<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/NCT02973295</url>
  </required_header>
  <id_info>
    <org_study_id>KBCRi/2016-GH01</org_study_id>
    <nct_id>NCT02973295</nct_id>
  </id_info>
  <brief_title>Silymarin in NAFLD</brief_title>
  <acronym>SINF</acronym>
  <official_title>Silymarin® - Efficacy in Treatment of Non-alcoholic Fatty Liver Disease (NAFLD) Controlled by Laboratory and and Elastographic Parameters</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital Rijeka</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Rijeka, Medical Faculty</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Belupo</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Rijeka, Faculty of Health studies</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital Rijeka</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study evaluates the influence of Silymarin in reducing laboratory, ultrasonographic&#xD;
      (Fibroscan) and metabolic components of NAFLD. Half of the patients will receive Silymarin&#xD;
      (Verum) while the other half will receive placebo&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In this study will participate patients who come to the regular ambulatory examinations&#xD;
      (referred by gastroenterologists, nephrologists or family physicians in the Department of&#xD;
      Gastroenterology and Department of Nephrology, dialysis and kidney transplantation KBC&#xD;
      Rijeka) and have one or more components of the metabolic syndrome (hypertension, diabetes,&#xD;
      obesity, dyslipidemia).Nonalcoholic fatty liver disease will be defined by transient&#xD;
      elastography (FibroScan, Echosens, Paris); Controlled Attenuation Parameter (CAP) for&#xD;
      assesment of liver steatosis and Liver Stiffness Measurements (LSM) for liver fibrosis. In&#xD;
      all patients other causes of chronic liver disease will be excluded; chronic viral hepatitis,&#xD;
      autoimmune diseases and other metabolic liver diseases as well as use of drugs than can cause&#xD;
      liver steatosis and fibrosis and alcoholic liver disease.&#xD;
&#xD;
      This study will include 350 patients. Taking into account the possible drop-out rate around&#xD;
      15% of the patients during the study period, a total of 400 patients will be randomized.&#xD;
      Patients will be randomized into two groups. The first group will be consisted of the&#xD;
      patients with NAFLD who will be receiving Verum therapy during the 6 month period. The second&#xD;
      group will be consisted of the patients with NAFLD who will be receiving placebo during the 6&#xD;
      months period, which will be identical to the Verum preparation in its packaging and form.&#xD;
&#xD;
      After the 6 months of therapy in all patients will be evaluated: liver enzymes and metabolic&#xD;
      laboratory parameters of NAFLD (insulin resistance, lipidogram and serum glucose), as well as&#xD;
      the TE-CAP in order to evaluate the efficiency of Silymarin for the treatment of NAFLD.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Sponsor withdrawn their agreement&#xD;
  </why_stopped>
  <start_date type="Actual">September 20, 2019</start_date>
  <completion_date type="Anticipated">June 30, 2021</completion_date>
  <primary_completion_date type="Anticipated">December 2020</primary_completion_date>
  <phase>Phase 4</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>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change (Reduction) of parameters of liver steatosis defined by CAP (Controlled Attenuation Parameter) and liver fibrosis defined by LSM (liver stiffness measurements) during the 6 months period</measure>
    <time_frame>0 week (Initiation) and during 24-25 week (End of the Study)</time_frame>
    <description>Transient elastography detected by FibroScan®, Echosense, France</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in liver enzymes in period of 6 months</measure>
    <time_frame>0 week (Initiation) and during 24-25 week (End of the Study)</time_frame>
    <description>AST (Aspartate Aminotransferase ) ALT (alanine aminotransferase), GGT (gamma-glutamyltransferase), ALP (Alkaline Phosphatase). All outcomes have the same units of measure (UI/L) and all together represents liver function test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in insulin resistance in period of 6 months</measure>
    <time_frame>0 week (Initiation) and during 24-25 week (End of the Study)</time_frame>
    <description>In the assessment of the insulin resistance HOMA-IR scoring system will be used (fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5.)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in lipidogram in period of 6 months</measure>
    <time_frame>0 week (Initiation) and during 24-25 week (End of the Study)</time_frame>
    <description>lipidogram (total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides) All outcomes have the same units of measure (umol/L) and all together represents lipid profile</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Non-Alcoholic Fatty Liver Disease</condition>
  <arm_group>
    <arm_group_label>Group Silymarin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Silymarin 2x200 mg 8 weeks (2x2 caps) Silymarin 2x100 mg 16 weeks (2x1 caps)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Group Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>2x2 placebo caps 8 weeks 2x1 placebo caps 16 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Silymarin</intervention_name>
    <description>Capsules contains 100 mg of silymarin</description>
