<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/NCT03802721</url>
  </required_header>
  <id_info>
    <org_study_id>LPI-8789</org_study_id>
    <secondary_id>R01ES028600</secondary_id>
    <nct_id>NCT03802721</nct_id>
  </id_info>
  <brief_title>Pharmacokinetics of Benzo[a]Pyrene: Impact of Diet</brief_title>
  <official_title>Pharmacokinetics of Benzo[a]Pyrene: Impact of Diet</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Oregon State University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Environmental Health Sciences (NIEHS)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Lawrence Livermore National Laboratory</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Pacific Northwest National Laboratory</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
  </sponsors>
  <source>Oregon State University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Evaluation of the pharmacokinetics for [14C]-benzo[a]pyrene ([14C]-BaP) and metabolites in&#xD;
      plasma and urine over 48 hours following a 50 ng dose (5.4 nCi) alone, following 7 days'&#xD;
      consumption of Brussels sprouts, and following 7 days' consumption of a supplement containing&#xD;
      3,3'-diindolylmethane (DIM).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The pharmacokinetics for [14C]-BaP and metabolites will be assessed by UHLPC-Accelerator Mass&#xD;
      Spectrometry (AMS, Lawrence Livermore National Laboratory) in plasma and urine collected over&#xD;
      48 hours following oral doses of 50 ng dose (5.4 nCi) alone, following 7 days' consumption of&#xD;
      Brussels sprouts, and following 7 days' consumption of a supplement containing&#xD;
      3,3'-diindolylmethane (DIM).&#xD;
&#xD;
      The investigators hypothesize that pre-administration of Brussels sprouts or DIM will alter&#xD;
      [14C]-BaP metabolism and increase the rate of elimination consistent with predictions based&#xD;
      on a previously developed Physiologically-Based Pharmacokinetic (PBPK) model for BaP.&#xD;
      Briefly, this hypothesis will be tested by dosing individuals with 50 ng [14C]-BaP alone and,&#xD;
      following a 3-week washout period, ingestion of about 50 g Brussels sprouts or 300 mg of&#xD;
      3,3'-diindolylmethane (DIM) supplement for 7 days prior to the [14C]-BaP micro-dose. The&#xD;
      impact of the supplement and the whole food will be assessed with respect to alterations in&#xD;
      uptake from the GI tract, metabolism and rate of elimination. The consumption of cruciferous&#xD;
      vegetables will be assessed at the beginning of the study by completion of a dietary&#xD;
      questionnaire to examine typical eating patterns in the previous 3 months and by collection&#xD;
      and extraction of blood and urine to assay for DIM by LC/ESI-MS/MS-SRM). In addition, for&#xD;
      each phase, urine will be assayed for DIM as an estimate of crucifer or DIM supplement&#xD;
      intake.&#xD;
&#xD;
      In preclinical and clinical studies, administration of Brussels sprouts or DIM impacts the&#xD;
      activity of the same enzymes responsible for the phase 1 (CYP1A1 and CYP1B1) and phase 2&#xD;
      enzymes (GSTM1, UGT, SULT). Monitoring changes in β-estradiol metabolites will confirm the&#xD;
      mechanism of alteration in the metabolic profile of [14C]-BaP.&#xD;
&#xD;
      Metabolite profiles and kinetics of elimination are predicted to be consistent with a BaP&#xD;
      physiologically based pharmacokinetic (PBPK) model developed by Pacific Northwest National&#xD;
      Laboratory (PNNL). A non-smoker, not exposed occupationally, receives 270-700 ng of BaP&#xD;
      daily; about 95% dietary. The WHO has set an estimated safe daily lifetime (70 year/70 Kg&#xD;
      individual, cancer endpoint) exposure to BaP of 42-350 ng. This protocol represents de&#xD;
      minimus risk.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 24, 2019</start_date>
  <completion_date type="Anticipated">December 2023</completion_date>
  <primary_completion_date type="Anticipated">June 2023</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>Deidentified samples will be analyzed by AMS at Lawrence Livermore National Laboratory and the pharmacokinetics determine at Pacific Northwest National Laboratory.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Plasma and urine 14C-BaP and 14C-BaP metabolite levels after oral dose</measure>
    <time_frame>48 hours</time_frame>
    <description>Plasma and urine levels of 14C-BaP and 14C-BaP metabolites measured by accelerator mass spectrometry</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Peak plasma concentration of 14C-BaP Cmax</measure>
    <time_frame>48 hours</time_frame>
    <description>Determination of highest concentration of 14C-BaP in plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time at highest plasma concentration of 14C-BaP Tmax</measure>
