<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/NCT01680640</url>
  </required_header>
  <id_info>
    <org_study_id>RHM MED1071</org_study_id>
    <nct_id>NCT01680640</nct_id>
  </id_info>
  <brief_title>Investigation of Synbiotic Treatment in NAFLD</brief_title>
  <acronym>INSYTE</acronym>
  <official_title>Investigation of the Effects of a Synbiotic on Liver Fat, Disease Biomarkers and Intestinal Microbiota in Non-alcoholic Fatty Liver Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital Southampton NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute for Health Research, United Kingdom</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital Southampton NHS Foundation Trust</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Non-alcoholic fatty liver disease (NAFLD) is a liver condition in which fat builds up in the&#xD;
      liver not caused by alcohol. The liver is an organ that is not designed to build up fat.&#xD;
      NAFLD is common in people who have too much body fat in their abdomen or who have diabetes&#xD;
      (high blood sugar), but does not always exist with these conditions. NAFLD can also occur in&#xD;
      thin people too. NAFLD can be harmful to the liver and may cause the liver to fail over time.&#xD;
      NAFLD may also cause adult (or type 2) diabetes and also heart disease. In people who already&#xD;
      have diabetes, NAFLD can cause glucose (sugar) levels to be too high.&#xD;
&#xD;
      Our intestines (guts) contain healthy bacteria and some harmful bacteria (bugs). This balance&#xD;
      of healthy and harmful bugs is essential for the normal workings of our intestine to digest&#xD;
      food. Providing these bacteria do not leak out into the blood they do not cause harm. If the&#xD;
      balance of healthy to harmful bugs is upset, the harmful can cause problems and leak out into&#xD;
      the blood. Because the liver is connected to the intestine by blood vessels the harmful&#xD;
      bacteria can get to the liver and cause problems. These bacteria can cause the liver and the&#xD;
      body to build up too much fat and might cause NAFLD and obesity. In this study, we will test&#xD;
      the effects of a supplement (synbiotic) taken during the day, that contains a mixture of&#xD;
      'good' healthy bacteria (probiotic) and a sugar (prebiotic) that is not broken down and&#xD;
      absorbed into the blood. We will test whether the synbiotic supplement has beneficial effects&#xD;
      on the NAFLD liver condition and on factors linked to too much body fat, diabetes and heart&#xD;
      disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      We will recruit people with NAFLD who have been diagnosed as part of their NHS (National&#xD;
      Health Service) care with having this condition. At present there is no treatment for this&#xD;
      condition.&#xD;
&#xD;
      Purpose and design:&#xD;
&#xD;
      We are asking the research question: &quot;Does the modulation of gut microflora with a synbiotic&#xD;
      improve non-alcoholic fatty liver disease and the related risk factors for heart disease and&#xD;
      type 2 diabetes?&quot;&#xD;
&#xD;
      Presently there is no treatment for this liver condition. Research evidence suggests that a&#xD;
      synbiotic supplement might be beneficial for this condition.&#xD;
&#xD;
      To address this research question we want to undertake a randomised double blind placebo&#xD;
      controlled trial recruiting people who have been diagnosed with NAFLD.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>December 2013</start_date>
  <completion_date type="Actual">January 2019</completion_date>
  <primary_completion_date type="Actual">January 2019</primary_completion_date>
  <phase>N/A</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>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Liver Fat</measure>
    <time_frame>baseline and 12 months</time_frame>
    <description>Change in liver fat percent was calculated as the percent liver fat at the end of the study, minus the percent of liver fat prior to the intervention. Change in liver fat percent ranged from -60.6% (good) to + 33.7% (bad).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Enhanced Liver Fibrosis Score (ELF)</measure>
    <time_frame>baseline and 12 months</time_frame>
    <description>Change in Enhanced Liver Fibrosis score (ELF) was calculated as ELF score at the end of the study minus ELF score prior to the intervention (at baseline). A decrease in the ELF score was considered good as it reflected a decrease in liver fibrosis, and an increase in ELF score was considered bad as it reflected an increase in liver fibrosis.&#xD;
Change in ELF scores ranged from -0.56 (good) to + 0.68 (bad).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in NAFLD Fibrosis Score</measure>
    <time_frame>baseline and 12 months</time_frame>
    <description>Change in NAFLD Fibrosis Score (NFS) was calculated as the NFS score at the end of the study, minus NFS score prior to the intervention (at baseline). A decrease in the NFS score was considered good because it reflected a decrease in liver fibrosis, and an increase in NFS score was considered bad, as it reflected an increase in liver fibrosis.&#xD;
Change in NFS scores ranged from -2.07 (good) to + 1.75 (bad)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Bifidobacterium Spp.</measure>
    <time_frame>baseline and 12 months</time_frame>
