xD;
      In both groups, treatment continues for up to 6 months in the absence of disease progression&#xD;
      or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30, 60, and 90 days.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">June 21, 2017</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in serum AFP-L3%</measure>
    <time_frame>Baseline to 6 months</time_frame>
    <description>Assessed by liquid-phase binding assay. A non-parametric two-sample Wilcoxon-Mann-Whitney test will be used to address the hypothesis.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in serum AFP</measure>
    <time_frame>Baseline to 6 months</time_frame>
    <description>Assessed by liquid-phase binding assay. 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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum IL-6</measure>
    <time_frame>Baseline to 6 months</time_frame>
    <description>Assessed by proximity extension assay and next generation sequencing. 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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in serum deoxycholic acid</measure>
    <time_frame>Baseline to 6 months</time_frame>
    <description>Assessed by liquid chromatography coupled with mass spectrometry. 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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in liver stiffness</measure>
    <time_frame>Baseline to 6 months</time_frame>
    <description>Assessed by liver elastography. 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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in fibrosis 4 index score</measure>
    <time_frame>Baseline to 6 months</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Model for End-Stage Liver Disease score</measure>
    <time_frame>Baseline to 6 months</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in serum bile acids</measure>
    <time_frame>Baseline to 6 months</time_frame>
    <description>Assessed by liquid chromatography coupled with mass spectrometry. 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.</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in serum immune markers</measure>
    <time_frame>Baseline to 6 months</time_frame>
    <description>Assessed by proximity extension assay and next generation sequencing. 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.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Cirrhosis</condition>
  <condition>Hepatocellular Carcinoma</condition>
  <arm_group>
    <arm_group_label>Group I (simvastatin)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive simvastatin PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood on study and CT/MRI throughout the trial.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group II (placebo)</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients receive placebo PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood on study and CT/MRI throughout the trial.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Biospecimen Collection</intervention_name>
    <description>Undergo collection of blood</description>
    <arm_group_label>Group I (simvastatin)</arm_group_label>
    <arm_group_label>Group II (placebo)</arm_group_label>
    <other_name>Biological Sample Collection</other_name>
    <other_name>Biospecimen Collected</other_name>
    <other_name>Specimen Collection</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Computed Tomography</intervention_name>
    <description>Undergo CT</description>
    <arm_group_label>Group I (simvastatin)</arm_group_label>
    <arm_group_label>Group II (placebo)</arm_group_label>
    <other_name>CAT</other_name>
    <other_name>CAT Scan</other_name>
    <other_name>Computed Axial Tomography</other_name>
    <other_name>Computerized Axial Tomography</other_name>
    <other_name>Computerized axial tomography (procedure)</other_name>
    <other_name>Computerized Tomography</other_name>
    <other_name>CT</other_name>
    <other_name>CT Scan</other_name>
    <other_name>tomography</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Magnetic Resonance Imaging</intervention_name>
    <description>Undergo MRI</description>
    <arm_group_label>Group I (simvastatin)</arm_group_label>
    <arm_group_label>Group II (placebo)</arm_group_label>
    <other_name>Magnetic Resonance</other_name>
    <other_name>Magnetic resonance imaging (procedure)</other_name>
    <other_name>Magnetic Resonance Imaging Scan</other_name>
    <other_name>Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance</other_name>
    <other_name>MR</other_name>
    <other_name>MR Imaging</other_name>
    <other_name>MRI</other_name>
    <other_name>MRI Scan</other_name>
    <other_name>NMR Imaging</other_name>
    <other_name>NMRI</other_name>
    <other_name>Nuclear Magnetic Resonance Imaging</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo Administration</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Group II (placebo)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Questionnaire Administration</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Group I (simvastatin)</arm_group_label>
    <arm_group_label>Group II (placebo)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Simvastatin</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Group I (simvastatin)</arm_group_label>
    <other_name>MK 733</other_name>
    <other_name>Synvinolin</other_name>
    <other_name>Zocor</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Confirmed diagnosis of liver cirrhosis assessed by the presence of clinical signs,&#xD;
             symptoms, body imaging (ultrasound, computed tomography [CT], or magnetic resonance&#xD;
             imaging [MRI]), or liver biopsy&#xD;
&#xD;
          -  Age &gt;= 18 years&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 1 (Karnofsky &gt;= 70%)&#xD;
&#xD;
          -  Leukocytes &gt;= 2,500/microliter&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,500/microliter&#xD;
&#xD;
          -  Platelets &gt;= 50,000/microliter&#xD;
&#xD;
          -  Hemoglobin &gt;= 8 g/dL&#xD;
&#xD;
          -  Total bilirubin =&lt; 3 x institutional upper limit of normal (ULN)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])&#xD;
             =&lt; 5 x institutional ULN&#xD;
