<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/NCT02229500</url>
  </required_header>
  <id_info>
    <org_study_id>BB/L004259/1_SUERC_1</org_study_id>
    <nct_id>NCT02229500</nct_id>
  </id_info>
  <brief_title>Investigating Optimal Propionate Delivery to the Colon Using Stable Isotope Labeling</brief_title>
  <official_title>Regulating Appetite by Targeting Nutrient Delivery in the Gut</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Scottish Universities Environmental Research Centre</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Biotechnology and Biological Sciences Research Council</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Glasgow</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Scottish Universities Environmental Research Centre</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Obesity, with its associated co-morbidities, is a major public health challenge. It is&#xD;
      estimated that by 2050, 60% of men and 50% of women will be clinically obese. Obesity is&#xD;
      associated with increased risk of developing diabetes, cardiovascular disease, and certain&#xD;
      cancers. The increasing epidemic of obesity has necessitated the study of the complex&#xD;
      mechanisms underlying energy homeostasis. Food intake, energy balance and body weight are&#xD;
      tightly regulated by the hypothalamus, brainstem and reward circuits, on the basis both of&#xD;
      cognitive inputs and of diverse humoral and neuronal signals of nutritional status. Several&#xD;
      gut hormones, including glucagon-like peptide-1 (GLP-1) and peptide YY3-36 (PYY), have been&#xD;
      shown to play an important role in regulating short-term food intake. Peripheral&#xD;
      administration of PYY or GLP-1 enhances satiety and reduces food intake in animals and man.&#xD;
      PYY, GLP-1 along with a host of other hormones are produced by the gut in response to&#xD;
      nutrient availability in different regions of the gut and provide an exquisite mechanism of&#xD;
      nutrient sensing in response to dietary intake. These hormones therefore represent potential&#xD;
      targets in the development of novel anti-obesity treatments. A novel and attractive strategy&#xD;
      to induce appetite regulation is the enrichment of foods with components that stimulate the&#xD;
      release of GLP-1 and PYY. The short chain fatty acids (SCFA) produced by microbial&#xD;
      fermentation of dietary fibre in the colon have been shown to stimulate the release of PYY&#xD;
      and GLP-1 from rodent enteroendocrine L cells, via stimulation of the G-protein coupled free&#xD;
      fatty acid receptors (FFAR) on colonic L cells. Of the SCFAs produced by colonic fermentation&#xD;
      of dietary fibre, propionate has the highest affinity for FFAR 2. Furthermore, propionate is&#xD;
      an end product of bacterial metabolism, and thus, unlike acetate, does not undergo conversion&#xD;
      to other SCFAs. Increasing colonic propionate is therefore an attractive target for appetite&#xD;
      modulation.&#xD;
&#xD;
      We have developed a novel delivery system for delivering propionate to the right site in the&#xD;
      colon and we now wish to optimise the delivery of propionate to the colon in man using stable&#xD;
      isotope labelling methods.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The role of SCFA in appetite regulation: SCFA have been shown to stimulate PYY and GLP-1&#xD;
      production in animal models and dietary fibre, of which SCFA are the major end products,&#xD;
      induce appetite regulation in humans. However the evidence underpinning which dietary fibres&#xD;
      induce appetite regulation in humans is very weak because of the difficulty in controlling&#xD;
      studies with very high fibre intake. In a recent project funded under the BBSRC DRINC&#xD;
      initiative (BB/H004815/1), we have the first direct evidence that SCFA can directly regulate&#xD;
      appetite in humans. Prior to this study, in order to achieve production of SCFA to a level,&#xD;
      which is high enough to induce appetite-regulating effects, very large amounts of dietary&#xD;
      fibre (&gt;25 g/d and up to 40 g/d) are required, and compliance with high fibre diets is poor&#xD;
      due to gastrointestinal side effects. Furthermore, supplementing diets with mixed high fibre&#xD;
      does not predictably or reliably increase colonic SCFA production or circulating levels of&#xD;