    <description>The change in percent of Bifidobacteria spp was computed as the percent of Bifidobactera spp at the end of the study minus the percent of Bifidobacteria prior to the intervention (at baseline).&#xD;
A positive change in percent (e.g +0.1 to 7.0%) in Bifidobacteria spp. was considered good and a negative change in percent (e.g. -0.1 to -0.5%) in Bifidobacteria spp. considered bad. (Minimum = -0.5% (bad) and Maximum = +7.0% (good)).</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">104</enrollment>
  <condition>Non-Alcoholic Fatty Liver Disease</condition>
  <arm_group>
    <arm_group_label>Synbiotic</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Fructo-oligosacharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis (BB-12) as minimum of 10 billion colony forming unit (CFU)/day (1 capsule a day).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Maltodextrin</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>4 grams of maltodextrin daily.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Synbiotic</intervention_name>
    <description>The synbiotic to be used is fructo-oligosacharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).</description>
    <arm_group_label>Synbiotic</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Maltodextrin</intervention_name>
    <arm_group_label>Maltodextrin</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Both men and women&#xD;
&#xD;
          -  Age &gt; 18 years&#xD;
&#xD;
          -  Liver fat diagnosed on normal clinical grounds including in most cases liver assessed&#xD;
             by Kleiner scoring system to classify severity, with no known aetiological factors for&#xD;
             underlying liver disease (e.g. exclusion of hepatitis A, B &amp; C, primary biliary&#xD;
             cirrhosis, autoimmune hepatitis, haemochromatosis). Last liver biopsy will be within 3&#xD;
             years of recruitment to the study.&#xD;
&#xD;
          -  Liver fat diagnosed by ultrasound, CT or magnetic resonance imaging (MRI) in patients&#xD;
             who also have either diabetes and/or features of the metabolic syndrome, without&#xD;
             evidence of known aetiological factors for underlying liver disease (e.g. exclusion of&#xD;
             hepatitis A, B &amp; C, primary biliary cirrhosis, autoimmune hepatitis,&#xD;
             haemochromatosis).&#xD;
&#xD;
          -  Alcohol consumption ≤ 14 units / week for women ≤ 21 units / week for men.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Alcohol consumption &gt; 15 units /week for women and &gt; 22 units /week for men.&#xD;
&#xD;
          -  Decompensated acute or chronic liver disease.&#xD;
&#xD;
          -  A history of viral hepatitis, diarrhoea, diverticulosis, irritable bowel syndrome,&#xD;
             inflammatory bowel diseases, coeliac disease (seropositivity for anti-endomysial&#xD;
             immunoglobulin A antibodies; immunoglobulin A (IgA) EMA).&#xD;
&#xD;
          -  Previous bariatric or other abdominal surgery.&#xD;
&#xD;
          -  Continuous use of antibiotics that may change gut microflora, probiotics, or&#xD;
             antisecretory drugs capable of causing achlorhydria within the 2 months preceding&#xD;
             enrolment, or evidence of immunoglobulin A or immunoglobulin deficiency (both of which&#xD;
             produce confounding effects during assessments of intestinal permeability and small&#xD;
             intestinal bacterial overgrowth).&#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>Christopher D Byrne, MBBCh, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Southampton/University Hospital Southampton NHS Foundation Trust</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Southamption General Hospital</name>
      <address>
        <city>Southampton</city>
        <state>Hants</state>
        <zip>SO166YD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>August 24, 2012</study_first_submitted>
  <study_first_submitted_qc>September 6, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 7, 2012</study_first_posted>
  <results_first_submitted>May 27, 2020</results_first_submitted>
  <results_first_submitted_qc>January 19, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">February 5, 2021</results_first_posted>
  <last_update_submitted>January 19, 2021</last_update_submitted>
  <last_update_submitted_qc>January 19, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">February 5, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>non alcoholic fatty liver disease</keyword>
  <keyword>NAFLD</keyword>
  <keyword>synbiotic</keyword>
  <keyword>gut microbiota</keyword>
  <keyword>intervention</keyword>
  <keyword>RCT (Randomized Clinical Trial)</keyword>
  <keyword>biomarkers</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>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>July 31, 2014</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/40/NCT01680640/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 4, 2014</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/40/NCT01680640/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Synbiotic</title>
          <description>Fructo-oligosaccharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).&#xD;
Synbiotic: The synbiotic to be used is fructo-oligosachharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).</description>
        </group>