&#xD;
          -  Creatinine =&lt; 1.5 x institutional ULN&#xD;
&#xD;
          -  Women who are able to become pregnant must have a confirmed negative pregnancy test&#xD;
             result prior to enrollment; women &gt;= 50 years of age who have not had a menstrual&#xD;
             period in the past year; and women who have had a hysterectomy, both ovaries removed,&#xD;
             or a tubal ligation; will not be required to have a pregnancy test&#xD;
&#xD;
          -  The effects of simvastatin on the developing human fetus at the recommended&#xD;
             therapeutic dose are unknown; for this reason, women who are able to become pregnant&#xD;
             must agree to use adequate contraception (hormonal or barrier method of birth control;&#xD;
             abstinence) prior to study entry and for the duration of study participation; should a&#xD;
             woman become pregnant or suspect she is pregnant while participating in this study,&#xD;
             she should inform her study physician immediately&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
             and medical release&#xD;
&#xD;
          -  Willing and able to comply with trial protocol and follow-up&#xD;
&#xD;
          -  Have had an abdominal imaging test (CT, MRI, or ultrasound) within the past 18 months&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior or current use of statin medication&#xD;
&#xD;
          -  Current systemic use of medications known to interact with statins and potentially&#xD;
             increase toxicity, including gemfibrozil, cyclosporine, danazol, lomitapide,&#xD;
             verapamil, diltiazem, dronedarone, amiodarone, amlodipine, ranolazine, strong CYP3A4&#xD;
             inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, human&#xD;
             immunodeficiency virus [HIV] protease inhibitors, boceprevir, telaprevir,&#xD;
             erythromycin, clarithromycin, telithromycin, nefazodone, or cobicistat-containing&#xD;
             products), or strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St.&#xD;
             John's wort, bosentan, efavirenz, etravirine, modafinil, nafcillin)&#xD;
&#xD;
          -  History of adverse effects, intolerance, or allergic reactions attributed to compounds&#xD;
             of similar chemical or biologic composition to simvastatin (i.e., other statin&#xD;
             medications)&#xD;
&#xD;
          -  Current use of any other investigational agents&#xD;
&#xD;
          -  Women who are pregnant or breastfeeding; pregnant women are excluded from this study&#xD;
             because simvastatin is a lipid-lowering agent with the potential for teratogenic or&#xD;
             abortifacient effects; it is not known whether simvastatin is excreted into human&#xD;
             milk; however, a small amount of another drug in this class does pass into breast&#xD;
             milk; because there is an unknown but potential risk for adverse events in nursing&#xD;
             infants secondary to treatment of the mother with simvastatin, breastfeeding should be&#xD;
             discontinued if the mother is treated with simvastatin&#xD;
&#xD;
          -  Prior liver transplant&#xD;
&#xD;
          -  Prior known or suspected hepatocellular carcinoma&#xD;
&#xD;
          -  Prior cholangiocarcinoma&#xD;
&#xD;
          -  Model for end-stage liver disease (MELD) &gt; 20&#xD;
&#xD;
          -  Any lab results that do not meet inclusion criteria after the Screen 1 blood tests&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          -  History of chronic myopathy&#xD;
&#xD;
          -  Prior germ cell cancer&#xD;
&#xD;
          -  History of active malignancy within the past 5 years (excluding basal/squamous cell&#xD;
             skin cancer or prostate cancer with a Gleason score 6 or less)&#xD;
&#xD;
          -  Known active infection with HIV&#xD;
&#xD;
          -  Medical contraindications to blood draw (e.g., hemophilia)&#xD;
&#xD;
          -  Concurrent illness which in the opinion of the investigators would compromise either&#xD;
             the patient or the integrity of the data&#xD;
&#xD;
          -  Current excessive alcohol consumption (average alcohol consumption of more than 5&#xD;
             drinks per day)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Marc T Goodman</last_name>
    <role>Principal Investigator</role>
    <affiliation>Northwestern University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cedars Sinai Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90048</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MedStar Georgetown University Hospital</name>
      <address>
        <city>Washington</city>
        <state>District of Columbia</state>
        <zip>20007</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwestern University</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centro Comprensivo de Cancer de UPR</name>
      <address>
        <city>San Juan</city>
        <zip>00927</zip>
        <country>Puerto Rico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Puerto Rico</name>
      <address>
        <city>San Juan</city>
        <zip>00936</zip>
        <country>Puerto Rico</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Puerto Rico</country>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>November 18, 2016</study_first_submitted>
  <study_first_submitted_qc>November 18, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 21, 2016</study_first_posted>
  <last_update_submitted>April 25, 2023</last_update_submitted>
  <last_update_submitted_qc>April 25, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 26, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Cirrhosis</mesh_term>
    <mesh_term>Fibrosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Simvastatin</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02968810
org study id: NCI-2016-01719
secondary id: NCI-2016-01719
secondary id: N01-CN-2012-00035
secondary id: NCI2015-06-03
secondary id: NWU2015-06-03
secondary id: N01CN00035
secondary id: P30CA060553
nct id: NCT02968810
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This 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.
PRIMARY OBJECTIVE:

