<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/NCT02241421</url>
  </required_header>
  <id_info>
    <org_study_id>11-3-072</org_study_id>
    <nct_id>NCT02241421</nct_id>
  </id_info>
  <brief_title>The Importance of the Gut Microbiota in Body Weight Control and Insulin Sensitivity</brief_title>
  <acronym>ANTIBIOTICS</acronym>
  <official_title>The Effect of the Knock Down of Gut Microbiota by Antibiotics on Parameters of Body Weight Control and Insulin Sensitivity</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Maastricht University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Top Institute Food and Nutrition</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Maastricht University Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      BACKGROUND: The relation between gut microbiota and obesity originates from animal studies,&#xD;
      showing that the change of gut microbiota can induce changes in both insulin resistance and&#xD;
      body composition. In addition, these studies have shown changes in gut permeability inducing&#xD;
      a pro-inflammatory state, changes in adipose tissue function and inflammation, effects on&#xD;
      energy harvesting and metabolism, skeletal muscle fatty acid partitioning and fat oxidation.&#xD;
      Human data is lacking, although several studies suggested that the composition of the gut&#xD;
      microbiota differs between lean and obese, and between diabetic and non-diabetic individuals.&#xD;
&#xD;
      OBJECTIVE: To provide insight in the physiological significance and underlying mechanisms&#xD;
      involved in the relation between gut microbiota, energy balance and insulin sensitivity in&#xD;
      overweight men with impaired glucose homeostasis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The view on the putative significance of gut microbiota in metabolism emerged from animal&#xD;
      studies. Bäcked et al. showed that germ free mice had 40% less body fat compared to&#xD;
      conventionally raised mice. Transplantation of a cecum-derived microbial community of&#xD;
      conventional mice into germ free mice, resulted in a significant increase of body weight and&#xD;
      insulin resistance within 2 weeks. Application of metagenomic techniques in leptin-deficient&#xD;
      ob/ob mice showed a different proportion of bacteria belonging when compared to lean,&#xD;
      wild-type or heterozygous mice, with a greater representation of Firmicutes and fewer&#xD;
      Bacteroidetes. This obese gut microbiome showed an enrichment in genes involved in energy&#xD;
      extraction from food, less energy left over in the faeces and higher contents of the&#xD;
      short-chain fatty acids (SCFAs) propionate, acetate and butyrate in the cecum.&#xD;
&#xD;
      Furthermore, microbiota composition may alter gut permeability, and may play a role in the&#xD;
      development of metabolic endotoxemia (inflammation) and related impairments in glucose&#xD;
      metabolism. In addition, the gut microbiota may determine AMP-activated protein kinase (AMPK)&#xD;
      levels in muscle and liver, thereby affecting fatty acid oxidation (substrate metabolism) and&#xD;
      fat storage. However, underlying mechanisms are not completely understood.&#xD;
&#xD;
      Therefore, researchers within the Top Institute Food and Nutrition (TIFN) have designed a&#xD;
      multidisciplinary project ('Microbiota, energy balance and metabolism'), to fill the unmet&#xD;
      gap between gut microbiota and human energy metabolism. The current protocol is designed to&#xD;
      clarify the role of the gut microbiota in host energy metabolism and insulin sensitivity,&#xD;
      with the main focus on underlying mechanisms.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>April 2012</start_date>
  <completion_date type="Actual">November 2014</completion_date>
  <primary_completion_date type="Actual">October 2014</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>Basic Science</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Insulin sensitivity</measure>
    <time_frame>up to two weeks</time_frame>
    <description>Before and after the intervention, insulin sensitivity will be measured by using the hyperinsulinemic-euglycemic clamp technique including a glucose tracer to accurately quantify glucose fluxes at the whole body level. Glucose and Insulin levels will be determined.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Fatty Acid Handling in the muscle</measure>
    <time_frame>up to two weeks</time_frame>
    <description>Because skeletal muscle is responsible for almost 80% of insulin-stimulated glucose disposal, and comprises up to 40% of total body mass, it can be considered to be a major tissue in the etiology of insulin resistance. Therefore, it is important to study the role of skeletal muscle substrate metabolism (fatty acid handling)in the context of this study. Fatty acids, glycerol, triacylglycerol and labelled palmitate in the chylomicron fraction will be measured.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Markers of inflammation</measure>
    <time_frame>up to two weeks</time_frame>
    <description>Low-grade inflammation seems to contribute to insulin resistance in obese insulin resistant subjects. Therefore, muscle and adipose tissue expression/secretion of inflammatory molecules (i.e. TNFα, IL-6) will be measured.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Energy expenditure</measure>
    <time_frame>up to two weeks</time_frame>
    <description>Indirect calorimetry measurements will be done to determine energy expenditure (O2 and CO2). While the gut microbiota plays an important role in nutrient metabolism and energy extraction from the diet, the determination of energy expenditure and energy content in faeces will provide important insight into the role of the gut microbiota in body weight regulation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Microbiota composition and energy content in faecal samples</measure>