        <group group_id="P2">
          <title>Maltodextrin</title>
          <description>4 grams of maltodextrin daily.&#xD;
Maltodextrin</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="55"/>
                <participants group_id="P2" count="49"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="45"/>
                <participants group_id="P2" count="44"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>The ITT analysis included all patients randomized who had baseline and end-of-study measurements, regardless of whether they were later found to be ineligible, a protocol violator, given the wrong treatment allocation, or never treated.</population>
      <group_list>
        <group group_id="B1">
          <title>Synbiotic</title>
          <description>Fructo-oligosaccharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).&#xD;
Synbiotic: The synbiotic to be used is fructo-oligosaccharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).</description>
        </group>
        <group group_id="B2">
          <title>Maltodextrin</title>
          <description>4 grams of maltodextrin daily.&#xD;
Maltodextrin</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="45"/>
            <count group_id="B2" value="44"/>
            <count group_id="B3" value="89"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="50.2" spread="12.4"/>
                    <measurement group_id="B2" value="51.6" spread="13.1"/>
                    <measurement group_id="B3" value="50.8" spread="12.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="31"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                    <measurement group_id="B2" value="27"/>
                    <measurement group_id="B3" value="58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="45"/>
                    <measurement group_id="B2" value="44"/>
                    <measurement group_id="B3" value="89"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United Kingdom</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="45"/>
                    <measurement group_id="B2" value="44"/>
                    <measurement group_id="B3" value="89"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>percentage liver fat</title>
          <description>This data reflects data collected at the Baseline time point. Liver fat percentage is calculated from magnetic resonance spectroscopy imaging. The percentage of liver fat is calculated from the peak measurement of lipid. Values are recorded on a scale from 0% (no liver fat) to 100% (high liver fat).</description>
          <units>percentage</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="26.9" lower_limit="9.7" upper_limit="38.4"/>
                    <measurement group_id="B2" value="22.9" lower_limit="12.9" upper_limit="44.7"/>
                    <measurement group_id="B3" value="25" lower_limit="24.6" upper_limit="36.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>ELF score</title>
          <description>This data reflects data collected at the Baseline time point. The ELF Score is a liver fibrosis score that is calculated by use of an algorithm: ELF score score = -7.412 + (ln(HA)*0.681) + (ln(P3NP)*0.775) + (ln(TIMP1)*0.494).&#xD;
HA=hyaluronic acid concentration P3NP=procollagen 3 amino terminal peptide concentration TIMP1=tissue inhibitor matrix metalloproteinase 1 concentration. All are measured in serum.&#xD;
Low scores &lt;7.7 are good for excluding fibrosis. High scores &gt;9.8 are good for identifying fibrosis.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6.9" spread="0.4"/>
                    <measurement group_id="B2" value="6.9" spread="0.3"/>
                    <measurement group_id="B3" value="6.9" spread="0.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>NAFLD fibrosis score</title>
          <description>This data reflects data collected at the Baseline time point. NAFLD fibrosis score (NFS) is calculated using the following algorithm: -1.675 +0.037 ×age (years) +0.094 ×BMI (kg/m2) +1.13 × impaired fasting glucose (IFG)/diabetes (yes=1, no=0) +0.99 × aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ratio -0.013 ×platelet (×109/l) -0.66 ×albumin (g/dl).&#xD;
The score is used to classify the probability of fibrosis. A scores &lt; -1.5 indicates a low probability, &gt; -1.5 to &lt; 0.67 indicates intermediate probability, and a score of &gt; 0.67 indicates a high probability of liver fibrosis.</description>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="-1.3" spread="1.3"/>
                    <measurement group_id="B2" value="-1.2" spread="1.3"/>
                    <measurement group_id="B3" value="-1.2" spread="1.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Bifidobacterium spp.</title>
          <description>This data reflects data collected at the Baseline time point. Total bacteria and Bifidobacterium spp. were quantified using quantitative polymerase chain reaction (qPCR). The percentage of Bifidobacteria spp was computed as the percent of Bifidobacteria spp and the denominator was the total number of all bacteria.</description>
          <units>percentage</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0.8" lower_limit="0.3" upper_limit="2.0"/>
                    <measurement group_id="B2" value="0.6" lower_limit="0.1" upper_limit="1.9"/>
                    <measurement group_id="B3" value="0.8" lower_limit="0.2" upper_limit="2.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Liver Fat</title>