      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:

      Ia. Serum AFP; Ib. Serum IL-6; Ic. Serum deoxycholic acid; Id. Liver stiffness; Ie. Fibrosis
      4 index (FIB-4) score; If. MELD score.

      EXPLORATORY OBJECTIVES:

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

      Ia. serum bile acid levels; Ib. serum immune markers.

      OUTLINE: Patients are randomized to 1 of 2 groups.

      GROUP I: Patients receive simvastatin orally (PO) once daily (QD). Patients also undergo
      collection of blood on study and computed tomography (CT) scans/magnetic resonance imaging
      (MRI) throughout the trial.

      GROUP II: Patients receive placebo PO QD. Patients also undergo collection of blood on study
      and CT/MRI throughout the trial.

      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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Double (Participant, Investigator)
measure: Change in serum AFP-L3%
time frame: Baseline to 6 months
description: Assessed by liquid-phase binding assay. A non-parametric two-sample Wilcoxon-Mann-Whitney test will be used to address the hypothesis.
measure: Change in serum AFP
time frame: Baseline to 6 months
description: Assessed by liquid-phase binding assay. 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.
measure: Change in serum IL-6
time frame: Baseline to 6 months
description: Assessed by proximity extension assay and next generation sequencing. 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.
measure: Change in serum deoxycholic acid
time frame: Baseline to 6 months
description: Assessed by liquid chromatography coupled with mass spectrometry. 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.
measure: Change in liver stiffness
time frame: Baseline to 6 months
description: Assessed by liver elastography. 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.
measure: Change in fibrosis 4 index score
time frame: Baseline to 6 months
description: 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.
measure: Change in Model for End-Stage Liver Disease score
time frame: Baseline to 6 months
description: 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.
measure: Change in serum bile acids
time frame: Baseline to 6 months
description: Assessed by liquid chromatography coupled with mass spectrometry. 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.
measure: Change in serum immune markers
time frame: Baseline to 6 months
description: Assessed by proximity extension assay and next generation sequencing. 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.
arm group label: Group I (simvastatin)
arm group type: Experimental
description: Patients receive simvastatin PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood on study and CT/MRI throughout the trial.
arm group label: Group II (placebo)
arm group type: Placebo Comparator
description: Patients receive placebo PO QD. Treatment continues for up to 6 months in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood on study and CT/MRI throughout the trial.
intervention type: Procedure
intervention name: Biospecimen Collection
description: Undergo collection of blood
arm group label: Group I (simvastatin)
arm group label: Group II (placebo)
other name: Biological Sample Collection
other name: Biospecimen Collected
other name: Specimen Collection
intervention type: Procedure
intervention name: Computed Tomography
description: Undergo CT
arm group label: Group I (simvastatin)
arm group label: Group II (placebo)
other name: CAT
other name: CAT Scan
other name: Computed Axial Tomography
other name: Computerized Axial Tomography
other name: Computerized axial tomography (procedure)
other name: Computerized Tomography
other name: CT
other name: CT Scan
other name: tomography
intervention type: Procedure
intervention name: Magnetic Resonance Imaging
description: Undergo MRI
arm group label: Group I (simvastatin)
arm group label: Group II (placebo)
other name: Magnetic Resonance
other name: Magnetic resonance imaging (procedure)
other name: Magnetic Resonance Imaging Scan
other name: Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
other name: MR
other name: MR Imaging
other name: MRI
other name: MRI Scan
other name: NMR Imaging
other name: NMRI
other name: Nuclear Magnetic Resonance Imaging
intervention type: Other
intervention name: Placebo Administration
description: Given PO
arm group label: Group II (placebo)
intervention type: Other
intervention name: Questionnaire Administration
description: Ancillary studies
arm group label: Group I (simvastatin)
arm group label: Group II (placebo)
intervention type: Drug
intervention name: Simvastatin
description: Given PO
arm group label: Group I (simvastatin)
other name: MK 733
other name: Synvinolin
other name: Zocor
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Marc T Goodman
role: Principal Investigator
affiliation: Northwestern University
facility: 
facility: 
facility: 
facility: 
facility: 
country: Puerto Rico
country: United States
responsible party type: Sponsor
mesh term: Liver Cirrhosis
mesh term: Fibrosis
mesh term: Simvastatin