      SCFA in all human populations because of the variability in gut microbial activity. Finally,&#xD;
      orally administered SCFAs are not palatable and are rapidly absorbed in the small intestine&#xD;
      where L cells are sparse. In our studies to date we have focussed on the SCFA propionate&#xD;
      because it has the highest affinity for the receptors and is an end product of metabolism in&#xD;
      the microbiota and therefore seems the obvious target to manipulate to investigate the&#xD;
      effects of SCFA on appetite regulation. To overcome the unpalatably high levels of&#xD;
      fermentable dietary fibre needed to significantly increase colonic propionate levels, and the&#xD;
      unpredictability in the production of the resulting SCFAs, we have developed and tested a&#xD;
      novel delivery system targeting the release of gram quantities of propionate in the proximal&#xD;
      colon. We estimate that our delivery system may lead to a 2-8 fold increase in colonic&#xD;
      propionate, a level very difficult to achieve through feeding a mixed fermentable fibre diet.&#xD;
      This level of propionate production might have been observed in ancestral diets and in parts&#xD;
      of rural Africa where dietary fibre intake is very high. We have also demonstrated that&#xD;
      delivery system increases plasma propionate levels, reduces food intake in acute studies of&#xD;
      appetite, and in a longer term study (24 weeks), positive effects on food intake, body&#xD;
      composition, glucose homeostasis, circulating lipids, cholesterol and liver function, liver&#xD;
      and visceral fat and weight management were observed. However, in these studies we&#xD;
      pragmatically chose an preparation that could be produced at scale. The amount of propionate&#xD;
      released can be varied which in itself may affect the rate and amount of propionate released.&#xD;
      For an ingredient, with the potential to be incorporated into a wide variety of foodstuffs,&#xD;
      we now wish to investigate the optimum delivery system preparation that delivers the maximal&#xD;
      propionate dose in the least amount of material.&#xD;
&#xD;
      We plan to use non-invasive, stable isotope labelling methodologies to determine propionate&#xD;
      bioavailability from a range of delivery system preparations, in order to determine the&#xD;
      optimum preparation for delivering maximal propionate to the proximal colon.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2014</start_date>
  <completion_date type="Actual">December 2015</completion_date>
  <primary_completion_date type="Actual">August 2015</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>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time to maximal 13C appearance in breath</measure>
    <time_frame>over 24 hrs</time_frame>
    <description>The time to peak maximal excretion in breath 13C (measured in breath 13CO2) will be the primary outcome criterion</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Area under curve of breath 13C excretion</measure>
    <time_frame>over 24hrs</time_frame>
    <description>The area under the curve of breath 13C excretion (measured in 13CO2) will be determined to assess amount of propionate released.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Effect of preparations on appetite</measure>
    <time_frame>0ver 8 hrs</time_frame>
    <description>The effect of different delivery system preparations on appetite will be determined by visual analog scale measurements and ad libitum food intake</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Optimum Propionate Delivery to the Large Intestine</condition>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Inulin control, 10g/d for 7 days. Isotope and appetite measurements on day 7</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Delivery system 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Delivery system, 28.5% w/w propionate, 10g/d for 7 days. Isotope and appetite measurements on day 7.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Delivery system 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Delivery system, 54% w/w propionate, 10g/d for 7 days. Isotope and appetite measurements on day 7.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Inulin</intervention_name>
    <arm_group_label>Control</arm_group_label>
    <other_name>Beneo-Orafti HP</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>2.5 g of propionate</intervention_name>