        <description>Change in liver fat percent was calculated as the percent liver fat at the end of the study, minus the percent of liver fat prior to the intervention. Change in liver fat percent ranged from -60.6% (good) to + 33.7% (bad).</description>
        <time_frame>baseline and 12 months</time_frame>
        <population>numerical difference between baseline measurement and 12 month measurement</population>
        <group_list>
          <group group_id="O1">
            <title>Synbiotic</title>
            <description>Fructo-oligosaccharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).&#xD;
Synbiotic: The synbiotic to be used is fructo-oligosaccharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).</description>
          </group>
          <group group_id="O2">
            <title>Maltodextrin</title>
            <description>4 grams of maltodextrin daily.&#xD;
Maltodextrin</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Liver Fat</title>
          <description>Change in liver fat percent was calculated as the percent liver fat at the end of the study, minus the percent of liver fat prior to the intervention. Change in liver fat percent ranged from -60.6% (good) to + 33.7% (bad).</description>
          <population>numerical difference between baseline measurement and 12 month measurement</population>
          <units>percentage of liver fat</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="45"/>
                <count group_id="O2" value="44"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.8" lower_limit="-7.98" upper_limit="0.38"/>
                    <measurement group_id="O2" value="-6.0" lower_limit="-10.6" upper_limit="-1.45"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>A total sample size of 100 participants, with a 14% drop out during the study and 43 participants in each group completing the study provided 85% power to detect a difference of 40% in liver fat (in the treatment arm compared with the placebo), using a power calculation test with a 0.05 two-sided significance level. For change in liver fat percentage (and other secondary outcomes), ANCOVA will also be undertaken to assess effect sizes in the intervention group and placebo.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>=0.05</p_value>
            <p_value_desc>The threshold for statistical significance was p=0.05</p_value_desc>
            <method>Regression, Linear</method>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>-3.8</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.8</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>For each primary outcome, a change variable was calculated as the difference between end of study and baseline measurements. Multiple regression analysis was used to assess the effect of synbiotic treatment on each of the change variables of interest.</non_inferiority_desc>
            <p_value>&lt;0.001</p_value>
            <method>Regression, Linear</method>
            <param_type>Median Difference (Final Values)</param_type>
            <param_value>-1.7</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change in Enhanced Liver Fibrosis Score (ELF)</title>
        <description>Change in Enhanced Liver Fibrosis score (ELF) was calculated as ELF score at the end of the study minus ELF score prior to the intervention (at baseline). A decrease in the ELF score was considered good as it reflected a decrease in liver fibrosis, and an increase in ELF score was considered bad as it reflected an increase in liver fibrosis.&#xD;
Change in ELF scores ranged from -0.56 (good) to + 0.68 (bad).</description>
        <time_frame>baseline and 12 months</time_frame>
        <population>numerical difference between baseline measurement and 12 month measurement</population>
        <group_list>
          <group group_id="O1">
            <title>Synbiotic</title>
            <description>Fructo-oligosaccharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).&#xD;
Synbiotic: The synbiotic to be used is fructo-oligosaccharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).</description>
          </group>
          <group group_id="O2">
            <title>Maltodextrin</title>
            <description>4 grams of maltodextrin daily.&#xD;
Maltodextrin</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Enhanced Liver Fibrosis Score (ELF)</title>
          <description>Change in Enhanced Liver Fibrosis score (ELF) was calculated as ELF score at the end of the study minus ELF score prior to the intervention (at baseline). A decrease in the ELF score was considered good as it reflected a decrease in liver fibrosis, and an increase in ELF score was considered bad as it reflected an increase in liver fibrosis.&#xD;
Change in ELF scores ranged from -0.56 (good) to + 0.68 (bad).</description>
          <population>numerical difference between baseline measurement and 12 month measurement</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="45"/>
                <count group_id="O2" value="44"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.12" lower_limit="0.03" upper_limit="0.19"/>
                    <measurement group_id="O2" value="0.13" lower_limit="0.05" upper_limit="0.19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>For each primary outcome, a change variable was calculated as the difference between end-of study and baseline measurements. Multiple regression analysis was used to assess the effect of synbiotic treatment on each of the change variables of interest.</non_inferiority_desc>