    <arm_group_label>Group Silymarin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo Oral Capsule</intervention_name>
    <description>Capsule will be identical in shape, size and color, packed in the same way like verum</description>
    <arm_group_label>Group Placebo</arm_group_label>
    <other_name>no other names</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  NAFLD patients&#xD;
&#xD;
          -  signed informed consent&#xD;
&#xD;
          -  possibility to follow instruction and the protocol&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  chronic B or C hepatitis&#xD;
&#xD;
          -  usage of hepatotoxic drugs in the period of 6 months before inclusion&#xD;
&#xD;
          -  chronic kidney insufficiency (grade 4 and 5), hemodialysis&#xD;
&#xD;
          -  any other chronic liver disease&#xD;
&#xD;
          -  opioid dependancy&#xD;
&#xD;
          -  any malignancy&#xD;
&#xD;
          -  HIV seropositivity&#xD;
&#xD;
          -  alcohol abuse&#xD;
&#xD;
          -  pregnancy&#xD;
&#xD;
          -  inability to follow the protocol&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Goran Hauser, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Clinical Hospital Centre Rijek, Croatia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Clinical Hospital Centre</name>
      <address>
        <city>Rijeka</city>
        <state>Kresimirova 42</state>
        <zip>51000</zip>
        <country>Croatia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Croatia</country>
  </location_countries>
  <reference>
    <citation>Festi D, Schiumerini R, Marzi L, Di Biase AR, Mandolesi D, Montrone L, Scaioli E, Bonato G, Marchesini-Reggiani G, Colecchia A. Review article: the diagnosis of non-alcoholic fatty liver disease -- availability and accuracy of non-invasive methods. Aliment Pharmacol Ther. 2013 Feb;37(4):392-400. doi: 10.1111/apt.12186. Epub 2012 Dec 20.</citation>
    <PMID>23278163</PMID>
  </reference>
  <reference>
    <citation>Mikolasevic I, Orlic L, Franjic N, Hauser G, Stimac D, Milic S. Transient elastography (FibroScan((R))) with controlled attenuation parameter in the assessment of liver steatosis and fibrosis in patients with nonalcoholic fatty liver disease - Where do we stand? World J Gastroenterol. 2016 Aug 28;22(32):7236-51. doi: 10.3748/wjg.v22.i32.7236.</citation>
    <PMID>27621571</PMID>
  </reference>
  <reference>
    <citation>Mikolasevic I, Milic S, Orlic L, Stimac D, Franjic N, Targher G. Factors associated with significant liver steatosis and fibrosis as assessed by transient elastography in patients with one or more components of the metabolic syndrome. J Diabetes Complications. 2016 Sep-Oct;30(7):1347-53. doi: 10.1016/j.jdiacomp.2016.05.014. Epub 2016 May 20.</citation>
    <PMID>27324703</PMID>
  </reference>
  <reference>
    <citation>Mikolasevic I, Orlic L, Hrstic I, Milic S. Metabolic syndrome and non-alcoholic fatty liver disease after liver or kidney transplantation. Hepatol Res. 2016 Aug;46(9):841-52. doi: 10.1111/hepr.12642. Epub 2016 Feb 4.</citation>
    <PMID>26713425</PMID>
  </reference>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>November 4, 2016</study_first_submitted>
  <study_first_submitted_qc>November 21, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 25, 2016</study_first_posted>
  <last_update_submitted>November 3, 2020</last_update_submitted>
  <last_update_submitted_qc>November 3, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 5, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital Rijeka</investigator_affiliation>
    <investigator_full_name>Goran Hauser</investigator_full_name>
    <investigator_title>Goran Hauser, Principal investigator</investigator_title>
  </responsible_party>
  <keyword>NAFLD;</keyword>
  <keyword>Fibroscan</keyword>
  <keyword>Silymarin</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Diseases</mesh_term>
    <mesh_term>Fatty Liver</mesh_term>
    <mesh_term>Non-alcoholic Fatty Liver Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Silymarin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>All patient data will be available to other researchers after interim analysis</ipd_description>
  </patient_data>
  <!-- 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/NCT02973295
org study id: KBCRi/2016-GH01
nct id: NCT02973295
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This study evaluates the influence of Silymarin in reducing laboratory, ultrasonographic
      (Fibroscan) and metabolic components of NAFLD. Half of the patients will receive Silymarin
      (Verum) while the other half will receive placebo
In this study will participate patients who come to the regular ambulatory examinations
      (referred by gastroenterologists, nephrologists or family physicians in the Department of
      Gastroenterology and Department of Nephrology, dialysis and kidney transplantation KBC
      Rijeka) and have one or more components of the metabolic syndrome (hypertension, diabetes,
      obesity, dyslipidemia).Nonalcoholic fatty liver disease will be defined by transient
      elastography (FibroScan, Echosens, Paris); Controlled Attenuation Parameter (CAP) for
      assesment of liver steatosis and Liver Stiffness Measurements (LSM) for liver fibrosis. In
      all patients other causes of chronic liver disease will be excluded; chronic viral hepatitis,
      autoimmune diseases and other metabolic liver diseases as well as use of drugs than can cause
      liver steatosis and fibrosis and alcoholic liver disease.

