<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/NCT04421079</url>
  </required_header>
  <id_info>
    <org_study_id>GCO 19-0848</org_study_id>
    <secondary_id>1U19AT010835-01</secondary_id>
    <nct_id>NCT04421079</nct_id>
  </id_info>
  <brief_title>Metabolism of Bioactive Dietary Polyphenol Preparation (BDPP)</brief_title>
  <official_title>Clinical Pharmacology and Target Validation of A Bioactive Dietary Polyphenol Preparation (BDPP) For Stress-Related Disorders</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Icahn School of Medicine at Mount Sinai</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Center for Complementary and Integrative Health (NCCIH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Icahn School of Medicine at Mount Sinai</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will characterize the clinical pharmacology of a select bioactive polyphenol-rich&#xD;
      preparation (Bioactive Dietary Polyphenol Preparation, BDPP) comprised of a select Concord&#xD;
      grape juice (CGJ), a select grape seed polyphenol extract (GSPE) and trans-resveratrol (RSV).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Stress-related disorders, such as depression, are some of the most disabling human illnesses&#xD;
      worldwide. Most currently available treatments for depression target neurochemical or&#xD;
      neurobiological mechanisms identified retrospectively following discovery of the drug's&#xD;
      initial antidepressant efficacy. Unfortunately, conventional pharmacological treatments&#xD;
      produce remission in less than 50% of patients, which highlights the need for novel, more&#xD;
      selective therapeutics targeting newly discovered pathological mechanisms underlying&#xD;
      depression. However, gaps in knowledge regarding the fundamental pathophysiology of&#xD;
      depression and other stress-related disorders (including anxiety disorders and posttraumatic&#xD;
      stress disorder [PTSD]) have limited advances in diagnosis and treatment of the illness.&#xD;
      Recently, work by the study team and others highlight the promise of understanding the&#xD;
      molecular mechanisms of resilience to stress as a novel approach treatment discovery for&#xD;
      these disorders.&#xD;
&#xD;
      Accumulating evidence suggests that immunological abnormalities, particularly imbalances in&#xD;
      select pro-inflammatory mediators, play important roles in the manifestation and persistence&#xD;
      of stress-related disorders such as depression in vulnerable individuals. In humans an acute&#xD;
      stress test delivered in a laboratory setting, as discussed below, has been shown to reliably&#xD;
      increase levels of circulating inflammatory markers. These inflammatory mediators, in&#xD;
      particular interleukin (IL)-6 and tumor necrosis factor (TNF)-α, have been shown to be&#xD;
      elevated in patients diagnosed with depression as well and are now recognized as important&#xD;
      biological signatures as well as key mechanistic contributory factors of stress-related&#xD;
      disorders . As such, inflammatory mediators are also considered important novel therapeutic&#xD;
      targets to promote resilience to stress and potentially prevent and treat depression.&#xD;
&#xD;
      Polyphenols, a select structural class of organic compounds that are abundantly found in some&#xD;
      plants, are potent anti-inflammatory reagents. Recent preclinical evidence from the study&#xD;
      team's highlights the potential value of a select bioactive polyphenol-rich preparation&#xD;
      (Bioactive Dietary Polyphenol Preparation, BDPP) in modulating stress-induced depression&#xD;
      phenotypes and enhancing stress resilience. BDPP is comprised of a select Concord grape juice&#xD;
      (CGJ), a select grape seed polyphenol extract (GSPE) and trans-resveratrol (RSV). The study&#xD;
      team's preclinical evidence suggests that the benefits of BDPP are mechanistically mediated,&#xD;
      in part, by the efficacy of select BDPP-derived, biologically available polyphenol&#xD;
      metabolites in modulating one or more key inflammatory signatures of stress-induced&#xD;
      depressive-like symptoms. In fact, the study team has identified a set of metabolites,&#xD;
      including dihydrocaffeic acid (DHCA), that demonstrate potent anti-inflammatory properties&#xD;
      (including IL-6 inhibition) and pro-resilience behavioral effects in a rodent stress model.&#xD;
      The study team hypothesized that BDPP treatment may alleviate stress response, in part, by&#xD;
      delivering, in vivo, certain biologically available BDPP-derived polyphenol metabolites that&#xD;
      are bioactive in modulating systemic expression of one or more inflammatory biological&#xD;