    <time_frame>up to two weeks</time_frame>
    <description>The composition of bacteria in the gut will be determined before and after intervention to link the composition to the primary and other secondary parameters. The energy content in the faeces will provide insight in the energy extraction capacity of the bacteria present.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gut wall permeability</measure>
    <time_frame>up to two weeks</time_frame>
    <description>A proposed hypothesis is that gut permeability plays an important role in the induction of inflammation in obese insulin resistant subjects. A multi-sugar whole gut permeability assay will be performed.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">57</enrollment>
  <condition>Obesity</condition>
  <condition>Insulin Resistance</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>No intervention: Placebo 3x2 capsules per day during 7 consecutive days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment Antibiotics: Amoxicillin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Experimental: Amoxicillin (broad spectrum antibiotics) 1500 mg/day (3x2 capsules of 250 mg) during 7 consecutive days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Treatment Antibiotics: Vancomycin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Experimental: Vancomycin (small spectrum antibiotics) 1500mg/day (3x2 capsules of 250 mg) during 7 consecutive days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Amoxicillin</intervention_name>
    <arm_group_label>Treatment Antibiotics: Amoxicillin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Vancomycin</intervention_name>
    <arm_group_label>Treatment Antibiotics: Vancomycin</arm_group_label>
    <other_name>Vancocin CP 250</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  male&#xD;
&#xD;
          -  35-70 years&#xD;
&#xD;
          -  caucasian&#xD;
&#xD;
          -  overweight/obese (BMI 25-35 kg/m2)&#xD;
&#xD;
          -  insulin resistant (Homeostasis Model of Assessment - Insulin Resistance (HOMA_IR) &gt;&#xD;
             2.2)&#xD;
&#xD;
          -  impaired glucose tolerance (IGT: 2h plasma glucose during 75g Oral Glucose Tolerance&#xD;
             Test(OGTT) 7.8-11.1 mmol/l) and/or impaired fasting glucose (plasma glucose ≥ 5.6&#xD;
             mmol/l)&#xD;
&#xD;
          -  body weight stable for at least three months (±3 kg)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  known allergic reaction to vancomycin, teicoplanin, amoxicillin and other β-lactam&#xD;
             antibiotics (penicillins and cefalosporins) or related antibiotics&#xD;
&#xD;
          -  diabetes mellitus&#xD;
&#xD;
          -  hearing disorders&#xD;
&#xD;
          -  cardiovascular disease&#xD;
&#xD;
          -  kidney disease&#xD;
&#xD;
          -  gastrointestinal disease&#xD;
&#xD;
          -  cancer&#xD;
&#xD;
          -  asthma or bronchitis&#xD;
&#xD;
          -  liver malfunction&#xD;
&#xD;
          -  major illness with a life expectancy &lt; 5 years&#xD;
&#xD;
          -  diseases affecting glucose tolerance (e.g. pheochromocytoma, Cushing's syndrome,&#xD;
             acromegaly), - - use of antibiotics in the past 3 months&#xD;
&#xD;
          -  plans to lose weight and participation in organized sports activities for &gt;3 hours per&#xD;
             week&#xD;
&#xD;
          -  The use of β-blockers, lipid lowering-drugs, glucose-lowering agents (including all&#xD;
             sulfonylureas, biguanides, α-glucosidase inhibitors, thiazolidinediones, repaglinide,&#xD;
             nateglinide and insulin), anti-oxidants or chronic corticosteroids treatment (&gt; 7&#xD;
             consecutive days of treatment)&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>35 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ellen E Blaak, Prof.Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Maastricht University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Maastricht University</name>
      <address>
        <city>Maastricht</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>September 2020</verification_date>
  <study_first_submitted>October 22, 2012</study_first_submitted>
  <study_first_submitted_qc>September 15, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 16, 2014</study_first_posted>
  <last_update_submitted>September 8, 2020</last_update_submitted>
  <last_update_submitted_qc>September 8, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">September 10, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Impaired glucose tolerance</keyword>
  <keyword>Glucose Metabolism Disorders</keyword>
  <keyword>Metabolic Diseases</keyword>
  <keyword>Endocrine System Diseases</keyword>
  <keyword>Hyperinsulinism</keyword>
  <keyword>Lipid metabolism</keyword>
  <keyword>Anti Bacterial Agents</keyword>
  <keyword>Gastro Intestinal Tract</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Insulin Resistance</mesh_term>
    <mesh_term>Body Weight</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Amoxicillin</mesh_term>
    <mesh_term>Vancomycin</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02241421
org study id: 11-3-072
nct id: NCT02241421
lead sponsor: 
collaborator: 
has dmc: No
BACKGROUND: The relation between gut microbiota and obesity originates from animal studies,
      showing that the change of gut microbiota can induce changes in both insulin resistance and
      body composition. In addition, these studies have shown changes in gut permeability inducing
      a pro-inflammatory state, changes in adipose tissue function and inflammation, effects on
      energy harvesting and metabolism, skeletal muscle fatty acid partitioning and fat oxidation.
      Human data is lacking, although several studies suggested that the composition of the gut
      microbiota differs between lean and obese, and between diabetic and non-diabetic individuals.

