<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/NCT02257879</url>
  </required_header>
  <id_info>
    <org_study_id>140204</org_study_id>
    <secondary_id>14-E-0204</secondary_id>
    <nct_id>NCT02257879</nct_id>
  </id_info>
  <brief_title>DHB Supplement Interaction Study</brief_title>
  <official_title>A Pharmacokinetic Study to Assess and Compare the Drug Interaction Risk of the Grapefruit Juice and Dietary Supplements Known to Inhibit CYP3A Enzyme Activity</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute of Environmental Health Sciences (NIEHS)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      - Drinking grapefruit juice changes how long it takes some medicines to be broken down in the&#xD;
      body. Researchers have found that a substance in grapefruit juice called DHB contributes to&#xD;
      this effect. Some dietary supplements contain DHB and claim to increase the absorption of any&#xD;
      and all supplements, medicine or any other drug. But these usually contain a lot more DHB&#xD;
      than a glass of grapefruit juice. Researchers want to study the effects of grapefruit juice&#xD;
      and supplements with DHB.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      - To compare how a certain dietary supplement (sold as DHB-300 ) versus grapefruit juice&#xD;
      affects how long it takes a person s body to break down medicines.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - Healthy volunteers ages 18 - 60.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will be screened with medical history, physical exam, and blood and urine&#xD;
           tests.&#xD;
&#xD;
        -  Participants will have 3 treatment visits. Participants cannot drive themselves home&#xD;
           from the visits. Each visit lasts about 13.5 hours and includes:&#xD;
&#xD;
        -  Questions about medications and participant s health.&#xD;
&#xD;
        -  Vital signs taken.&#xD;
&#xD;
        -  A finger probe to measure oxygen.&#xD;
&#xD;
        -  Blood and urine sampling throughout the visit.&#xD;
&#xD;
        -  An IV line inserted into an arm vein. It will stay there throughout the visit.&#xD;
&#xD;
        -  Study treatments:&#xD;
&#xD;
        -  Midazolam hydrochloride a syrup given to make people sleepy.&#xD;
&#xD;
        -  Loperamide a tablet for treating diarrhea.&#xD;
&#xD;
        -  1 glass of water, 1 glass of grapefruit juice, or 1 pill of DHB-300. A different one&#xD;
           will be given at each treatment visit.&#xD;
&#xD;
        -  One week before each visit, participants cannot have certain fruits and juices. They&#xD;
           must fast the night before each visit.&#xD;
&#xD;
        -  For the 3 days after each visit, participants will return to the clinic 4 times. Their&#xD;
           vital signs will be checked and blood will be drawn.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      6 ,7 -dihydroxybergamottin (DHB) is one of the components of grapefruit juice and is a known&#xD;
      irreversible inhibitor of intestinal cytochrome P450 3A (CYP3A). A single serving (240 mL) of&#xD;
      grapefruit juice (GFJ) contains less than or equal to 5 mg of DHB. The pharmacokinetic&#xD;
      boosting effect of GFJ has fueled the marketing of dietary supplements labeled to contain DHB&#xD;
      e.g. DHB 300 (TM) and Trisorbagen that enhance absorption naturally, While these supplements&#xD;
      have been found to inhibit CYP3A activity, the DHB content in these supplements is much lower&#xD;
      than that, of GFJ. Moreover, the effects of such supplements on the pharmacokinetics of&#xD;
      CYP3A-metabolized drugs are largely unknown. This single-center, open-label, randomized,&#xD;
      3-period, single-dose, crossover study in healthy volunteers will compare the drug&#xD;
      interaction risk of a dietary supplement known to affect CYP3A with GFJ. The primary&#xD;
      objective of this study is to compare the effects of a supplement known to affect CYP3A&#xD;
      (e.g.Trisorbagen) with those of GFJ and water on the pharmacokinetics of two model&#xD;
      substrates, the FDA-recommended CYP3A probe substrate midazolam, and the dual&#xD;
      CYP3A/P-glycoprotein (P-gp) substrate loperamide. This dual-probe substrate approach to&#xD;
      assess drug interaction risk will provide mechanistic insight into any interaction observed.&#xD;
      Eligible volunteers (n=12) will undergo 3 phases, each comprising an exposure visit and 4&#xD;
      subsequent post-exposure visits to collect blood and urine over 72 or 12 hours, respectively.&#xD;
      Exposure visits will be scheduled at least 2 weeks apart to allow washout between the phases.&#xD;
      At each exposure visit, participants will be administered oral doses of midazolam&#xD;
