<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/NCT04501042</url>
  </required_header>
  <id_info>
    <org_study_id>201903037RIND</org_study_id>
    <nct_id>NCT04501042</nct_id>
  </id_info>
  <brief_title>Investigation on the Role of Gut-liver Axis for Non-alcoholic Steatohepatitis Through Bariatric Surgery</brief_title>
  <official_title>Investigation on Novel Route of Gut Microbiota Products for Bariatric Surgery to Improve Non-alcoholic Steatohepatitis and Development on Therapeutic Implications</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Taiwan University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ministry of Science and Technology, Taiwan</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>National Taiwan University Hospital</source>
  <oversight_info>
    <has_dmc>No</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>
      Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease.&#xD;
      Non-alcoholic steatohepatitis (NASH) is an aggressive form of NAFLD with remarkable&#xD;
      inflammatory features which may cause advanced fibrosis and liver cancer. So far there is no&#xD;
      FDA-approved drug for treating NASH. A 10% weight loss by life style modification is a&#xD;
      standard recommendation to treat NASH which achieves only 10-20% success rate in clinical&#xD;
      practice. Thus, the development of therapeutics to prevent and treat NASH is certainly an&#xD;
      unmet need. For now, the mechanism of how simple steatosis progresses to NASH remains unclear&#xD;
      and accumulating evidences suggest the role of gut microbiota may be essential. Studies have&#xD;
      also noted the bariatric surgery effectively improve diabetes and NASH with significant&#xD;
      alterations in the composition and function of gut microbiome. In this study, the&#xD;
      investigators aim to investigate the role of gut microbiota in the pathophysiology of NASH by&#xD;
      comparing NAFLD severity, gut microbiome, metabolomics, immune profiles among patients before&#xD;
      and after the bariatric surgery. With these efforts, the investigators wish to decipher the&#xD;
      mechanism of how bariatric surgery may improve NASH through changing the gut microbiota and&#xD;
      find out microbe-associated molecular signatures between NASH and NAFLD through this study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators anticipate to recruit 140 morbidly obese patients who will receive&#xD;
      bariatric surgery including 100 patients receiving sleeve gastrectomy (SG) and 40 receiving&#xD;
      gastric bypass surgery (GB). Liver biopsy will be performed during the operation to confirm&#xD;
      the histological scores of NAFLD severity. The investigators expect to have 50% NASH and 50%&#xD;
      NAFL patients from these morbidly obese patients based on previous domestic data. (i.e. 50&#xD;
      patients receiving SG to have NASH and 50 patients receiving SG to have NAFL; 20 patients&#xD;
      receiving GB to have NASH and 20 patients receiving GB to have NAFL.) In this study, the&#xD;
      investigators have two study objectives which are as follows.&#xD;
&#xD;
        1. The first objective is to discover potential mechanisms among gut-liver axis for&#xD;
           preventing or promoting NAFL to NASH by comparing (1) fecal microbiome composition and&#xD;
           metabolomics, (2) peripheral blood biochemistry, metabolomics, immune cell phenotypes,&#xD;
           and cytokines (3) portal vein biochemistry, metabolomics, immune cell phenotypes, and&#xD;
           cytokines (4) Liver metabolomics and RNA-seq (5) gut permeability test&#xD;
           (lactulose/mannitol challenge) (6) host genetic susceptibility for NAFLD (PNPLA3 and&#xD;
           TM6SF2) between the tissue-proved NASH and NAFL patients in this study with a&#xD;
           cross-sectional comparison.&#xD;
&#xD;
        2. The second objective is to longitudinally investigate the potential mechanisms of&#xD;
           bariatric surgery for improving NASH via a gut-microbiota dependent pathway. Clinical&#xD;
           and experimental data before (baseline) and after (1st, 3rd, 6th months) bariatric&#xD;
           surgery will be collected which include (1) non-invasive evaluation of NAFLD severity&#xD;
           (Fibroscan, MRI-PDFF (proton density fat fraction) and MRE), (2) blood biochemistry,&#xD;
           metabolomics, immune cell phenotypes, and cytokines (3) fecal microbiome and&#xD;
           metabolomics (4) gut permeability test (5) liver biopsy histology (if available)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">May 16, 2019</start_date>
  <completion_date type="Anticipated">September 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">April 1, 2024</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Change of NAFLD severity score (histology) from baseline to the 6th month</measure>