            <p_value>1.00</p_value>
            <method>Regression, Linear</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.1</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change in NAFLD Fibrosis Score</title>
        <description>Change in NAFLD Fibrosis Score (NFS) was calculated as the NFS score at the end of the study, minus NFS score prior to the intervention (at baseline). A decrease in the NFS score was considered good because it reflected a decrease in liver fibrosis, and an increase in NFS score was considered bad, as it reflected an increase in liver fibrosis.&#xD;
Change in NFS scores ranged from -2.07 (good) to + 1.75 (bad)</description>
        <time_frame>baseline and 12 months</time_frame>
        <population>numerical difference between baseline measurement and 12 month measurement</population>
        <group_list>
          <group group_id="O1">
            <title>Synbiotic</title>
            <description>Fructo-oligosaccharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).&#xD;
Synbiotic: The synbiotic to be used is fructo-oligosaccharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).</description>
          </group>
          <group group_id="O2">
            <title>Maltodextrin</title>
            <description>4 grams of maltodextrin daily.&#xD;
Maltodextrin</description>
          </group>
        </group_list>
        <measure>
          <title>Change in NAFLD Fibrosis Score</title>
          <description>Change in NAFLD Fibrosis Score (NFS) was calculated as the NFS score at the end of the study, minus NFS score prior to the intervention (at baseline). A decrease in the NFS score was considered good because it reflected a decrease in liver fibrosis, and an increase in NFS score was considered bad, as it reflected an increase in liver fibrosis.&#xD;
Change in NFS scores ranged from -2.07 (good) to + 1.75 (bad)</description>
          <population>numerical difference between baseline measurement and 12 month measurement</population>
          <units>units on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="45"/>
                <count group_id="O2" value="44"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1.3" lower_limit="-1.68" upper_limit="-0.92"/>
                    <measurement group_id="O2" value="-1.2" lower_limit="-1.58" upper_limit="-0.82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>For each primary outcome, a change variable was calculated as the difference between end of study and baseline measurements. Multiple regression analysis was used to assess the effect of synbiotic treatment on each of the change variables of interest.</non_inferiority_desc>
            <p_value>0.80</p_value>
            <method>Regression, Linear</method>
            <param_type>Mean Difference (Final Values)</param_type>
            <param_value>0.2</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change in Bifidobacterium Spp.</title>
        <description>The change in percent of Bifidobacteria spp was computed as the percent of Bifidobactera spp at the end of the study minus the percent of Bifidobacteria prior to the intervention (at baseline).&#xD;
A positive change in percent (e.g +0.1 to 7.0%) in Bifidobacteria spp. was considered good and a negative change in percent (e.g. -0.1 to -0.5%) in Bifidobacteria spp. considered bad. (Minimum = -0.5% (bad) and Maximum = +7.0% (good)).</description>
        <time_frame>baseline and 12 months</time_frame>
        <population>numerical difference between baseline measurement and 12 month measurement</population>
        <group_list>
          <group group_id="O1">
            <title>Synbiotic</title>
            <description>Fructo-oligosaccharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).&#xD;
Synbiotic: The synbiotic to be used is fructo-oligosaccharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).</description>
          </group>
          <group group_id="O2">
            <title>Maltodextrin</title>
            <description>4 grams of maltodextrin daily.&#xD;
Maltodextrin</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Bifidobacterium Spp.</title>
          <description>The change in percent of Bifidobacteria spp was computed as the percent of Bifidobactera spp at the end of the study minus the percent of Bifidobacteria prior to the intervention (at baseline).&#xD;
A positive change in percent (e.g +0.1 to 7.0%) in Bifidobacteria spp. was considered good and a negative change in percent (e.g. -0.1 to -0.5%) in Bifidobacteria spp. considered bad. (Minimum = -0.5% (bad) and Maximum = +7.0% (good)).</description>
          <population>numerical difference between baseline measurement and 12 month measurement</population>
          <units>percentage of fecal Bifidobacterium spp</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="45"/>
                <count group_id="O2" value="44"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.72" lower_limit="0.89" upper_limit="2.55"/>
                    <measurement group_id="O2" value="-0.02" lower_limit="-0.46" upper_limit="0.42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>For each primary outcome, a change variable was calculated as the difference between end of study and baseline measurements. Multiple regression analysis was used to assess the effect of synbiotic treatment on each of the change variables of interest.</non_inferiority_desc>