    <time_frame>48 hours</time_frame>
    <description>Determination of time at which plasma concentration of 14C-BaP is highest</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under plasma concentration of 14C-BaP versus time curve AUC</measure>
    <time_frame>48 hours</time_frame>
    <description>Integration of concentration of 14C-BaP in plasma over time</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of elimination of 14C-BaP</measure>
    <time_frame>48 hours</time_frame>
    <description>Determination of constants for rate of elimination of 14C-BaP from plasma</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metabolites of 14C-BaP in plasma</measure>
    <time_frame>48 hours</time_frame>
    <description>Determination of plasma metabolites of 14C-BaP</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metabolites of 14C-BaP in urine</measure>
    <time_frame>48 hours</time_frame>
    <description>Determination of urinary metabolites of 14C-BaP</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metabolites of B-estradiol in urine</measure>
    <time_frame>-7 days and 48 hours</time_frame>
    <description>Determination of urinary metabolites of B-estradiol</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metabolites of B-estradiol in plasma</measure>
    <time_frame>-7 days and 48 hours</time_frame>
    <description>Determination of plasma metabolites of B-estradiol</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metabolites of DIM in plasma</measure>
    <time_frame>-7 days and 48 hours</time_frame>
    <description>Determination of plasma metabolites of DIM</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Metabolites of DIM in urine</measure>
    <time_frame>-7 days and 48 hours</time_frame>
    <description>Determination of urinary metabolites of DIM</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">7</enrollment>
  <condition>Environmental Exposure</condition>
  <arm_group>
    <arm_group_label>50 ng dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Capsule containing 50 ng (5.4 nCi) [14C]-benzo[a]pyrene (BaP)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Brussels sprouts before 50 ng dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will consume 50 g (about 1/2 cup) of lightly steamed Brussels sprouts each evening for 7 days prior to taking capsule containing 50 ng (5.4 nCi) [14C]-benzo[a]pyrene (BaP)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>DIM supplement before 50 ng dose</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will consume 300 mg DIM supplement ( 2 capsules of BioResponse DIM® 150) each evening for 7 days prior to taking capsule containing 50 ng (5.4 nCi) [14C]-benzo[a]pyrene (BaP). A 300 mg DIM dose will be co-administrated with the 50 ng BaP dose</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>[14C]-benzo[a]pyrene</intervention_name>
    <description>Oral micro-dose (50 ng) (5.4 nCi)</description>
    <arm_group_label>50 ng dose</arm_group_label>
    <other_name>Carcinogenic PAH environmental pollutant</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Brussels sprouts before 50 ng dose</intervention_name>
    <description>Brussels sprouts for 7 days before 50 ng (5.4 nCi) dose of BaP</description>
    <arm_group_label>Brussels sprouts before 50 ng dose</arm_group_label>
    <other_name>Brussels sprouts and carcinogenic PAH</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>DIM supplement before 50 ng dose</intervention_name>
    <description>DIM supplement for 7 days before 50 ng (5.4 nCi) dose of BaP and coadministration with DIM supplement</description>
    <arm_group_label>DIM supplement before 50 ng dose</arm_group_label>
    <other_name>Cruciferous vegetable supplement and carcinogenic PAH</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 21-65 (inclusive)&#xD;
&#xD;
          -  If female, must be post-menopausal or have had surgical sterilization to eliminate any&#xD;
             possibility for fetal exposure&#xD;
&#xD;
          -  Willing to defer blood donation for one month before, throughout, and one month after&#xD;
             completion of study activities&#xD;
&#xD;
          -  Willing to avoid consuming cruciferous vegetables, I3C or DIM supplements, smoked or&#xD;
             cured meat or cheeses, or charcoal-grilled meats for 2 weeks prior to and during each&#xD;
             study cycle (gas grilled foods acceptable)&#xD;
&#xD;
          -  Health history review and physical assessment showing general good health, as&#xD;
             determined by study physician. Acceptable physical exam may have been conducted as&#xD;
             part of protocol 8233 or 8554 if subject has not had significant changes in health&#xD;