    <time_frame>Baseline and 6 months after bariatric surgery</time_frame>
    <description>Liver biopsy will be performed before and after surgery (if available) to acquire histology evaluation</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change of NAFLD severity measured by Fibroscan from baseline to the 6th month</measure>
    <time_frame>Baseline and 6 months after bariatric surgery</time_frame>
    <description>Fibroscan (CAP and kPa)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change of NAFLD severity measured by MRI proton density fat fraction from baseline to the</measure>
    <time_frame>Baseline and 6 months after bariatric surgery</time_frame>
    <description>MRI proton density fat fraction (%)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change of NAFLD severity measured by magnetic resonance elastography from baseline to the</measure>
    <time_frame>Baseline and 6 months after bariatric surgery</time_frame>
    <description>magnetic resonance elastography (kPa)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change of gut microbiome profiles</measure>
    <time_frame>Baseline, 1st month, 3rd month and 6th month after surgery</time_frame>
    <description>fecal 16S ribosomal RNA sequencing and shotgun metagenome sequencing</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of body fluid metabolomic profiles</measure>
    <time_frame>Baseline, 1st month, 3rd month and 6th month after surgery</time_frame>
    <description>Metabolites in blood fluids measured by liquid chromatography mass spectrometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of Immune profiles</measure>
    <time_frame>Baseline, 1st month, 3rd month and 6th month after surgery</time_frame>
    <description>Immune cell phenotype patterns in body fluids measured by flow cytometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of gut permeability test</measure>
    <time_frame>Baseline and 6 months after bariatric surgery</time_frame>
    <description>Lactulose/Mannitol challenge test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of gene expression profiles of liver tissue</measure>
    <time_frame>Baseline and 6 months after bariatric surgery (if available)</time_frame>
    <description>gene expression measured by RNA-seq</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of metabolomic profiles of liver tissue</measure>
    <time_frame>Baseline and 6 months after bariatric surgery (if available)</time_frame>
    <description>Metabolites in liver tissue measured by liquid chromatography mass</description>
  </secondary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Anticipated">140</enrollment>
  <condition>Non-Alcoholic Fatty Liver Disease</condition>
  <condition>Non-Alcoholic Steatohepatitis</condition>
  <condition>Bariatric Surgery</condition>
  <arm_group>
    <arm_group_label>Obese patients tissue proved NASH</arm_group_label>
    <description>age &gt;20，morbid obesity who will receive bariatric surgery, tissue proved NASH</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Obese patients tissue proved NAFL</arm_group_label>
    <description>age &gt;20，morbid obesity who will receive bariatric surgery, tissue proved NAFL</description>
  </arm_group>
  <arm_group>
    <arm_group_label>NASH (before bariatric surgery)</arm_group_label>
    <description>age &gt;20，morbid obesity receiving bariatric surgery and was proved NASH histologically. Data collected before bariatric surgery.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>NASH (after bariatric surgery)</arm_group_label>
    <description>age &gt;20，morbid obesity receiving bariatric surgery and was proved NASH histologically. Data collected after bariatric surgery.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Bariatric surgery</intervention_name>
    <description>Bariatric surgery</description>
    <arm_group_label>NASH (after bariatric surgery)</arm_group_label>
    <arm_group_label>NASH (before bariatric surgery)</arm_group_label>
    <other_name>Liver biopsy</other_name>
    <other_name>Portal vein sampling</other_name>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Peripheral blood and portal vein (during operation) samples will be collected in this study.&#xD;
      Plasma for biochemistry and metabolomics measurement, Buffy coat for NAFLD-susceptible single&#xD;
      nucleotide polymorphism (SNP) detection (i.e. PNPLA3, TM6SF2...etc), peripheral blood&#xD;
      mononuclear cell (PBMC) for flow cytometry, urine samples for lactulose/mannitol measurement&#xD;
      (gut permeability test), fecal samples for metagenomics and metabolomics studies.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Morbidly obese patients who planned to receive bariatric surgery&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Age &gt;20，morbidly obese patients who will receive bariatric surgery.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Average daily alcohol intake &gt;20 grams,&#xD;