      This study will include 350 patients. Taking into account the possible drop-out rate around
      15% of the patients during the study period, a total of 400 patients will be randomized.
      Patients will be randomized into two groups. The first group will be consisted of the
      patients with NAFLD who will be receiving Verum therapy during the 6 month period. The second
      group will be consisted of the patients with NAFLD who will be receiving placebo during the 6
      months period, which will be identical to the Verum preparation in its packaging and form.

      After the 6 months of therapy in all patients will be evaluated: liver enzymes and metabolic
      laboratory parameters of NAFLD (insulin resistance, lipidogram and serum glucose), as well as
      the TE-CAP in order to evaluate the efficiency of Silymarin for the treatment of NAFLD.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Change (Reduction) of parameters of liver steatosis defined by CAP (Controlled Attenuation Parameter) and liver fibrosis defined by LSM (liver stiffness measurements) during the 6 months period
time frame: 0 week (Initiation) and during 24-25 week (End of the Study)
description: Transient elastography detected by FibroScan®, Echosense, France
measure: Change in liver enzymes in period of 6 months
time frame: 0 week (Initiation) and during 24-25 week (End of the Study)
description: AST (Aspartate Aminotransferase ) ALT (alanine aminotransferase), GGT (gamma-glutamyltransferase), ALP (Alkaline Phosphatase). All outcomes have the same units of measure (UI/L) and all together represents liver function test.
measure: Change in insulin resistance in period of 6 months
time frame: 0 week (Initiation) and during 24-25 week (End of the Study)
description: In the assessment of the insulin resistance HOMA-IR scoring system will be used (fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5.)
measure: Change in lipidogram in period of 6 months
time frame: 0 week (Initiation) and during 24-25 week (End of the Study)
description: lipidogram (total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides) All outcomes have the same units of measure (umol/L) and all together represents lipid profile
arm group label: Group Silymarin
arm group type: Experimental
description: Silymarin 2x200 mg 8 weeks (2x2 caps) Silymarin 2x100 mg 16 weeks (2x1 caps)
arm group label: Group Placebo
arm group type: Placebo Comparator
description: 2x2 placebo caps 8 weeks 2x1 placebo caps 16 weeks
intervention type: Drug
intervention name: Silymarin
description: Capsules contains 100 mg of silymarin
arm group label: Group Silymarin
intervention type: Other
intervention name: Placebo Oral Capsule
description: Capsule will be identical in shape, size and color, packed in the same way like verum
arm group label: Group Placebo
other name: no other names
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Goran Hauser, MD, PhD
role: Principal Investigator
affiliation: Clinical Hospital Centre Rijek, Croatia
facility: 
country: Croatia
citation: Festi D, Schiumerini R, Marzi L, Di Biase AR, Mandolesi D, Montrone L, Scaioli E, Bonato G, Marchesini-Reggiani G, Colecchia A. Review article: the diagnosis of non-alcoholic fatty liver disease -- availability and accuracy of non-invasive methods. Aliment Pharmacol Ther. 2013 Feb;37(4):392-400. doi: 10.1111/apt.12186. Epub 2012 Dec 20.
PMID: 23278163
citation: Mikolasevic I, Orlic L, Franjic N, Hauser G, Stimac D, Milic S. Transient elastography (FibroScan((R))) with controlled attenuation parameter in the assessment of liver steatosis and fibrosis in patients with nonalcoholic fatty liver disease - Where do we stand? World J Gastroenterol. 2016 Aug 28;22(32):7236-51. doi: 10.3748/wjg.v22.i32.7236.
PMID: 27621571
citation: Mikolasevic I, Milic S, Orlic L, Stimac D, Franjic N, Targher G. Factors associated with significant liver steatosis and fibrosis as assessed by transient elastography in patients with one or more components of the metabolic syndrome. J Diabetes Complications. 2016 Sep-Oct;30(7):1347-53. doi: 10.1016/j.jdiacomp.2016.05.014. Epub 2016 May 20.
PMID: 27324703
citation: Mikolasevic I, Orlic L, Hrstic I, Milic S. Metabolic syndrome and non-alcoholic fatty liver disease after liver or kidney transplantation. Hepatol Res. 2016 Aug;46(9):841-52. doi: 10.1111/hepr.12642. Epub 2016 Feb 4.
PMID: 26713425
responsible party type: Principal Investigator
investigator affiliation: University Hospital Rijeka
investigator full name: Goran Hauser
investigator title: Goran Hauser, Principal investigator
mesh term: Liver Diseases
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
mesh term: Silymarin
sharing ipd: Yes
ipd description: All patient data will be available to other researchers after interim analysis