             status.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Smoker (tobacco or other substances) or use of smokeless tobacco in past 3 months or&#xD;
             living with smoker&#xD;
&#xD;
          -  Regular use of medications that affect gut motility or nutrient absorption (e.g.&#xD;
             cholestyramine, sucralfate, orlistat, pro- or anti-motility agents)&#xD;
&#xD;
          -  History of gastrointestinal surgery (e.g. bariatric surgery, cholecystectomy) or&#xD;
             gastrointestinal disorder (Crohn's disease, celiac disease, IBS, or colitis)&#xD;
&#xD;
          -  Current or history of kidney or liver disease&#xD;
&#xD;
          -  Prior high-dose 14C exposure from medical tests. (micro-dose 14C exposure not&#xD;
             exclusionary)&#xD;
&#xD;
          -  Occupational PAH exposure (e.g. roofers, asphalt pavers, fire-fighters, etc.)&#xD;
&#xD;
          -  Regular use of indole-3-carbinol or DIM dietary supplements&#xD;
&#xD;
          -  Allergy or intolerance to Brussels sprouts or similar foods&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Oregon State University</name>
      <address>
        <city>Corvallis</city>
        <state>Oregon</state>
        <zip>97331</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>January 10, 2019</study_first_submitted>
  <study_first_submitted_qc>January 10, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 14, 2019</study_first_posted>
  <last_update_submitted>March 29, 2023</last_update_submitted>
  <last_update_submitted_qc>March 29, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 30, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Oregon State University</investigator_affiliation>
    <investigator_full_name>David Williams</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Benzo[a]pyrene</keyword>
  <keyword>Accelerator Mass Spectrometry</keyword>
  <keyword>Polycyclic Aromatic Hydrocarbons</keyword>
  <keyword>cruciferous vegetable</keyword>
  <keyword>Brussels sprouts</keyword>
  <keyword>3,3'-diindolylmethane</keyword>
  <keyword>DIM</keyword>
  <keyword>indole-3-carbinol</keyword>
  <keyword>I3C</keyword>
  <keyword>PAH</keyword>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Deidentified samples sent to Lawrence Livermore National Laboratory Deidentified data sent to Pacific Northwest National Laboratory</ipd_description>
  </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/NCT03802721
org study id: LPI-8789
secondary id: R01ES028600
nct id: NCT03802721
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
Evaluation of the pharmacokinetics for [14C]-benzo[a]pyrene ([14C]-BaP) and metabolites in
      plasma and urine over 48 hours following a 50 ng dose (5.4 nCi) alone, following 7 days'
      consumption of Brussels sprouts, and following 7 days' consumption of a supplement containing
      3,3'-diindolylmethane (DIM).
The pharmacokinetics for [14C]-BaP and metabolites will be assessed by UHLPC-Accelerator Mass
      Spectrometry (AMS, Lawrence Livermore National Laboratory) in plasma and urine collected over
      48 hours following oral doses of 50 ng dose (5.4 nCi) alone, following 7 days' consumption of
      Brussels sprouts, and following 7 days' consumption of a supplement containing
      3,3'-diindolylmethane (DIM).

      The investigators hypothesize that pre-administration of Brussels sprouts or DIM will alter
      [14C]-BaP metabolism and increase the rate of elimination consistent with predictions based
      on a previously developed Physiologically-Based Pharmacokinetic (PBPK) model for BaP.
      Briefly, this hypothesis will be tested by dosing individuals with 50 ng [14C]-BaP alone and,
      following a 3-week washout period, ingestion of about 50 g Brussels sprouts or 300 mg of
      3,3'-diindolylmethane (DIM) supplement for 7 days prior to the [14C]-BaP micro-dose. The
      impact of the supplement and the whole food will be assessed with respect to alterations in
      uptake from the GI tract, metabolism and rate of elimination. The consumption of cruciferous
      vegetables will be assessed at the beginning of the study by completion of a dietary
      questionnaire to examine typical eating patterns in the previous 3 months and by collection
      and extraction of blood and urine to assay for DIM by LC/ESI-MS/MS-SRM). In addition, for
      each phase, urine will be assayed for DIM as an estimate of crucifer or DIM supplement
      intake.

      In preclinical and clinical studies, administration of Brussels sprouts or DIM impacts the
      activity of the same enzymes responsible for the phase 1 (CYP1A1 and CYP1B1) and phase 2
      enzymes (GSTM1, UGT, SULT). Monitoring changes in β-estradiol metabolites will confirm the
      mechanism of alteration in the metabolic profile of [14C]-BaP.

