<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/NCT04465032</url>
  </required_header>
  <id_info>
    <org_study_id>GE17-05</org_study_id>
    <nct_id>NCT04465032</nct_id>
  </id_info>
  <brief_title>The Effect of Consecutive Fecal Microbiota Transplantation on Non-Alcoholic Fatty Liver Disease (NAFLD)</brief_title>
  <acronym>NAFTx</acronym>
  <official_title>The Effect of Consecutive Fecal Microbiota Transplantation on Non-Alcoholic Fatty Liver Disease (NAFLD) - a Randomized-controlled Trial -</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Leiden University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Dutch Donor Feces Bank</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Vedanta Biosciences</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Leiden University Medical Center</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>
      Nonalcoholic fatty liver disease (NAFLD) is a disease of alarmingly increasing prevalence,&#xD;
      linked to metabolic, cardiovascular and malignant morbidity and without any officially&#xD;
      approved treatment. It is increasingly recognized that the gut microbiome is implicated in&#xD;
      the pathogenesis and progression of numerous chronic diseases, including NAFLD. Through the&#xD;
      so-called gut-liver axis, the liver is exposed to gut-bacterial-derived products, including&#xD;
      toxins (lipopolysaccharides), enzymes (methylamines), alcohol, and short-chain fatty acids&#xD;
      (mainly acetate, propionate, and butyrate), that may lead to accumulation of triglycerides,&#xD;
      inflammatory responses, oxidative stress and accompanying damage to the hepatocytes. The&#xD;
      primary objective is to study the effect of consecutive FMT on liver fat accumulation&#xD;
      measured by Magnetic Resonance Images (MRI) LiverMultiscan at 12 weeks. Secondary objectives&#xD;
      are weight, waist, blood pressure, metabolic parameters (including glucose, cholesterol,&#xD;
      pancreatic beta-cell function, HOMA-IR), objective and subjective stress indicators,&#xD;
      gut-microbiota and bile composition and liver enzymes. Stool samples will be collected for&#xD;
      microbiota analysis at time point 0, 3, 6 and 12 weeks.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Nonalcoholic fatty liver disease (NAFLD) is a disease of alarmingly increasing prevalence,&#xD;
      linked to metabolic, cardiovascular and malignant morbidity and without any officially&#xD;
      approved treatment. It is increasingly recognized that the gut microbiome is implicated in&#xD;
      the pathogenesis and progression of numerous chronic diseases, including NAFLD. Through the&#xD;
      so-called gut-liver axis, the liver is exposed to gut-bacterial-derived products, including&#xD;
      toxins (lipopolysaccharides), enzymes (methylamines), alcohol, and short-chain fatty acids&#xD;
      (mainly acetate, propionate, and butyrate), that may lead to accumulation of triglycerides,&#xD;
      inflammatory responses, oxidative stress and accompanying damage to the hepatocytes. The&#xD;
      investigators hypothesize that altered gut microbiota underlie (hepatic) insulin resistance&#xD;
      and liver fat accumulation in NAFLD patients. Fecal microbiota transplantation, through&#xD;
      amelioration of gut-microbiota released products like lipopolysaccharides, short-chain fatty&#xD;
      acids, alcohol and enzymes, and changes in bile acids, may positively affect NAFLD.&#xD;
&#xD;
      During the study 20 patients will be randomized for infusion of allogenic (lean donor) or&#xD;
      autologous (own) feces by gastroscopy at time points 0, 3 and 6 weeks on a 1:1 basis. Prior&#xD;
      to randomization, and at 12 weeks, all patients will undergo LiverMultiscan to non-invasively&#xD;
      quantify liver fat accumulation and other features of NAFLD. In addition, various metabolic&#xD;
      parameters (lipids, HOMA-IR), objective and subjective stress indicators, gut-microbiota and&#xD;
      bile composition, and liver enzymes will be measured.&#xD;
&#xD;
      The primary objective is to study the effect on consecutive FMT on liver fat accumulation&#xD;
      measured by Magnetic Resonance Images (MRI) LiverMultiscan at 12 weeks. Secondary objectives&#xD;
      are alterations in anthropometrical data (weight, waist, blood pressure), changes in fecal&#xD;
      microbiota, liver enzymes, bile composition and metabolic parameters including glucose,&#xD;
      lipids, pancreatic beta-cell function and insulin resistance measured as HOMA-IR and&#xD;
      objective and subjective stress indicators.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">December 10, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2021</completion_date>
  <primary_completion_date type="Anticipated">March 31, 2021</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>
    <intervention_model_description>Double-blinded randomized controlled trial, randomization 1:1 to allogenic and autologous gut microbiome transplantation</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Double-blinded RCT, randomization by Dutch Donor Feces Bank</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>the effect on consecutive FMT on liver fat accumulation</measure>
    <time_frame>12 weeks</time_frame>
    <description>measured by MRI Livermultiscan</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>alterations in anthropometric data</measure>
