<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/NCT02203240</url>
  </required_header>
  <id_info>
    <org_study_id>VT13261005</org_study_id>
    <nct_id>NCT02203240</nct_id>
  </id_info>
  <brief_title>Cocoa and Metabolic Health in Prediabetes</brief_title>
  <official_title>Dietary Cocoa for Inhibition of Metabolic Endotoxemia and Glucose Intolerance</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Virginia Polytechnic Institute and State University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The Hershey Company</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Virginia Polytechnic Institute and State University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine the impact of consuming cocoa on blood glucose&#xD;
      levels, glucose metabolism, and other markers of pre-diabetes in overweight and/or obese&#xD;
      individuals. Our hypothesis is that consumption of cocoa improves insulin sensitivity and&#xD;
      glucose metabolism in subjects at risk for developing type-2 diabetes.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>June 2014</start_date>
  <completion_date type="Actual">May 2016</completion_date>
  <primary_completion_date type="Actual">December 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>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in insulin sensitivity</measure>
    <time_frame>Baseline and 4 weeks</time_frame>
    <description>Insulin sensitivity will be determined using Bergman's minimal model (MINMOD Millennium software) via a frequently sampled intravenous glucose tolerance test (IVGTT). Fasting baseline blood samples will be taken prior to the dextrose injection (0.3 g/kg; 50% solution) at minute 0. Venous samples will be collected at minutes 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, and 18. Insulin (0.025 U/kg) will be injected at minute 20. Venous sampling will continue at minutes 22, 23, 24, 25, 27, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, and 180. Glucose concentration will be immediately analyzed an automated glucose oxidase analyzer. Insulin will be later measured from serum using the Immulite 1000 immunoassay analyzer.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in blood glucose response to a mixed meal</measure>
    <time_frame>Baseline and 1 week</time_frame>
    <description>The test meal will be 2-8 oz. servings of a meal replacement beverage providing a mixed macronutrient profile, supplemented with either a cocoa beverage dry mix (10 g cocoa) or a calorie-matched placebo beverage mix (0 g cocoa). Blood samples will be taken at baseline and subsequently 1, 2, 3, and 4 hours after the first sip of the test beverage. Plasma glucose concentrations will be analyzed immediately using a glucose auto-analyzer (Yellow Springs Instruments).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in hormone secretion response to a mixed meal</measure>
    <time_frame>Baseline and 1 week</time_frame>
    <description>Serum insulin, GLP-1, GIP, and C-peptide concentrations will be determined using commercially available enzyme-linked immunosorbent assay (ELISA) kits from the blood samples drawn at baseline, 1, 2, 3, and 4 hours during the mixed meal challenge.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in skeletal muscle metabolic flexibility</measure>
    <time_frame>Baseline and 4 weeks</time_frame>
    <description>Subjects will consume a high fat meal containing 820 kcal; 52 g total carbohydrates, 24 g protein, and 58 g fat. During the high fat challenge session, two skeletal muscle biopsies will be conducted on alternate legs; one before the high fat meal and one 4 hours later. Biopsies of the vastus lateralis will be performed using a 5 mm modified Bergström needle. Collected tissue will be washed in 0.9% sterile saline to remove blood and tissue. Samples will be weighed and added to buffer and placed on ice for immediate analysis of substrate flexibility. For substrate flexibility, pyruvate oxidation will be used to assess the activity of pyruvate dehydrogenase. Calculated metabolic flexibility is expressed as a ratio of pyruvate oxidation to pyruvate oxidation + free fatty acids.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in blood endotoxin levels</measure>
    <time_frame>Baseline and 4 weeks</time_frame>
    <description>During the high fat challenge (see Outcome 4), blood samples will be collected at baseline and 1, 2, 3, and 4 h after the first bite of the meal. Serum endotoxin will be measured in duplicate using Limulus Amebocyte Lysate Pyrogent ® 5000 assay kits.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in gut permeability</measure>
    <time_frame>Baseline and 4 weeks</time_frame>
    <description>The four-sugar [40 g sucrose, 1 g mannitol, 1 g sucralose and 5 g lactulose] probe test will be used to assess total gut permeability. After an overnight fast and urine evacuation, participants will be asked to consume the sugar-probe beverage within 5 minutes. They will be given two breakfast sandwiches to consume immediately. Participants will be instructed to collect all of their urine in a provided container from the time the beverage was consumed (0 h) until 5 h. A second urine collection container will be filled between 6-24 h. Twenty-four hours later, the volume of urine in each container will be measured and aliquots collected for later analysis. Gastroduodenal permeability is defined as sucrose/mannitol ratio (0-5 h). Small intestinal permeability is defined as the calculated lactulose/mannitol ratio for 0-5 samples. Colonic permeability is defined as both the 6-24 h lactulose/mannitol ratio and 6-24 h sucralose/mannitol ratio.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Prediabetes</condition>
  <arm_group>
    <arm_group_label>Cocoa</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>3 servings of polyphenol-rich cocoa beverage consumed per day.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>3 servings of non-cocoa beverage consumed per day.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Cocoa</intervention_name>