      hydrochloride (2.5 mg) and loperamide (16 mg) concomitantly with water (240 mL), GFJ (240&#xD;
      mL), or Trisorbagen (with 240 mL water) according to a randomized treatment sequence. Blood&#xD;
      and urine will be collected pre-dose and post-dose over 72 (blood) or 12 (urine) hours for&#xD;
      subsequent analyses of relevant pharmacokinetic outcomes of each probe substrate, including&#xD;
      the primary endpoints area under the concentration-time curve from time zero (pre-dose) to&#xD;
      infinity (AUC0-inf) and maximum observed concentration (Cmax). Secondary endpoints include&#xD;
      geometric means, estimates of treatment differences, within-subject and between-subject&#xD;
      treatment variance, as well as the 95% confidence intervals around those estimates.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    due to constraints with collaborator and subject matter expert, recruitment was unable to begin&#xD;
  </why_stopped>
  <start_date type="Actual">October 3, 2014</start_date>
  <completion_date type="Actual">April 20, 2020</completion_date>
  <primary_completion_date type="Actual">April 20, 2020</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Crossover</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Pharmacokinetic measures (AUC0 inf, Cmax) of systemic drug exposure</measure>
    <time_frame>AUC from 0-72 h -inf</time_frame>
    <description>PK measures of systemic probe drug exposure (AUCO-inf and Cmax), determined via conventional non-compartmental methods using Phoenix WinNonlin (v6.2)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Geometric means, estimates of treatment differences, within-subject and between-subject treatment variance, and the 95% confidence intervals around those estimates</measure>
    <time_frame>AUC from 0-72 h -inf</time_frame>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">0</enrollment>
  <condition>Healthy Volunteers</condition>
  <arm_group>
    <arm_group_label>Sequence A</arm_group_label>
    <description>water - GFJ - supplement</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sequence B</arm_group_label>
    <description>GFJ - supplement - water</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sequence C</arm_group_label>
    <description>supplement - water - GFJ</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Participants will be recruited from the Environmental Polymorphisms Registry. Prior to&#xD;
        enrollment in this study the participant will be required to enroll in the Environmental&#xD;
        Polymorphisms Registry.@@@@@@&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  Age 18-60&#xD;
&#xD;
          -  Men and non-pregnant women&#xD;
&#xD;
          -  Participant in the Environmental Polymorphisms Registry. Prior to enrollment in this&#xD;
             study the participant will be required to enroll in the -Environmental Polymorphisms&#xD;
             Registry.&#xD;
&#xD;
          -  Willing to abstain from fruit juices, star fruit, grapefruit and grapefruit-related&#xD;
             fruits (e.g., pomelo, Seville orange), and grapefruitcontaining products for 1 week&#xD;
             prior to Exposure Visits and for the 4 follow-up visits.&#xD;
&#xD;
          -  Willing to fast (with the exception of water) from midnight prior to the screening&#xD;
             visit and each Exposure Visit, including abstaining from&#xD;
&#xD;
        alcohol and caffeinated beverages&#xD;
&#xD;
        -Ability to successfully complete treatment visits, including securing transportation&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Women who are currently pregnant or breastfeeding&#xD;
&#xD;
          -  Current use of known CYP3A inhibitors or inducers, which in the opinion of the&#xD;
             Investigator poses an unacceptable risk to the patient or to the validity of study&#xD;
             results. Candidates will be asked about medication use during the screening process&#xD;
             and on the day of the exposure visits. The collected data will be reviewed by the PI&#xD;
             or designee to confirm the candidates eligibility.&#xD;
&#xD;
          -  Known liver dysfunction or disease as defined by:&#xD;
&#xD;
               -  ALT - higher than the normative value and/or determined abnormal by the PI&#xD;
&#xD;
               -  AST higher than the normative value and/or determined abnormal by the PI&#xD;
&#xD;
               -  ALP higher than the normative value and/or determined abnormal by the PI&#xD;
&#xD;
        Known kidney dysfunction or disease or:&#xD;
&#xD;
          -  Estimated Glomerular Filtration Rate (eGFR)- &lt;60 ml/min per the MDRD equation&#xD;
&#xD;
               -  Heart disease&#xD;
&#xD;
               -  Pre-existing and known history of psychiatric disorders&#xD;