    <description>This system delivers approximately 2.5 g of propionate to the colon in a 10g dose.</description>
    <arm_group_label>Delivery system 1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>5 g of propionate</intervention_name>
    <description>This delivers approximately 5g of propionate to the colon per 10g dose</description>
    <arm_group_label>Delivery system 2</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  overweight males (BMI 25-35 kg/m2) aged between 21 - 65&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Weight change of &gt; 3kg in the preceding 2 months&#xD;
&#xD;
          -  Current smokers&#xD;
&#xD;
          -  Substance abuse&#xD;
&#xD;
          -  Excess alcohol intake&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Diabetes&#xD;
&#xD;
          -  Cardiovascular disease&#xD;
&#xD;
          -  Cancer&#xD;
&#xD;
          -  Gastrointestinal disease&#xD;
&#xD;
          -  Kidney disease&#xD;
&#xD;
          -  Liver disease&#xD;
&#xD;
          -  Pancreatitis&#xD;
&#xD;
          -  Use of any medication&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Douglas Morrison, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Glasgow</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Glasgow Clinical Research Facility</name>
      <address>
        <city>Glasgow</city>
        <state>Lanarkshire</state>
        <zip>G4 0SF</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>April 2016</verification_date>
  <study_first_submitted>August 28, 2014</study_first_submitted>
  <study_first_submitted_qc>August 29, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 1, 2014</study_first_posted>
  <last_update_submitted>April 27, 2016</last_update_submitted>
  <last_update_submitted_qc>April 27, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">April 28, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Propionate</keyword>
  <keyword>Microbiome</keyword>
  <keyword>Dietary Fibre</keyword>
  <keyword>Short chain fatty acids</keyword>
  <!-- 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/NCT02229500
org study id: BB/L004259/1_SUERC_1
nct id: NCT02229500
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
Obesity, with its associated co-morbidities, is a major public health challenge. It is
      estimated that by 2050, 60% of men and 50% of women will be clinically obese. Obesity is
      associated with increased risk of developing diabetes, cardiovascular disease, and certain
      cancers. The increasing epidemic of obesity has necessitated the study of the complex
      mechanisms underlying energy homeostasis. Food intake, energy balance and body weight are
      tightly regulated by the hypothalamus, brainstem and reward circuits, on the basis both of
      cognitive inputs and of diverse humoral and neuronal signals of nutritional status. Several
      gut hormones, including glucagon-like peptide-1 (GLP-1) and peptide YY3-36 (PYY), have been
      shown to play an important role in regulating short-term food intake. Peripheral
      administration of PYY or GLP-1 enhances satiety and reduces food intake in animals and man.
      PYY, GLP-1 along with a host of other hormones are produced by the gut in response to
      nutrient availability in different regions of the gut and provide an exquisite mechanism of
      nutrient sensing in response to dietary intake. These hormones therefore represent potential
      targets in the development of novel anti-obesity treatments. A novel and attractive strategy
      to induce appetite regulation is the enrichment of foods with components that stimulate the
      release of GLP-1 and PYY. The short chain fatty acids (SCFA) produced by microbial
      fermentation of dietary fibre in the colon have been shown to stimulate the release of PYY
      and GLP-1 from rodent enteroendocrine L cells, via stimulation of the G-protein coupled free
      fatty acid receptors (FFAR) on colonic L cells. Of the SCFAs produced by colonic fermentation
      of dietary fibre, propionate has the highest affinity for FFAR 2. Furthermore, propionate is
      an end product of bacterial metabolism, and thus, unlike acetate, does not undergo conversion
      to other SCFAs. Increasing colonic propionate is therefore an attractive target for appetite
      modulation.

      We have developed a novel delivery system for delivering propionate to the right site in the
      colon and we now wish to optimise the delivery of propionate to the colon in man using stable
      isotope labelling methods.