    <time_frame>3, 6 and 12 weeks</time_frame>
    <description>differences in weight in kilograms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>alterations in anthropometric data</measure>
    <time_frame>3, 6 and 12 weeks</time_frame>
    <description>differences in systolic and diastolic blood pressure in mmHg</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>alterations in anthropometric data</measure>
    <time_frame>3, 6 and 12 weeks</time_frame>
    <description>differences in waist in centimeters</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>alterations in pancreatic beta-cell function and insulin resistance</measure>
    <time_frame>3, 6 and 12 weeks</time_frame>
    <description>measured by plasma C-peptide in nmol/L derived during OGTT + arginin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>alterations in pancreatic beta-cell function and insulin resistance</measure>
    <time_frame>3, 6 and 12 weeks</time_frame>
    <description>measured by glucose in mmol/L derived during OGTT + arginin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>alterations in pancreatic beta-cell function and insulin resistance</measure>
    <time_frame>3, 6 and 12 weeks</time_frame>
    <description>measured by insulin in mU/L derived during OGTT + arginin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>alterations in liver enzymes</measure>
    <time_frame>3, 6 and 12 weeks</time_frame>
    <description>Aspartaat aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma glutamyl transpeptidase (GGT), alkalic phosphatase (AF), bilirubin</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>change in bile composition</measure>
    <time_frame>3 and 6 weeks</time_frame>
    <description>measured using endoscopic bile samples (qualitative measurements)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>change in bacterial species in small intestine and feces</measure>
    <time_frame>3 and 6 weeks</time_frame>
    <description>measured by endoscopic duodenal biopsies and fecal samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>changes in lipid homeostasis</measure>
    <time_frame>3, 6 and 12 weeks</time_frame>
    <description>cholesterol, HDL, LDL, triglycerides</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>alterations in psychological stress</measure>
    <time_frame>0 and 12 weeks</time_frame>
    <description>by measuring cortisol levels in hair samples</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>alterations in psychological stress</measure>
    <time_frame>week 1, week 4, week 7, week 9 during 7 days</time_frame>
    <description>by reporting psychological stress daily using stress diaries on a scale from 1-10 (non-validated scale)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>alterations in psychological stress</measure>
    <time_frame>0 and 12 weeks</time_frame>
    <description>by Perceived Stres Scale (PSS) questionnaires, scores on a scale from 0-40</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>changes in physical activity</measure>
    <time_frame>during 14 weeks</time_frame>
    <description>measuring physical activity by steps with FitBit activity tracker</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>changes in physical activity</measure>
    <time_frame>during 14 weeks</time_frame>
    <description>measuring physical activity by active minutes with FitBit activity tracker</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>changes in physical activity</measure>
    <time_frame>during 14 weeks</time_frame>
    <description>measuring physical activity by heart rate with FitBit activity tracker</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>NAFLD</condition>
  <arm_group>
    <arm_group_label>Autologous gut microbiome transplantation</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Three autologous (own) fecal transplantations (at baseline, 3 and 6 weeks)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Allogenic gut microbiome transplantation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Three allogenic (lean donor) fecal transplantations (at baseline, 3 and 6 weeks)</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Gut microbiome transplantation</intervention_name>
    <description>Fecal transplantation will be performed at baseline and at week 3 and 6. At the Department of Clinical Bacteriology either the autologous or allogenic feces is prepared for donation by an experienced lab co-worker. The fecal transplantation will be performed via gastroduodenal endoscopy at the Department of Gastroenterology by an experienced endoscopist. To alleviate the procedure, midazolam is offered to the participants. Following placement of the endoscope in the horizontal duodenum, 150 mL feces solution is inserted via the endoscope.</description>
    <arm_group_label>Allogenic gut microbiome transplantation</arm_group_label>
    <arm_group_label>Autologous gut microbiome transplantation</arm_group_label>
    <other_name>Fecal transplantation</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Obese (BMI &gt; 27 kg/m2)&#xD;
&#xD;
          -  Males and postmenopausal females&#xD;
&#xD;
          -  Aged 18 to 70 years&#xD;
&#xD;
          -  Hepatic steatosis defined as increased hyperechogenicity of the liver on abdominal&#xD;
             ultrasound and/or histological signs of steatosis&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Exclusion criteria for MRI (claustrophobia, pacemaker, metal implants, etc)&#xD;