      signatures of stress.&#xD;
&#xD;
      Based on the scientific rationale outlined above, this study will characterize the clinical&#xD;
      pharmacology of BDPP, including pharmacokinetics, pharmacodynamics and tolerability, and test&#xD;
      the dose-dependent effect of BDPP on inflammatory markers at baseline and in response to&#xD;
      acute stress in healthy volunteers using a rigorous double-blind, randomized, placebo&#xD;
      controlled design. Response to acute stress will be measured using the validated human&#xD;
      laboratory stress paradigm, the Trier Social Stress Test (TSST). The results of this study&#xD;
      will critically inform future clinical trial testing of BDPP for the treatment stress-related&#xD;
      disorders such as depression by establishing key knowledge regarding the clinical&#xD;
      pharmacology and biological effects on inflammatory mediators for BDPP metabolites in humans.&#xD;
&#xD;
      Plasma mass of each polyphenol will be used for analysis instead of concentration to adjust&#xD;
      for individual differences in volume of distribution (plasma volume). Plasma volume for each&#xD;
      participant will be calculated by subtracting blood cell volume (determined by hematocrit)&#xD;
      from blood volume. Area under the plasma polyphenol mass by time curve (AUC) will be&#xD;
      calculated by the middle Reimann Sum method. After confirming normality by the Shapiro-Wilk&#xD;
      test, peak plasma mass and AUC for each metabolite (primarily DHCA) will compared by means of&#xD;
      analysis of covariance (ANCOVA) between different doses of BDPP, wherein exposure is modeled.&#xD;
      Baseline and 24 hours urine polyphenol metabolites will be used as covariates in the&#xD;
      analysis. The dose dependent effects of BDPP on markers of inflammation will be tested using&#xD;
      the multiple linear regression analysis with corrections for confounding factors (age, gender&#xD;
      and BMI). The study team will collect clinical and other biological measures from&#xD;
      participants for subsequent analyses to explore associations between changes in blood levels&#xD;
      of IL-6 with changes in clinical measures (e.g., perceived stress using the PSS) and&#xD;
      biological measures (baseline cortisol levels). The exploratory analyses will perform partial&#xD;
      correlations on regression coefficients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 19, 2021</start_date>
  <completion_date type="Anticipated">August 2024</completion_date>
  <primary_completion_date type="Anticipated">August 2024</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>This is a single center, double-blind, placebo-controlled, randomized phase I trial. Each subject will be randomized to a daily low, medium or high dose of BDPP or placebo.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Participants and investigators will be masked to whether they are assigned to study supplement or placebo.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>DHCA level</measure>
    <time_frame>up to Week 5</time_frame>
    <description>Bioavailability assessed to show a dose-dependent increase in key BDPP metabolites, including DHCA.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>IL-6 levels</measure>
    <time_frame>up to Week 5</time_frame>
    <description>Inflammatory marker IL-6 Levels</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Anticipated">88</enrollment>
  <condition>Healthy Control</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Comparable placebos</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Low Dose BDPP</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>8 oz. Concord grape juice + 450 mg Grape seed polyphenol extract + 150 mg Trans-resveratrol</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Medium Dose BDPP</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>16 oz. Concord grape juice + 900 mg Grape seed polyphenol extract + 300 mg Trans-resveratrol</description>
  </arm_group>
  <arm_group>
    <arm_group_label>High Dose BDPP</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>24 oz. Concord grape juice + 1200mg Grape seed polyphenol extract + 450mg Trans-resveratrol</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Trans-resveratrol</intervention_name>
    <description>150mg, 300mg, 450mg</description>
    <arm_group_label>High Dose BDPP</arm_group_label>
    <arm_group_label>Low Dose BDPP</arm_group_label>
    <arm_group_label>Medium Dose BDPP</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Concord grape juice</intervention_name>
    <description>8 oz, 16 oz, 24 oz</description>
    <arm_group_label>High Dose BDPP</arm_group_label>