The role of SCFA in appetite regulation: SCFA have been shown to stimulate PYY and GLP-1
      production in animal models and dietary fibre, of which SCFA are the major end products,
      induce appetite regulation in humans. However the evidence underpinning which dietary fibres
      induce appetite regulation in humans is very weak because of the difficulty in controlling
      studies with very high fibre intake. In a recent project funded under the BBSRC DRINC
      initiative (BB/H004815/1), we have the first direct evidence that SCFA can directly regulate
      appetite in humans. Prior to this study, in order to achieve production of SCFA to a level,
      which is high enough to induce appetite-regulating effects, very large amounts of dietary
      fibre (>25 g/d and up to 40 g/d) are required, and compliance with high fibre diets is poor
      due to gastrointestinal side effects. Furthermore, supplementing diets with mixed high fibre
      does not predictably or reliably increase colonic SCFA production or circulating levels of
      SCFA in all human populations because of the variability in gut microbial activity. Finally,
      orally administered SCFAs are not palatable and are rapidly absorbed in the small intestine
      where L cells are sparse. In our studies to date we have focussed on the SCFA propionate
      because it has the highest affinity for the receptors and is an end product of metabolism in
      the microbiota and therefore seems the obvious target to manipulate to investigate the
      effects of SCFA on appetite regulation. To overcome the unpalatably high levels of
      fermentable dietary fibre needed to significantly increase colonic propionate levels, and the
      unpredictability in the production of the resulting SCFAs, we have developed and tested a
      novel delivery system targeting the release of gram quantities of propionate in the proximal
      colon. We estimate that our delivery system may lead to a 2-8 fold increase in colonic
      propionate, a level very difficult to achieve through feeding a mixed fermentable fibre diet.
      This level of propionate production might have been observed in ancestral diets and in parts
      of rural Africa where dietary fibre intake is very high. We have also demonstrated that
      delivery system increases plasma propionate levels, reduces food intake in acute studies of
      appetite, and in a longer term study (24 weeks), positive effects on food intake, body
      composition, glucose homeostasis, circulating lipids, cholesterol and liver function, liver
      and visceral fat and weight management were observed. However, in these studies we
      pragmatically chose an preparation that could be produced at scale. The amount of propionate
      released can be varied which in itself may affect the rate and amount of propionate released.
      For an ingredient, with the potential to be incorporated into a wide variety of foodstuffs,
      we now wish to investigate the optimum delivery system preparation that delivers the maximal
      propionate dose in the least amount of material.

      We plan to use non-invasive, stable isotope labelling methodologies to determine propionate
      bioavailability from a range of delivery system preparations, in order to determine the
      optimum preparation for delivering maximal propionate to the proximal colon.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Triple (Participant, Care Provider, Investigator)
measure: Time to maximal 13C appearance in breath
time frame: over 24 hrs
description: The time to peak maximal excretion in breath 13C (measured in breath 13CO2) will be the primary outcome criterion
measure: Area under curve of breath 13C excretion
time frame: over 24hrs
description: The area under the curve of breath 13C excretion (measured in 13CO2) will be determined to assess amount of propionate released.
measure: Effect of preparations on appetite
time frame: 0ver 8 hrs
description: The effect of different delivery system preparations on appetite will be determined by visual analog scale measurements and ad libitum food intake
arm group label: Control
arm group type: Active Comparator
description: Inulin control, 10g/d for 7 days. Isotope and appetite measurements on day 7
arm group label: Delivery system 1
arm group type: Experimental
description: Delivery system, 28.5% w/w propionate, 10g/d for 7 days. Isotope and appetite measurements on day 7.
arm group label: Delivery system 2
arm group type: Experimental
description: Delivery system, 54% w/w propionate, 10g/d for 7 days. Isotope and appetite measurements on day 7.
intervention type: Dietary Supplement
intervention name: Inulin
arm group label: Control
other name: Beneo-Orafti HP
intervention type: Dietary Supplement
intervention name: 2.5 g of propionate
description: This system delivers approximately 2.5 g of propionate to the colon in a 10g dose.
arm group label: Delivery system 1
intervention type: Dietary Supplement
intervention name: 5 g of propionate
description: This delivers approximately 5g of propionate to the colon per 10g dose
arm group label: Delivery system 2
criteria: 
gender: Male
minimum age: 21 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Douglas Morrison, PhD
role: Principal Investigator
affiliation: University of Glasgow
facility: 
country: United Kingdom
responsible party type: Sponsor