&#xD;
          -  Hepatitis B carriers, Hepatitis C carriers,&#xD;
&#xD;
          -  people with liver disease caused by other causes&#xD;
&#xD;
          -  liver cirrhosis,&#xD;
&#xD;
          -  diseases related to abnormal blood coagulation,&#xD;
&#xD;
          -  inflammatory bowel disease,&#xD;
&#xD;
          -  routine use of steroids or immunity Inhibitors and other immunomodulatory drugs&#xD;
&#xD;
          -  ursodeoxycholic and other drugs that affect bile acid metabolism&#xD;
&#xD;
          -  those who have used antibiotics or probiotics within one month&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ming-Shiang Wu, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Taiwan University Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Wei-Kai Wu</last_name>
    <phone>+886-2-23717101</phone>
    <email>weikaiwu0115@gmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>National Taiwan University Hospital</name>
      <address>
        <city>Taipei</city>
        <zip>100</zip>
        <country>Taiwan</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ming-Shiang Wu, MD, PhD</last_name>
      <phone>+886-2-23123456</phone>
      <phone_ext>65043</phone_ext>
      <email>mingshiang@ntu.edu.tw</email>
    </contact>
  </location>
  <location_countries>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>July 22, 2020</study_first_submitted>
  <study_first_submitted_qc>August 2, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 6, 2020</study_first_posted>
  <last_update_submitted>September 25, 2022</last_update_submitted>
  <last_update_submitted_qc>September 25, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 27, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Non-Alcoholic Steatohepatitis</keyword>
  <keyword>Bariatric Surgery</keyword>
  <keyword>Gut Microbiota</keyword>
  <keyword>Gut-Liver Axis</keyword>
  <keyword>Metabolomics</keyword>
  <keyword>Metagenomics</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>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT04501042
org study id: 201903037RIND
nct id: NCT04501042
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease.
      Non-alcoholic steatohepatitis (NASH) is an aggressive form of NAFLD with remarkable
      inflammatory features which may cause advanced fibrosis and liver cancer. So far there is no
      FDA-approved drug for treating NASH. A 10% weight loss by life style modification is a
      standard recommendation to treat NASH which achieves only 10-20% success rate in clinical
      practice. Thus, the development of therapeutics to prevent and treat NASH is certainly an
      unmet need. For now, the mechanism of how simple steatosis progresses to NASH remains unclear
      and accumulating evidences suggest the role of gut microbiota may be essential. Studies have
      also noted the bariatric surgery effectively improve diabetes and NASH with significant
      alterations in the composition and function of gut microbiome. In this study, the
      investigators aim to investigate the role of gut microbiota in the pathophysiology of NASH by
      comparing NAFLD severity, gut microbiome, metabolomics, immune profiles among patients before
      and after the bariatric surgery. With these efforts, the investigators wish to decipher the
      mechanism of how bariatric surgery may improve NASH through changing the gut microbiota and
      find out microbe-associated molecular signatures between NASH and NAFLD through this study.
The investigators anticipate to recruit 140 morbidly obese patients who will receive
      bariatric surgery including 100 patients receiving sleeve gastrectomy (SG) and 40 receiving
      gastric bypass surgery (GB). Liver biopsy will be performed during the operation to confirm
      the histological scores of NAFLD severity. The investigators expect to have 50% NASH and 50%
      NAFL patients from these morbidly obese patients based on previous domestic data. (i.e. 50
      patients receiving SG to have NASH and 50 patients receiving SG to have NAFL; 20 patients
      receiving GB to have NASH and 20 patients receiving GB to have NAFL.) In this study, the
      investigators have two study objectives which are as follows.

        1. The first objective is to discover potential mechanisms among gut-liver axis for
           preventing or promoting NAFL to NASH by comparing (1) fecal microbiome composition and
           metabolomics, (2) peripheral blood biochemistry, metabolomics, immune cell phenotypes,
           and cytokines (3) portal vein biochemistry, metabolomics, immune cell phenotypes, and
           cytokines (4) Liver metabolomics and RNA-seq (5) gut permeability test
           (lactulose/mannitol challenge) (6) host genetic susceptibility for NAFLD (PNPLA3 and
           TM6SF2) between the tissue-proved NASH and NAFL patients in this study with a
           cross-sectional comparison.