      OBJECTIVE: To provide insight in the physiological significance and underlying mechanisms
      involved in the relation between gut microbiota, energy balance and insulin sensitivity in
      overweight men with impaired glucose homeostasis.
The view on the putative significance of gut microbiota in metabolism emerged from animal
      studies. Bäcked et al. showed that germ free mice had 40% less body fat compared to
      conventionally raised mice. Transplantation of a cecum-derived microbial community of
      conventional mice into germ free mice, resulted in a significant increase of body weight and
      insulin resistance within 2 weeks. Application of metagenomic techniques in leptin-deficient
      ob/ob mice showed a different proportion of bacteria belonging when compared to lean,
      wild-type or heterozygous mice, with a greater representation of Firmicutes and fewer
      Bacteroidetes. This obese gut microbiome showed an enrichment in genes involved in energy
      extraction from food, less energy left over in the faeces and higher contents of the
      short-chain fatty acids (SCFAs) propionate, acetate and butyrate in the cecum.

      Furthermore, microbiota composition may alter gut permeability, and may play a role in the
      development of metabolic endotoxemia (inflammation) and related impairments in glucose
      metabolism. In addition, the gut microbiota may determine AMP-activated protein kinase (AMPK)
      levels in muscle and liver, thereby affecting fatty acid oxidation (substrate metabolism) and
      fat storage. However, underlying mechanisms are not completely understood.

      Therefore, researchers within the Top Institute Food and Nutrition (TIFN) have designed a
      multidisciplinary project ('Microbiota, energy balance and metabolism'), to fill the unmet
      gap between gut microbiota and human energy metabolism. The current protocol is designed to
      clarify the role of the gut microbiota in host energy metabolism and insulin sensitivity,
      with the main focus on underlying mechanisms.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Insulin sensitivity
time frame: up to two weeks
description: Before and after the intervention, insulin sensitivity will be measured by using the hyperinsulinemic-euglycemic clamp technique including a glucose tracer to accurately quantify glucose fluxes at the whole body level. Glucose and Insulin levels will be determined.
measure: Fatty Acid Handling in the muscle
time frame: up to two weeks
description: Because skeletal muscle is responsible for almost 80% of insulin-stimulated glucose disposal, and comprises up to 40% of total body mass, it can be considered to be a major tissue in the etiology of insulin resistance. Therefore, it is important to study the role of skeletal muscle substrate metabolism (fatty acid handling)in the context of this study. Fatty acids, glycerol, triacylglycerol and labelled palmitate in the chylomicron fraction will be measured.
measure: Markers of inflammation
time frame: up to two weeks
description: Low-grade inflammation seems to contribute to insulin resistance in obese insulin resistant subjects. Therefore, muscle and adipose tissue expression/secretion of inflammatory molecules (i.e. TNFα, IL-6) will be measured.
measure: Energy expenditure
time frame: up to two weeks
description: Indirect calorimetry measurements will be done to determine energy expenditure (O2 and CO2). While the gut microbiota plays an important role in nutrient metabolism and energy extraction from the diet, the determination of energy expenditure and energy content in faeces will provide important insight into the role of the gut microbiota in body weight regulation.
measure: Microbiota composition and energy content in faecal samples
time frame: up to two weeks
description: The composition of bacteria in the gut will be determined before and after intervention to link the composition to the primary and other secondary parameters. The energy content in the faeces will provide insight in the energy extraction capacity of the bacteria present.
measure: Gut wall permeability
time frame: up to two weeks
description: A proposed hypothesis is that gut permeability plays an important role in the induction of inflammation in obese insulin resistant subjects. A multi-sugar whole gut permeability assay will be performed.
arm group label: Placebo
arm group type: Placebo Comparator
description: No intervention: Placebo 3x2 capsules per day during 7 consecutive days.
arm group label: Treatment Antibiotics: Amoxicillin
arm group type: Experimental
description: Experimental: Amoxicillin (broad spectrum antibiotics) 1500 mg/day (3x2 capsules of 250 mg) during 7 consecutive days.
arm group label: Treatment Antibiotics: Vancomycin
arm group type: Experimental
description: Experimental: Vancomycin (small spectrum antibiotics) 1500mg/day (3x2 capsules of 250 mg) during 7 consecutive days
intervention type: Drug
intervention name: Amoxicillin
arm group label: Treatment Antibiotics: Amoxicillin
intervention type: Drug
intervention name: Vancomycin
arm group label: Treatment Antibiotics: Vancomycin
other name: Vancocin CP 250
intervention type: Other
intervention name: Placebo
arm group label: Placebo
criteria: 
gender: Male
minimum age: 35 Years
maximum age: 70 Years
healthy volunteers: No
last name: Ellen E Blaak, Prof.Dr.
role: Principal Investigator
affiliation: Maastricht University
facility: 
country: Netherlands
responsible party type: Sponsor
mesh term: Insulin Resistance
mesh term: Body Weight
mesh term: Amoxicillin
mesh term: Vancomycin