    <arm_group_label>Cocoa</arm_group_label>
  </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;
          -  Body Mass Index (BMI) greater than or equal to 25 and less than 40.&#xD;
&#xD;
          -  Have at least one of the following: 1) impaired fasting glucose (IFG) after an&#xD;
             overnight fast with plasma glucose concentration between 100-125 mg/dl, 2) impaired&#xD;
             glucose tolerance (IGT) as identified by the standard Oral Glucose Tolerance Test&#xD;
             (OGTT) with 2 hour plasma glucose concentration between 140-200 mg/dl following 75 g&#xD;
             glucose OGTT, 3) HbA1c levels between 5.7-6.4% or 4) considered at risk to developing&#xD;
             type 2 diabetes by the American Diabetes Association risk assessment. If subjects are&#xD;
             above the prediabetic range for any of these tests (indicating they may be type 2&#xD;
             diabetic), they will be excluded and referred to their physician.&#xD;
&#xD;
          -  Weight stable (+/-2 kg) for the last 6 months.&#xD;
&#xD;
          -  Sedentary to recreationally active (less than 2 d/wk, 20 min/d).&#xD;
&#xD;
          -  Have a blood pressure that is less than 160/100 mmHg, total cholesterol that is less&#xD;
             than 300 mg/dl and a triglyceride concentration of less than 450 mg/dl.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Past or current history of coronary heart disease, stroke or major cardiovascular&#xD;
             disease events, respiratory diseases, endocrine or metabolic diseases (including type&#xD;
             1 and type 2 diabetes), inflammatory bowel disease, cancer, or neurological or&#xD;
             hematological disorders that would compromise the study or the health of the subject.&#xD;
&#xD;
          -  Past or current history of gastrointestinal disorders (including lactose intolerance,&#xD;
             ulcers, cancer (stomach, intestinal, colon, pancreatic, liver, etc) NASH, NAFLD,&#xD;
             cirrhosis, IBD/IBS, celiac disease, etc).&#xD;
&#xD;
          -  Current use of any medication including but not limited to cholesterol lowering&#xD;
             medication (including fibric acid derivatives and niacin), antibiotics,&#xD;
             immunosuppressive drugs, azole antifungals, non-steroidal anti-inflammatory drugs&#xD;
             (NSAIDs), hormone replacement therapy or antioxidants/supplements.&#xD;
&#xD;
          -  Use of antibiotics, prebiotics, or probiotics within the prior 3 months.&#xD;
&#xD;
          -  Smoking or other tobacco use&#xD;
&#xD;
          -  Habitual consumption of alcohol more than 2 servings/d for males and 1 serving/d for&#xD;
             females.&#xD;
&#xD;
          -  Strict vegetarians or vegans, or strong aversions to major food groups that may be&#xD;
             part of the controlled diet.&#xD;
&#xD;
          -  Recent surgery&#xD;
&#xD;
          -  History of alcohol or drug abuse.&#xD;
&#xD;
          -  Pregnant or plan to become pregnant&#xD;
&#xD;
          -  Allergic to either lidocaine or bupivacaine&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Andrew P Neilson, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Virginia Polytechnic Institute and State University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Human Integrative Physiology Laboratory</name>
      <address>
        <city>Blacksburg</city>
        <state>Virginia</state>
        <zip>24061</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>July 26, 2014</study_first_submitted>
  <study_first_submitted_qc>July 26, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 29, 2014</study_first_posted>
  <last_update_submitted>September 19, 2022</last_update_submitted>
  <last_update_submitted_qc>September 19, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 21, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Virginia Polytechnic Institute and State University</investigator_affiliation>
    <investigator_full_name>Andrew P. Neilson</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>Cacao</keyword>
  <keyword>Polyphenols</keyword>
  <keyword>Prediabetic State</keyword>
  <keyword>Blood Glucose</keyword>
  <keyword>Glucose Intolerance</keyword>
  <keyword>Diabetes Mellitus, Type 2</keyword>
  <keyword>Obesity</keyword>
  <keyword>Muscle, Skeletal</keyword>
  <keyword>Endotoxins</keyword>
  <keyword>Gut Permeability</keyword>
  <keyword>Incretins</keyword>
  <keyword>Metabolic Flexibility</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prediabetic State</mesh_term>
    <mesh_term>Glucose Intolerance</mesh_term>
  </condition_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/NCT02203240
org study id: VT13261005
nct id: NCT02203240
lead sponsor: 
collaborator: 
has dmc: No
The purpose of this study is to determine the impact of consuming cocoa on blood glucose
      levels, glucose metabolism, and other markers of pre-diabetes in overweight and/or obese
      individuals. Our hypothesis is that consumption of cocoa improves insulin sensitivity and
      glucose metabolism in subjects at risk for developing type-2 diabetes.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Double (Participant, Investigator)
measure: Change in insulin sensitivity
time frame: Baseline and 4 weeks
description: Insulin sensitivity will be determined using Bergman's minimal model (MINMOD Millennium software) via a frequently sampled intravenous glucose tolerance test (IVGTT). Fasting baseline blood samples will be taken prior to the dextrose injection (0.3 g/kg; 50% solution) at minute 0. Venous samples will be collected at minutes 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, and 18. Insulin (0.025 U/kg) will be injected at minute 20. Venous sampling will continue at minutes 22, 23, 24, 25, 27, 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, and 180. Glucose concentration will be immediately analyzed an automated glucose oxidase analyzer. Insulin will be later measured from serum using the Immulite 1000 immunoassay analyzer.