&#xD;
          -  Any other liver disease than NAFLD/NASH&#xD;
&#xD;
          -  Present excessive alcohol use defined as &gt; 2 units/day&#xD;
&#xD;
          -  Recent use (&lt; 3 months) of antibiotics&#xD;
&#xD;
          -  use of possible drugs interfering microbiota or recent (&lt; 3 months) changes in dosages&#xD;
&#xD;
          -  use of GLP-1 RA or SU-derivatives&#xD;
&#xD;
          -  Recent (&lt; 3 months) weight change (&gt;5%)&#xD;
&#xD;
          -  Cardiovascular co-morbidity defined as heart failure, coronary insufficiency and&#xD;
             hypertension in past history&#xD;
&#xD;
          -  Previous use of glucocorticosteroids, hormonal substitution, pagitaxel, theofyllin,&#xD;
             amiodarone, myelosuppresive agents.&#xD;
&#xD;
          -  A psychiatric, addictive or any other disorder that compromises the subjects ability&#xD;
             to understand the study content and to give written informed consent for participation&#xD;
             in the study&#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_contact>
    <last_name>Maarten Tushuizen, MD PhD</last_name>
    <phone>+31 71 5263541</phone>
    <email>m.e.tushuizen@lumc.nl</email>
  </overall_contact>
  <location>
    <facility>
      <name>Leiden University Medical Center</name>
      <address>
        <city>Leiden</city>
        <zip>2333 ZA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Maarten Tushuizen, MD, PhD</last_name>
      <email>m.e.tushuizen@lumc.nl</email>
    </contact>
    <contact_backup>
      <last_name>Merel Ruissen, MD</last_name>
      <email>m.m.ruissen@lumc.nl</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>January 8, 2020</study_first_submitted>
  <study_first_submitted_qc>July 7, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 9, 2020</study_first_posted>
  <last_update_submitted>July 7, 2020</last_update_submitted>
  <last_update_submitted_qc>July 7, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 9, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Leiden University Medical Center</investigator_affiliation>
    <investigator_full_name>metushuizen</investigator_full_name>
    <investigator_title>Principle investigator</investigator_title>
  </responsible_party>
  <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/NCT04465032
org study id: GE17-05
nct id: NCT04465032
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Nonalcoholic fatty liver disease (NAFLD) is a disease of alarmingly increasing prevalence,
      linked to metabolic, cardiovascular and malignant morbidity and without any officially
      approved treatment. It is increasingly recognized that the gut microbiome is implicated in
      the pathogenesis and progression of numerous chronic diseases, including NAFLD. Through the
      so-called gut-liver axis, the liver is exposed to gut-bacterial-derived products, including
      toxins (lipopolysaccharides), enzymes (methylamines), alcohol, and short-chain fatty acids
      (mainly acetate, propionate, and butyrate), that may lead to accumulation of triglycerides,
      inflammatory responses, oxidative stress and accompanying damage to the hepatocytes. The
      primary objective is to study the effect of consecutive FMT on liver fat accumulation
      measured by Magnetic Resonance Images (MRI) LiverMultiscan at 12 weeks. Secondary objectives
      are weight, waist, blood pressure, metabolic parameters (including glucose, cholesterol,
      pancreatic beta-cell function, HOMA-IR), objective and subjective stress indicators,
      gut-microbiota and bile composition and liver enzymes. Stool samples will be collected for
      microbiota analysis at time point 0, 3, 6 and 12 weeks.
Nonalcoholic fatty liver disease (NAFLD) is a disease of alarmingly increasing prevalence,
      linked to metabolic, cardiovascular and malignant morbidity and without any officially
      approved treatment. It is increasingly recognized that the gut microbiome is implicated in
      the pathogenesis and progression of numerous chronic diseases, including NAFLD. Through the
      so-called gut-liver axis, the liver is exposed to gut-bacterial-derived products, including
      toxins (lipopolysaccharides), enzymes (methylamines), alcohol, and short-chain fatty acids
      (mainly acetate, propionate, and butyrate), that may lead to accumulation of triglycerides,
      inflammatory responses, oxidative stress and accompanying damage to the hepatocytes. The
      investigators hypothesize that altered gut microbiota underlie (hepatic) insulin resistance
      and liver fat accumulation in NAFLD patients. Fecal microbiota transplantation, through
      amelioration of gut-microbiota released products like lipopolysaccharides, short-chain fatty
      acids, alcohol and enzymes, and changes in bile acids, may positively affect NAFLD.

      During the study 20 patients will be randomized for infusion of allogenic (lean donor) or
      autologous (own) feces by gastroscopy at time points 0, 3 and 6 weeks on a 1:1 basis. Prior
      to randomization, and at 12 weeks, all patients will undergo LiverMultiscan to non-invasively
      quantify liver fat accumulation and other features of NAFLD. In addition, various metabolic
      parameters (lipids, HOMA-IR), objective and subjective stress indicators, gut-microbiota and
      bile composition, and liver enzymes will be measured.