      Metabolite profiles and kinetics of elimination are predicted to be consistent with a BaP
      physiologically based pharmacokinetic (PBPK) model developed by Pacific Northwest National
      Laboratory (PNNL). A non-smoker, not exposed occupationally, receives 270-700 ng of BaP
      daily; about 95% dietary. The WHO has set an estimated safe daily lifetime (70 year/70 Kg
      individual, cancer endpoint) exposure to BaP of 42-350 ng. This protocol represents de
      minimus risk.
allocation: Non-Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Single (Outcomes Assessor)
masking description: Deidentified samples will be analyzed by AMS at Lawrence Livermore National Laboratory and the pharmacokinetics determine at Pacific Northwest National Laboratory.
measure: Plasma and urine 14C-BaP and 14C-BaP metabolite levels after oral dose
time frame: 48 hours
description: Plasma and urine levels of 14C-BaP and 14C-BaP metabolites measured by accelerator mass spectrometry
measure: Peak plasma concentration of 14C-BaP Cmax
time frame: 48 hours
description: Determination of highest concentration of 14C-BaP in plasma
measure: Time at highest plasma concentration of 14C-BaP Tmax
time frame: 48 hours
description: Determination of time at which plasma concentration of 14C-BaP is highest
measure: Area under plasma concentration of 14C-BaP versus time curve AUC
time frame: 48 hours
description: Integration of concentration of 14C-BaP in plasma over time
measure: Rate of elimination of 14C-BaP
time frame: 48 hours
description: Determination of constants for rate of elimination of 14C-BaP from plasma
measure: Metabolites of 14C-BaP in plasma
time frame: 48 hours
description: Determination of plasma metabolites of 14C-BaP
measure: Metabolites of 14C-BaP in urine
time frame: 48 hours
description: Determination of urinary metabolites of 14C-BaP
measure: Metabolites of B-estradiol in urine
time frame: -7 days and 48 hours
description: Determination of urinary metabolites of B-estradiol
measure: Metabolites of B-estradiol in plasma
time frame: -7 days and 48 hours
description: Determination of plasma metabolites of B-estradiol
measure: Metabolites of DIM in plasma
time frame: -7 days and 48 hours
description: Determination of plasma metabolites of DIM
measure: Metabolites of DIM in urine
time frame: -7 days and 48 hours
description: Determination of urinary metabolites of DIM
arm group label: 50 ng dose
arm group type: Experimental
description: Capsule containing 50 ng (5.4 nCi) [14C]-benzo[a]pyrene (BaP)
arm group label: Brussels sprouts before 50 ng dose
arm group type: Experimental
description: Subjects will consume 50 g (about 1/2 cup) of lightly steamed Brussels sprouts each evening for 7 days prior to taking capsule containing 50 ng (5.4 nCi) [14C]-benzo[a]pyrene (BaP)
arm group label: DIM supplement before 50 ng dose
arm group type: Experimental
description: Subjects will consume 300 mg DIM supplement ( 2 capsules of BioResponse DIM® 150) each evening for 7 days prior to taking capsule containing 50 ng (5.4 nCi) [14C]-benzo[a]pyrene (BaP). A 300 mg DIM dose will be co-administrated with the 50 ng BaP dose
intervention type: Drug
intervention name: [14C]-benzo[a]pyrene
description: Oral micro-dose (50 ng) (5.4 nCi)
arm group label: 50 ng dose
other name: Carcinogenic PAH environmental pollutant
intervention type: Drug
intervention name: Brussels sprouts before 50 ng dose
description: Brussels sprouts for 7 days before 50 ng (5.4 nCi) dose of BaP
arm group label: Brussels sprouts before 50 ng dose
other name: Brussels sprouts and carcinogenic PAH
intervention type: Drug
intervention name: DIM supplement before 50 ng dose
description: DIM supplement for 7 days before 50 ng (5.4 nCi) dose of BaP and coadministration with DIM supplement
arm group label: DIM supplement before 50 ng dose
other name: Cruciferous vegetable supplement and carcinogenic PAH
criteria: 
gender: All
minimum age: 21 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Oregon State University
investigator full name: David Williams
investigator title: Professor
sharing ipd: No
ipd description: Deidentified samples sent to Lawrence Livermore National Laboratory Deidentified data sent to Pacific Northwest National Laboratory