&#xD;
               -  Known history of Myasthenia gravis&#xD;
&#xD;
               -  Current use of quinidine, ritonavir, and saquinavir (potential interaction with&#xD;
                  loperamide)&#xD;
&#xD;
               -  Current use of study drug-related medications (benzodiazepines, opioids, herbal&#xD;
                  supplements; temporary discontinuation per the investigator s discretion may be&#xD;
                  allowed). Candidates will be asked about medication use during the screening&#xD;
                  process and also during each of their exposure visits. The collected data will be&#xD;
                  reviewed by the PI or designee to confirm the candidates eligibility.&#xD;
&#xD;
               -  Known allergy or hypersensitivity to any study treatments (i.e., to GFJ, DHB,&#xD;
                  midazolam, loperamide, green, black or white pepper, and -Indian Gooseberry),any&#xD;
                  opioids, or benzodiazepines&#xD;
&#xD;
               -  History of acute-angle glaucoma&#xD;
&#xD;
               -  History of sleep apnea&#xD;
&#xD;
               -  Current diagnosis of anemia, as defined by hemoglobin concentration &lt;13 g/dL for&#xD;
                  males and hemoglobin concentration &lt;11 g/dL for females or hematocrit values&#xD;
                  (determined by lancet-induced drop of blood from the fingertip or via clinical&#xD;
                  labs) Hematocrit must be at least 34% for women and 36% for men on every visit.&#xD;
&#xD;
               -  Blood donation within the past 8 weeks of the exposure visit.&#xD;
&#xD;
               -  Use of medications for which consumption of GFJ is contraindicated and which in&#xD;
                  the opinion of the Investigator would pose an unacceptable risk to the patient if&#xD;
                  discontinued or continued while consuming GFJ. Candidates will be asked about&#xD;
                  medication use during the screening process. The collected data will be reviewed&#xD;
                  by the PI or designee to confirm the candidates eligibility.&#xD;
&#xD;
               -  Any other conditions or substance use that in the opinion of the Investigator&#xD;
                  would pose an unacceptable risk to the patient or to the validity of the study&#xD;
                  results. Candidates will be asked about health conditions during the screening&#xD;
                  process. The collected data will be reviewed by the PI or designee to confirm the&#xD;
                  candidates eligibility.&#xD;
&#xD;
               -  BMI &gt;35.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Shepherd H Schurman, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute of Environmental Health Sciences (NIEHS)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>NIEHS Clinical Research Unit (CRU)</name>
      <address>
        <city>Research Triangle Park</city>
        <state>North Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-E-0204.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <reference>
    <citation>de Castro WV, Mertens-Talcott S, Derendorf H, Butterweck V. Grapefruit juice-drug interactions: Grapefruit juice and its components inhibit P-glycoprotein (ABCB1) mediated transport of talinolol in Caco-2 cells. J Pharm Sci. 2007 Oct;96(10):2808-17. doi: 10.1002/jps.20975.</citation>
    <PMID>17542018</PMID>
  </reference>
  <reference>
    <citation>Paine MF, Oberlies NH. Clinical relevance of the small intestine as an organ of drug elimination: drug-fruit juice interactions. Expert Opin Drug Metab Toxicol. 2007 Feb;3(1):67-80. doi: 10.1517/17425255.3.1.67.</citation>
    <PMID>17269895</PMID>
  </reference>
  <reference>
    <citation>Lang M, Seifert MH, Wolf KK, Aschenbrenner A, Baumgartner R, Wieber T, Trentinaglia V, Blisse M, Tajima N, Yamashita T, Vitt D, Noda H. Discovery and hit-to-lead optimization of novel allosteric glucokinase activators. Bioorg Med Chem Lett. 2011 Sep 15;21(18):5417-22. doi: 10.1016/j.bmcl.2011.06.128. Epub 2011 Jul 18.</citation>
    <PMID>21813277</PMID>
  </reference>
  <verification_date>April 2020</verification_date>
  <study_first_submitted>October 3, 2014</study_first_submitted>
  <study_first_submitted_qc>October 4, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 7, 2014</study_first_posted>
  <last_update_submitted>April 21, 2020</last_update_submitted>
  <last_update_submitted_qc>April 21, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">April 24, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Midazolam</keyword>
  <keyword>CYP3A</keyword>
  <keyword>Loperamide</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/NCT02257879
org study id: 140204
secondary id: 14-E-0204
nct id: NCT02257879
lead sponsor: 
Background:

      - Drinking grapefruit juice changes how long it takes some medicines to be broken down in the
      body. Researchers have found that a substance in grapefruit juice called DHB contributes to
      this effect. Some dietary supplements contain DHB and claim to increase the absorption of any
      and all supplements, medicine or any other drug. But these usually contain a lot more DHB
      than a glass of grapefruit juice. Researchers want to study the effects of grapefruit juice
      and supplements with DHB.

      Objective:

      - To compare how a certain dietary supplement (sold as DHB-300 ) versus grapefruit juice
      affects how long it takes a person s body to break down medicines.

      Eligibility:

      - Healthy volunteers ages 18 - 60.

      Design:

        -  Participants will be screened with medical history, physical exam, and blood and urine
           tests.

        -  Participants will have 3 treatment visits. Participants cannot drive themselves home
           from the visits. Each visit lasts about 13.5 hours and includes:

        -  Questions about medications and participant s health.

        -  Vital signs taken.

        -  A finger probe to measure oxygen.

        -  Blood and urine sampling throughout the visit.

        -  An IV line inserted into an arm vein. It will stay there throughout the visit.

        -  Study treatments:

        -  Midazolam hydrochloride a syrup given to make people sleepy.

        -  Loperamide a tablet for treating diarrhea.

        -  1 glass of water, 1 glass of grapefruit juice, or 1 pill of DHB-300. A different one
           will be given at each treatment visit.

        -  One week before each visit, participants cannot have certain fruits and juices. They
           must fast the night before each visit.