      The primary objective is to study the effect on consecutive FMT on liver fat accumulation
      measured by Magnetic Resonance Images (MRI) LiverMultiscan at 12 weeks. Secondary objectives
      are alterations in anthropometrical data (weight, waist, blood pressure), changes in fecal
      microbiota, liver enzymes, bile composition and metabolic parameters including glucose,
      lipids, pancreatic beta-cell function and insulin resistance measured as HOMA-IR and
      objective and subjective stress indicators.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Double-blinded randomized controlled trial, randomization 1:1 to allogenic and autologous gut microbiome transplantation
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Double-blinded RCT, randomization by Dutch Donor Feces Bank
measure: the effect on consecutive FMT on liver fat accumulation
time frame: 12 weeks
description: measured by MRI Livermultiscan
measure: alterations in anthropometric data
time frame: 3, 6 and 12 weeks
description: differences in weight in kilograms
measure: alterations in anthropometric data
time frame: 3, 6 and 12 weeks
description: differences in systolic and diastolic blood pressure in mmHg
measure: alterations in anthropometric data
time frame: 3, 6 and 12 weeks
description: differences in waist in centimeters
measure: alterations in pancreatic beta-cell function and insulin resistance
time frame: 3, 6 and 12 weeks
description: measured by plasma C-peptide in nmol/L derived during OGTT + arginin
measure: alterations in pancreatic beta-cell function and insulin resistance
time frame: 3, 6 and 12 weeks
description: measured by glucose in mmol/L derived during OGTT + arginin
measure: alterations in pancreatic beta-cell function and insulin resistance
time frame: 3, 6 and 12 weeks
description: measured by insulin in mU/L derived during OGTT + arginin
measure: alterations in liver enzymes
time frame: 3, 6 and 12 weeks
description: Aspartaat aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma glutamyl transpeptidase (GGT), alkalic phosphatase (AF), bilirubin
measure: change in bile composition
time frame: 3 and 6 weeks
description: measured using endoscopic bile samples (qualitative measurements)
measure: change in bacterial species in small intestine and feces
time frame: 3 and 6 weeks
description: measured by endoscopic duodenal biopsies and fecal samples
measure: changes in lipid homeostasis
time frame: 3, 6 and 12 weeks
description: cholesterol, HDL, LDL, triglycerides
measure: alterations in psychological stress
time frame: 0 and 12 weeks
description: by measuring cortisol levels in hair samples
measure: alterations in psychological stress
time frame: week 1, week 4, week 7, week 9 during 7 days
description: by reporting psychological stress daily using stress diaries on a scale from 1-10 (non-validated scale)
measure: alterations in psychological stress
time frame: 0 and 12 weeks
description: by Perceived Stres Scale (PSS) questionnaires, scores on a scale from 0-40
measure: changes in physical activity
time frame: during 14 weeks
description: measuring physical activity by steps with FitBit activity tracker
measure: changes in physical activity
time frame: during 14 weeks
description: measuring physical activity by active minutes with FitBit activity tracker
measure: changes in physical activity
time frame: during 14 weeks
description: measuring physical activity by heart rate with FitBit activity tracker
arm group label: Autologous gut microbiome transplantation
arm group type: Active Comparator
description: Three autologous (own) fecal transplantations (at baseline, 3 and 6 weeks)
arm group label: Allogenic gut microbiome transplantation
arm group type: Experimental
description: Three allogenic (lean donor) fecal transplantations (at baseline, 3 and 6 weeks)
intervention type: Other
intervention name: Gut microbiome transplantation
description: Fecal transplantation will be performed at baseline and at week 3 and 6. At the Department of Clinical Bacteriology either the autologous or allogenic feces is prepared for donation by an experienced lab co-worker. The fecal transplantation will be performed via gastroduodenal endoscopy at the Department of Gastroenterology by an experienced endoscopist. To alleviate the procedure, midazolam is offered to the participants. Following placement of the endoscope in the horizontal duodenum, 150 mL feces solution is inserted via the endoscope.
arm group label: Allogenic gut microbiome transplantation
arm group label: Autologous gut microbiome transplantation
other name: Fecal transplantation
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Maarten Tushuizen, MD PhD
phone: +31 71 5263541
email: m.e.tushuizen@lumc.nl
facility: 
status: Recruiting
contact: 
contact backup: 
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: Leiden University Medical Center
investigator full name: metushuizen
investigator title: Principle investigator
mesh term: Liver Diseases
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
sharing ipd: No