        2. The second objective is to longitudinally investigate the potential mechanisms of
           bariatric surgery for improving NASH via a gut-microbiota dependent pathway. Clinical
           and experimental data before (baseline) and after (1st, 3rd, 6th months) bariatric
           surgery will be collected which include (1) non-invasive evaluation of NAFLD severity
           (Fibroscan, MRI-PDFF (proton density fat fraction) and MRE), (2) blood biochemistry,
           metabolomics, immune cell phenotypes, and cytokines (3) fecal microbiome and
           metabolomics (4) gut permeability test (5) liver biopsy histology (if available)
observational model: Case-Control
time perspective: Prospective
measure: Change of NAFLD severity score (histology) from baseline to the 6th month
time frame: Baseline and 6 months after bariatric surgery
description: Liver biopsy will be performed before and after surgery (if available) to acquire histology evaluation
measure: Change of NAFLD severity measured by Fibroscan from baseline to the 6th month
time frame: Baseline and 6 months after bariatric surgery
description: Fibroscan (CAP and kPa)
measure: Change of NAFLD severity measured by MRI proton density fat fraction from baseline to the
time frame: Baseline and 6 months after bariatric surgery
description: MRI proton density fat fraction (%)
measure: Change of NAFLD severity measured by magnetic resonance elastography from baseline to the
time frame: Baseline and 6 months after bariatric surgery
description: magnetic resonance elastography (kPa)
measure: Change of gut microbiome profiles
time frame: Baseline, 1st month, 3rd month and 6th month after surgery
description: fecal 16S ribosomal RNA sequencing and shotgun metagenome sequencing
measure: Change of body fluid metabolomic profiles
time frame: Baseline, 1st month, 3rd month and 6th month after surgery
description: Metabolites in blood fluids measured by liquid chromatography mass spectrometry
measure: Change of Immune profiles
time frame: Baseline, 1st month, 3rd month and 6th month after surgery
description: Immune cell phenotype patterns in body fluids measured by flow cytometry
measure: Change of gut permeability test
time frame: Baseline and 6 months after bariatric surgery
description: Lactulose/Mannitol challenge test
measure: Change of gene expression profiles of liver tissue
time frame: Baseline and 6 months after bariatric surgery (if available)
description: gene expression measured by RNA-seq
measure: Change of metabolomic profiles of liver tissue
time frame: Baseline and 6 months after bariatric surgery (if available)
description: Metabolites in liver tissue measured by liquid chromatography mass
arm group label: Obese patients tissue proved NASH
description: age >20，morbid obesity who will receive bariatric surgery, tissue proved NASH
arm group label: Obese patients tissue proved NAFL
description: age >20，morbid obesity who will receive bariatric surgery, tissue proved NAFL
arm group label: NASH (before bariatric surgery)
description: age >20，morbid obesity receiving bariatric surgery and was proved NASH histologically. Data collected before bariatric surgery.
arm group label: NASH (after bariatric surgery)
description: age >20，morbid obesity receiving bariatric surgery and was proved NASH histologically. Data collected after bariatric surgery.
intervention type: Procedure
intervention name: Bariatric surgery
description: Bariatric surgery
arm group label: NASH (after bariatric surgery)
arm group label: NASH (before bariatric surgery)
other name: Liver biopsy
other name: Portal vein sampling
Peripheral blood and portal vein (during operation) samples will be collected in this study.
      Plasma for biochemistry and metabolomics measurement, Buffy coat for NAFLD-susceptible single
      nucleotide polymorphism (SNP) detection (i.e. PNPLA3, TM6SF2...etc), peripheral blood
      mononuclear cell (PBMC) for flow cytometry, urine samples for lactulose/mannitol measurement
      (gut permeability test), fecal samples for metagenomics and metabolomics studies.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 20 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Ming-Shiang Wu, MD, PhD
role: Principal Investigator
affiliation: National Taiwan University Hospital
last name: Wei-Kai Wu
phone: +886-2-23717101
email: weikaiwu0115@gmail.com
facility: 
status: Recruiting
contact: 
country: Taiwan
responsible party type: Sponsor
mesh term: Liver Diseases
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
sharing ipd: No