    <arm_group_label>Low Dose BDPP</arm_group_label>
    <arm_group_label>Medium Dose BDPP</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Grape seed polyphenol extract</intervention_name>
    <description>450mg, 900mg, 1200mg</description>
    <arm_group_label>High Dose BDPP</arm_group_label>
    <arm_group_label>Low Dose BDPP</arm_group_label>
    <arm_group_label>Medium Dose BDPP</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Comparable placebo supplement which is manufactured according to GMP and will contain inert substances.</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female aged 18-55 years;&#xD;
&#xD;
          -  Body max index (BMI) &lt;30;&#xD;
&#xD;
          -  Participants must have a level of understanding of the English language sufficient to&#xD;
             agree to all tests and examinations required by the study and must be able to&#xD;
             participate fully in the informed consent process.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any psychiatric diagnosis as defined by the Diagnostic and Statistical Manual of&#xD;
             Mental Disorders, Fifth Edition (DSM-5);&#xD;
&#xD;
          -  Subjects who meet criteria for a substance or alcohol use disorder in the past 2&#xD;
             years;&#xD;
&#xD;
          -  Female participants who are pregnant or nursing or plan to become pregnant;&#xD;
&#xD;
          -  Any unstable medical illnesses including hepatic, renal, gastroenterologic,&#xD;
             respiratory, cardiovascular (including ischemic heart disease); endocrinologic,&#xD;
             neurologic, immunologic, or hematologic disease;&#xD;
&#xD;
          -  Clinically significant abnormalities of laboratory tests, physical examination, or&#xD;
             electrocardiogram;&#xD;
&#xD;
          -  Any diagnosed inflammatory or autoimmune disorder, including but not limited to&#xD;
             rheumatoid arthritis, ankylosing spondylitis, myositis, vasculitis, systemic lupus&#xD;
             erythematosus, Sjogren's Syndrome, or scleroderma;&#xD;
&#xD;
          -  Any use of medication or nutritional supplement known to affect inflammation,&#xD;
             including but not limited to non-steroidal anti-inflammatory agents (NSAIDs), aspirin,&#xD;
             acetaminophen, COX-2 selective inhibitors, omega-3 fatty acids, turmeric extract,&#xD;
             ginger extract, vitamin E, and &quot;Devil's claw&quot;;&#xD;
&#xD;
          -  Individuals using supplements known to affect polyphenol levels;&#xD;
&#xD;
          -  Presence of a condition or abnormality that in the opinion of the Investigator would&#xD;
             compromise the safety of the patient or the quality of the data.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>James Murrough, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Icahn School of Medicine at Mount Sinai</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Maxine Marchidan</last_name>
    <phone>212-585-4620</phone>
    <email>maxine.marchidan@mssm.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Sara Hameed</last_name>
    <phone>212-585-4619</phone>
    <email>sara.hameed@mssm.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Icahn School of Medicine at Mount Sinai</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Maxine Marchidan</last_name>
      <phone>212-585-4620</phone>
      <email>maxine.marchidan@mssm.edu</email>
    </contact>
    <contact_backup>
      <last_name>Sara Hameed</last_name>
      <phone>212-585-4619</phone>
      <email>sara.hameed@mssm.edu</email>
    </contact_backup>
    <investigator>
      <last_name>James Murrough, MD, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>June 4, 2020</study_first_submitted>
  <study_first_submitted_qc>June 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 9, 2020</study_first_posted>
  <last_update_submitted>September 14, 2023</last_update_submitted>
  <last_update_submitted_qc>September 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Icahn School of Medicine at Mount Sinai</investigator_affiliation>
    <investigator_full_name>James Murrough</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Polyphenol</keyword>
  <keyword>Dietary Supplement</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Resveratrol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04421079
org study id: GCO 19-0848
secondary id: 1U19AT010835-01
nct id: NCT04421079
lead sponsor: 
collaborator: 
is fda regulated drug: No
is fda regulated device: No
This study will characterize the clinical pharmacology of a select bioactive polyphenol-rich
      preparation (Bioactive Dietary Polyphenol Preparation, BDPP) comprised of a select Concord
      grape juice (CGJ), a select grape seed polyphenol extract (GSPE) and trans-resveratrol (RSV).