        -  For the 3 days after each visit, participants will return to the clinic 4 times. Their
           vital signs will be checked and blood will be drawn.
6 ,7 -dihydroxybergamottin (DHB) is one of the components of grapefruit juice and is a known
      irreversible inhibitor of intestinal cytochrome P450 3A (CYP3A). A single serving (240 mL) of
      grapefruit juice (GFJ) contains less than or equal to 5 mg of DHB. The pharmacokinetic
      boosting effect of GFJ has fueled the marketing of dietary supplements labeled to contain DHB
      e.g. DHB 300 (TM) and Trisorbagen that enhance absorption naturally, While these supplements
      have been found to inhibit CYP3A activity, the DHB content in these supplements is much lower
      than that, of GFJ. Moreover, the effects of such supplements on the pharmacokinetics of
      CYP3A-metabolized drugs are largely unknown. This single-center, open-label, randomized,
      3-period, single-dose, crossover study in healthy volunteers will compare the drug
      interaction risk of a dietary supplement known to affect CYP3A with GFJ. The primary
      objective of this study is to compare the effects of a supplement known to affect CYP3A
      (e.g.Trisorbagen) with those of GFJ and water on the pharmacokinetics of two model
      substrates, the FDA-recommended CYP3A probe substrate midazolam, and the dual
      CYP3A/P-glycoprotein (P-gp) substrate loperamide. This dual-probe substrate approach to
      assess drug interaction risk will provide mechanistic insight into any interaction observed.
      Eligible volunteers (n=12) will undergo 3 phases, each comprising an exposure visit and 4
      subsequent post-exposure visits to collect blood and urine over 72 or 12 hours, respectively.
      Exposure visits will be scheduled at least 2 weeks apart to allow washout between the phases.
      At each exposure visit, participants will be administered oral doses of midazolam
      hydrochloride (2.5 mg) and loperamide (16 mg) concomitantly with water (240 mL), GFJ (240
      mL), or Trisorbagen (with 240 mL water) according to a randomized treatment sequence. Blood
      and urine will be collected pre-dose and post-dose over 72 (blood) or 12 (urine) hours for
      subsequent analyses of relevant pharmacokinetic outcomes of each probe substrate, including
      the primary endpoints area under the concentration-time curve from time zero (pre-dose) to
      infinity (AUC0-inf) and maximum observed concentration (Cmax). Secondary endpoints include
      geometric means, estimates of treatment differences, within-subject and between-subject
      treatment variance, as well as the 95% confidence intervals around those estimates.
observational model: Case-Crossover
time perspective: Prospective
measure: Pharmacokinetic measures (AUC0 inf, Cmax) of systemic drug exposure
time frame: AUC from 0-72 h -inf
description: PK measures of systemic probe drug exposure (AUCO-inf and Cmax), determined via conventional non-compartmental methods using Phoenix WinNonlin (v6.2)
measure: Geometric means, estimates of treatment differences, within-subject and between-subject treatment variance, and the 95% confidence intervals around those estimates
time frame: AUC from 0-72 h -inf
arm group label: Sequence A
description: water - GFJ - supplement
arm group label: Sequence B
description: GFJ - supplement - water
arm group label: Sequence C
description: supplement - water - GFJ
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Shepherd H Schurman, M.D.
role: Principal Investigator
affiliation: National Institute of Environmental Health Sciences (NIEHS)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-E-0204.html
description: NIH Clinical Center Detailed Web Page
citation: de Castro WV, Mertens-Talcott S, Derendorf H, Butterweck V. Grapefruit juice-drug interactions: Grapefruit juice and its components inhibit P-glycoprotein (ABCB1) mediated transport of talinolol in Caco-2 cells. J Pharm Sci. 2007 Oct;96(10):2808-17. doi: 10.1002/jps.20975.
PMID: 17542018
citation: Paine MF, Oberlies NH. Clinical relevance of the small intestine as an organ of drug elimination: drug-fruit juice interactions. Expert Opin Drug Metab Toxicol. 2007 Feb;3(1):67-80. doi: 10.1517/17425255.3.1.67.
PMID: 17269895
citation: Lang M, Seifert MH, Wolf KK, Aschenbrenner A, Baumgartner R, Wieber T, Trentinaglia V, Blisse M, Tajima N, Yamashita T, Vitt D, Noda H. Discovery and hit-to-lead optimization of novel allosteric glucokinase activators. Bioorg Med Chem Lett. 2011 Sep 15;21(18):5417-22. doi: 10.1016/j.bmcl.2011.06.128. Epub 2011 Jul 18.
PMID: 21813277
responsible party type: Sponsor