            <p_value>&lt;0.001</p_value>
            <method>Beta-diversity indexes</method>
            <method_desc>Beta-diversity indexes were first visualized through a Principal Coordinates Analysis (PCoA)</method_desc>
            <param_type>Median Difference (Final Values)</param_type>
            <param_value>0.97</param_value>
            <ci_n_sides>2-Sided</ci_n_sides>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>The adverse event data were collected over the period of the study between baseline and end of study (total period 12 months).</time_frame>
      <desc>We used the clinicaltrials.gov definition for adverse event and/or serious adverse event.</desc>
      <group_list>
        <group group_id="E1">
          <title>Synbiotic</title>
          <description>Fructo-oligosaccharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).&#xD;
Synbiotic: The synbiotic to be used is fructo-oligosaccharide with a degree of polymerization &lt; 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).</description>
        </group>
        <group group_id="E2">
          <title>Maltodextrin</title>
          <description>4 grams of maltodextrin daily.&#xD;
Maltodextrin</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>NHS guideline</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>myocardial infarction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>abdominal pain, surgery</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Back pain after Liver biopsy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>orthopedic</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>urinary tract cancer</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>breast cancer</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>chest infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>NHS guideline</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="35" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="30" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>chest pain, alterations on ecg</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>otorhinolaryngological disorders</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>ophtalmology disorders</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>diverticulosis, intestinal disorders</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Nausea, vomitting and diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Headache, collapse, dizziness</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="6" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>dental problems</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>anxiety and depression</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>hypertension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Liver alteration other than NAFLD</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperglycaemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>nutrient deficiency</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Joint pain, back pain</sub_title>
                <counts group_id="E1" subjects_affected="19" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="16" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>urinary tract disorders</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>breast disorders</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Flu, chest infection</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>dermatological problems</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="49"/>
              </event>
              <event>
                <sub_title>Skin infection, abrasion, rash</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Post adipose tissue biopsy pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>vascular disorders</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="55"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="49"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>We choose one strain of bacteria in the synbiotic. The study was designed as a phase-2 clinical trial using magnetic resonance spectroscopy (MRS) and not liver biopsy. We deliberately did not include a lifestyle intervention as we wanted to test the effect of the synbiotic alone.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Christopher D Byrne</name_or_title>
      <organization>University of Southampton</organization>
      <phone>44 (0)23 8120 8818</phone>
      <email>cdtb@soton.ac.uk</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01680640
org study id: RHM MED1071
nct id: NCT01680640
lead sponsor: 
collaborator: 
has dmc: No
Non-alcoholic fatty liver disease (NAFLD) is a liver condition in which fat builds up in the
      liver not caused by alcohol. The liver is an organ that is not designed to build up fat.
      NAFLD is common in people who have too much body fat in their abdomen or who have diabetes
      (high blood sugar), but does not always exist with these conditions. NAFLD can also occur in
      thin people too. NAFLD can be harmful to the liver and may cause the liver to fail over time.
      NAFLD may also cause adult (or type 2) diabetes and also heart disease. In people who already
      have diabetes, NAFLD can cause glucose (sugar) levels to be too high.