Stress-related disorders, such as depression, are some of the most disabling human illnesses
      worldwide. Most currently available treatments for depression target neurochemical or
      neurobiological mechanisms identified retrospectively following discovery of the drug's
      initial antidepressant efficacy. Unfortunately, conventional pharmacological treatments
      produce remission in less than 50% of patients, which highlights the need for novel, more
      selective therapeutics targeting newly discovered pathological mechanisms underlying
      depression. However, gaps in knowledge regarding the fundamental pathophysiology of
      depression and other stress-related disorders (including anxiety disorders and posttraumatic
      stress disorder [PTSD]) have limited advances in diagnosis and treatment of the illness.
      Recently, work by the study team and others highlight the promise of understanding the
      molecular mechanisms of resilience to stress as a novel approach treatment discovery for
      these disorders.

      Accumulating evidence suggests that immunological abnormalities, particularly imbalances in
      select pro-inflammatory mediators, play important roles in the manifestation and persistence
      of stress-related disorders such as depression in vulnerable individuals. In humans an acute
      stress test delivered in a laboratory setting, as discussed below, has been shown to reliably
      increase levels of circulating inflammatory markers. These inflammatory mediators, in
      particular interleukin (IL)-6 and tumor necrosis factor (TNF)-α, have been shown to be
      elevated in patients diagnosed with depression as well and are now recognized as important
      biological signatures as well as key mechanistic contributory factors of stress-related
      disorders . As such, inflammatory mediators are also considered important novel therapeutic
      targets to promote resilience to stress and potentially prevent and treat depression.

      Polyphenols, a select structural class of organic compounds that are abundantly found in some
      plants, are potent anti-inflammatory reagents. Recent preclinical evidence from the study
      team's highlights the potential value of a select bioactive polyphenol-rich preparation
      (Bioactive Dietary Polyphenol Preparation, BDPP) in modulating stress-induced depression
      phenotypes and enhancing stress resilience. BDPP is comprised of a select Concord grape juice
      (CGJ), a select grape seed polyphenol extract (GSPE) and trans-resveratrol (RSV). The study
      team's preclinical evidence suggests that the benefits of BDPP are mechanistically mediated,
      in part, by the efficacy of select BDPP-derived, biologically available polyphenol
      metabolites in modulating one or more key inflammatory signatures of stress-induced
      depressive-like symptoms. In fact, the study team has identified a set of metabolites,
      including dihydrocaffeic acid (DHCA), that demonstrate potent anti-inflammatory properties
      (including IL-6 inhibition) and pro-resilience behavioral effects in a rodent stress model.
      The study team hypothesized that BDPP treatment may alleviate stress response, in part, by
      delivering, in vivo, certain biologically available BDPP-derived polyphenol metabolites that
      are bioactive in modulating systemic expression of one or more inflammatory biological
      signatures of stress.

      Based on the scientific rationale outlined above, this study will characterize the clinical
      pharmacology of BDPP, including pharmacokinetics, pharmacodynamics and tolerability, and test
      the dose-dependent effect of BDPP on inflammatory markers at baseline and in response to
      acute stress in healthy volunteers using a rigorous double-blind, randomized, placebo
      controlled design. Response to acute stress will be measured using the validated human
      laboratory stress paradigm, the Trier Social Stress Test (TSST). The results of this study
      will critically inform future clinical trial testing of BDPP for the treatment stress-related
      disorders such as depression by establishing key knowledge regarding the clinical
      pharmacology and biological effects on inflammatory mediators for BDPP metabolites in humans.