measure: Change in blood glucose response to a mixed meal
time frame: Baseline and 1 week
description: The test meal will be 2-8 oz. servings of a meal replacement beverage providing a mixed macronutrient profile, supplemented with either a cocoa beverage dry mix (10 g cocoa) or a calorie-matched placebo beverage mix (0 g cocoa). Blood samples will be taken at baseline and subsequently 1, 2, 3, and 4 hours after the first sip of the test beverage. Plasma glucose concentrations will be analyzed immediately using a glucose auto-analyzer (Yellow Springs Instruments).
measure: Change in hormone secretion response to a mixed meal
time frame: Baseline and 1 week
description: Serum insulin, GLP-1, GIP, and C-peptide concentrations will be determined using commercially available enzyme-linked immunosorbent assay (ELISA) kits from the blood samples drawn at baseline, 1, 2, 3, and 4 hours during the mixed meal challenge.
measure: Change in skeletal muscle metabolic flexibility
time frame: Baseline and 4 weeks
description: Subjects will consume a high fat meal containing 820 kcal; 52 g total carbohydrates, 24 g protein, and 58 g fat. During the high fat challenge session, two skeletal muscle biopsies will be conducted on alternate legs; one before the high fat meal and one 4 hours later. Biopsies of the vastus lateralis will be performed using a 5 mm modified Bergström needle. Collected tissue will be washed in 0.9% sterile saline to remove blood and tissue. Samples will be weighed and added to buffer and placed on ice for immediate analysis of substrate flexibility. For substrate flexibility, pyruvate oxidation will be used to assess the activity of pyruvate dehydrogenase. Calculated metabolic flexibility is expressed as a ratio of pyruvate oxidation to pyruvate oxidation + free fatty acids.
measure: Change in blood endotoxin levels
time frame: Baseline and 4 weeks
description: During the high fat challenge (see Outcome 4), blood samples will be collected at baseline and 1, 2, 3, and 4 h after the first bite of the meal. Serum endotoxin will be measured in duplicate using Limulus Amebocyte Lysate Pyrogent ® 5000 assay kits.
measure: Change in gut permeability
time frame: Baseline and 4 weeks
description: The four-sugar [40 g sucrose, 1 g mannitol, 1 g sucralose and 5 g lactulose] probe test will be used to assess total gut permeability. After an overnight fast and urine evacuation, participants will be asked to consume the sugar-probe beverage within 5 minutes. They will be given two breakfast sandwiches to consume immediately. Participants will be instructed to collect all of their urine in a provided container from the time the beverage was consumed (0 h) until 5 h. A second urine collection container will be filled between 6-24 h. Twenty-four hours later, the volume of urine in each container will be measured and aliquots collected for later analysis. Gastroduodenal permeability is defined as sucrose/mannitol ratio (0-5 h). Small intestinal permeability is defined as the calculated lactulose/mannitol ratio for 0-5 samples. Colonic permeability is defined as both the 6-24 h lactulose/mannitol ratio and 6-24 h sucralose/mannitol ratio.
arm group label: Cocoa
arm group type: Experimental
description: 3 servings of polyphenol-rich cocoa beverage consumed per day.
arm group label: Placebo
arm group type: Placebo Comparator
description: 3 servings of non-cocoa beverage consumed per day.
intervention type: Other
intervention name: Cocoa
arm group label: Cocoa
intervention type: Other
intervention name: Placebo
arm group label: Placebo
criteria: 
gender: All
minimum age: 40 Years
maximum age: 75 Years
healthy volunteers: No
last name: Andrew P Neilson, PhD
role: Principal Investigator
affiliation: Virginia Polytechnic Institute and State University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Virginia Polytechnic Institute and State University
investigator full name: Andrew P. Neilson
investigator title: Assistant Professor
mesh term: Prediabetic State
mesh term: Glucose Intolerance