      Our intestines (guts) contain healthy bacteria and some harmful bacteria (bugs). This balance
      of healthy and harmful bugs is essential for the normal workings of our intestine to digest
      food. Providing these bacteria do not leak out into the blood they do not cause harm. If the
      balance of healthy to harmful bugs is upset, the harmful can cause problems and leak out into
      the blood. Because the liver is connected to the intestine by blood vessels the harmful
      bacteria can get to the liver and cause problems. These bacteria can cause the liver and the
      body to build up too much fat and might cause NAFLD and obesity. In this study, we will test
      the effects of a supplement (synbiotic) taken during the day, that contains a mixture of
      'good' healthy bacteria (probiotic) and a sugar (prebiotic) that is not broken down and
      absorbed into the blood. We will test whether the synbiotic supplement has beneficial effects
      on the NAFLD liver condition and on factors linked to too much body fat, diabetes and heart
      disease.
We will recruit people with NAFLD who have been diagnosed as part of their NHS (National
      Health Service) care with having this condition. At present there is no treatment for this
      condition.

      Purpose and design:

      We are asking the research question: "Does the modulation of gut microflora with a synbiotic
      improve non-alcoholic fatty liver disease and the related risk factors for heart disease and
      type 2 diabetes?"

      Presently there is no treatment for this liver condition. Research evidence suggests that a
      synbiotic supplement might be beneficial for this condition.

      To address this research question we want to undertake a randomised double blind placebo
      controlled trial recruiting people who have been diagnosed with NAFLD.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Change in Liver Fat
time frame: baseline and 12 months
description: Change in liver fat percent was calculated as the percent liver fat at the end of the study, minus the percent of liver fat prior to the intervention. Change in liver fat percent ranged from -60.6% (good) to + 33.7% (bad).
measure: Change in Enhanced Liver Fibrosis Score (ELF)
time frame: baseline and 12 months
description: Change in Enhanced Liver Fibrosis score (ELF) was calculated as ELF score at the end of the study minus ELF score prior to the intervention (at baseline). A decrease in the ELF score was considered good as it reflected a decrease in liver fibrosis, and an increase in ELF score was considered bad as it reflected an increase in liver fibrosis.
Change in ELF scores ranged from -0.56 (good) to + 0.68 (bad).
measure: Change in NAFLD Fibrosis Score
time frame: baseline and 12 months
description: Change in NAFLD Fibrosis Score (NFS) was calculated as the NFS score at the end of the study, minus NFS score prior to the intervention (at baseline). A decrease in the NFS score was considered good because it reflected a decrease in liver fibrosis, and an increase in NFS score was considered bad, as it reflected an increase in liver fibrosis.
Change in NFS scores ranged from -2.07 (good) to + 1.75 (bad)
measure: Change in Bifidobacterium Spp.
time frame: baseline and 12 months
description: The change in percent of Bifidobacteria spp was computed as the percent of Bifidobactera spp at the end of the study minus the percent of Bifidobacteria prior to the intervention (at baseline).
A positive change in percent (e.g +0.1 to 7.0%) in Bifidobacteria spp. was considered good and a negative change in percent (e.g. -0.1 to -0.5%) in Bifidobacteria spp. considered bad. (Minimum = -0.5% (bad) and Maximum = +7.0% (good)).
arm group label: Synbiotic
arm group type: Active Comparator
description: Fructo-oligosacharide with a degree of polymerization < 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis (BB-12) as minimum of 10 billion colony forming unit (CFU)/day (1 capsule a day).
arm group label: Maltodextrin
arm group type: Placebo Comparator
description: 4 grams of maltodextrin daily.
intervention type: Dietary Supplement
intervention name: Synbiotic
description: The synbiotic to be used is fructo-oligosacharide with a degree of polymerization < 10 at 4 g/twice a day (two sticks a day) plus Bifidobacterium animalis subsp. lactis BB-12 as minimum of 10 billion CFU/day (1 capsule a day).
arm group label: Synbiotic
intervention type: Dietary Supplement
intervention name: Maltodextrin
arm group label: Maltodextrin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Christopher D Byrne, MBBCh, PhD
role: Principal Investigator
affiliation: University of Southampton/University Hospital Southampton NHS Foundation Trust
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Liver Diseases
mesh term: Fatty Liver
mesh term: Non-alcoholic Fatty Liver Disease
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: We choose one strain of bacteria in the synbiotic. The study was designed as a phase-2 clinical trial using magnetic resonance spectroscopy (MRS) and not liver biopsy. We deliberately did not include a lifestyle intervention as we wanted to test the effect of the synbiotic alone.
point of contact: 