      Plasma mass of each polyphenol will be used for analysis instead of concentration to adjust
      for individual differences in volume of distribution (plasma volume). Plasma volume for each
      participant will be calculated by subtracting blood cell volume (determined by hematocrit)
      from blood volume. Area under the plasma polyphenol mass by time curve (AUC) will be
      calculated by the middle Reimann Sum method. After confirming normality by the Shapiro-Wilk
      test, peak plasma mass and AUC for each metabolite (primarily DHCA) will compared by means of
      analysis of covariance (ANCOVA) between different doses of BDPP, wherein exposure is modeled.
      Baseline and 24 hours urine polyphenol metabolites will be used as covariates in the
      analysis. The dose dependent effects of BDPP on markers of inflammation will be tested using
      the multiple linear regression analysis with corrections for confounding factors (age, gender
      and BMI). The study team will collect clinical and other biological measures from
      participants for subsequent analyses to explore associations between changes in blood levels
      of IL-6 with changes in clinical measures (e.g., perceived stress using the PSS) and
      biological measures (baseline cortisol levels). The exploratory analyses will perform partial
      correlations on regression coefficients.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: This is a single center, double-blind, placebo-controlled, randomized phase I trial. Each subject will be randomized to a daily low, medium or high dose of BDPP or placebo.
primary purpose: Basic Science
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Participants and investigators will be masked to whether they are assigned to study supplement or placebo.
measure: DHCA level
time frame: up to Week 5
description: Bioavailability assessed to show a dose-dependent increase in key BDPP metabolites, including DHCA.
measure: IL-6 levels
time frame: up to Week 5
description: Inflammatory marker IL-6 Levels
arm group label: Placebo
arm group type: Placebo Comparator
description: Comparable placebos
arm group label: Low Dose BDPP
arm group type: Active Comparator
description: 8 oz. Concord grape juice + 450 mg Grape seed polyphenol extract + 150 mg Trans-resveratrol
arm group label: Medium Dose BDPP
arm group type: Active Comparator
description: 16 oz. Concord grape juice + 900 mg Grape seed polyphenol extract + 300 mg Trans-resveratrol
arm group label: High Dose BDPP
arm group type: Active Comparator
description: 24 oz. Concord grape juice + 1200mg Grape seed polyphenol extract + 450mg Trans-resveratrol
intervention type: Dietary Supplement
intervention name: Trans-resveratrol
description: 150mg, 300mg, 450mg
arm group label: High Dose BDPP
arm group label: Low Dose BDPP
arm group label: Medium Dose BDPP
intervention type: Dietary Supplement
intervention name: Concord grape juice
description: 8 oz, 16 oz, 24 oz
arm group label: High Dose BDPP
arm group label: Low Dose BDPP
arm group label: Medium Dose BDPP
intervention type: Dietary Supplement
intervention name: Grape seed polyphenol extract
description: 450mg, 900mg, 1200mg
arm group label: High Dose BDPP
arm group label: Low Dose BDPP
arm group label: Medium Dose BDPP
intervention type: Drug
intervention name: Placebo
description: Comparable placebo supplement which is manufactured according to GMP and will contain inert substances.
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: James Murrough, MD, PhD
role: Principal Investigator
affiliation: Icahn School of Medicine at Mount Sinai
last name: Maxine Marchidan
phone: 212-585-4620
email: maxine.marchidan@mssm.edu
last name: Sara Hameed
phone: 212-585-4619
email: sara.hameed@mssm.edu
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Icahn School of Medicine at Mount Sinai
investigator full name: James Murrough
investigator title: Associate Professor
mesh term: Resveratrol
sharing ipd: No