<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/NCT03809234</url>
  </required_header>
  <id_info>
    <org_study_id>201811167</org_study_id>
    <nct_id>NCT03809234</nct_id>
  </id_info>
  <brief_title>Pgp Transporter and CNS Biodistribution of Ondansetron in Healthy Volunteers</brief_title>
  <official_title>Effects of Pgp Transporter Inhibition on CNS Biodistribution of Ondansetron in Healthy Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Washington University School of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</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>
      To determine the time-course of plasma and CSF concentrations of intravenous (IV) ondansetron&#xD;
      in healthy subjects, with and without selective inhibition of Pgp efflux transporter.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study hypothesis is that inhibition of Pgp efflux transporters will increase the CNS&#xD;
      bio-distribution of the 5-HT3R antagonist ondansetron.&#xD;
&#xD;
      Specifically:&#xD;
&#xD;
        1. Intravenous administration of ondansetron is expected to yield low CSF exposure.&#xD;
&#xD;
        2. Co-administration of ondansetron with intravenous tariquidar, an inhibitor of Pgp efflux&#xD;
           transporters, will result in increased CSF exposure of ondansetron.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Adverse effects related to study procedure (not study drug)&#xD;
  </why_stopped>
  <start_date type="Actual">May 20, 2019</start_date>
  <completion_date type="Actual">November 30, 2020</completion_date>
  <primary_completion_date type="Actual">November 30, 2020</primary_completion_date>
  <phase>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>Other</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>CSF penetration of ondansetron with and without tariquidar - area under the curve (AUC)</measure>
    <time_frame>48 hours</time_frame>
    <description>CSF penetration of intravenous ondansetron will be determined as AUCCSF0-∞ of ondansetron, and compared between the two sessions, with and without tariquidar</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cmax CSF</measure>
    <time_frame>48 hours</time_frame>
    <description>Maximum CSF concentration (Cmax CSF) of ondansetron, compared between the sessions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CSF:plasma concentration ratio</measure>
    <time_frame>48 hours</time_frame>
    <description>CSF:plasma concentration ratio of ondansetron, compared between the two sessions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Cmax</measure>
    <time_frame>48 hours</time_frame>
    <description>Maximum plasma concentration (Cmax) of ondansetron, compared between the sessions</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Evaluation of analgesic effect of ondansetron in an experimental heat pain model</measure>
    <time_frame>48 hours</time_frame>
    <description>Comparison of analgesic effect of ondansetron in an experimental heat pain model: HPTT (as Δ°C from baseline) will be compared between the sessions at 30 min and 50 min after ondansetron infusion completion</description>
  </other_outcome>
  <other_outcome>
    <measure>Assessment of analgesic effect of ondansetron in an experimental cold pain model</measure>
    <time_frame>48 hours</time_frame>
    <description>Comparison of analgesic effect of ondansetron in an experimental cold pain model duration of tolerance and pain rating after 120 second (or maximum tolerable) hand submersion in 3-5°C water will be compared between the sessions at 40 minutes.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>Neuropathic Pain</condition>
  <arm_group>
    <arm_group_label>Ondansetron with Tariquidar</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The participants will receive an IV ondansetron infusion with tariquidar. Participants will receive either 8mg or 16 mg of iv ondansetron, with 4mg/kg tariguidar.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ondansetron with Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>The participants will receive an IV ondansetron infusion with D5W as placebo. Participants will receive either 8mg or 16 mg of iv ondansetron.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ondansetron 8mg with Saline &amp; Tariquidar</intervention_name>
    <description>Each participant will receive two IV infusions of ondansetron, 24 hours apart. In the first and second sessions, respectively, placebo (D5W) or tariquidar (4mg/kg dose in D5W) 22 will be administered IV over 60 minutes. Ondansetron will be diluted in 50mL 0.9% normal saline, and tariquidar will be diluted in 250mL D5W.</description>
    <arm_group_label>Ondansetron with Placebo</arm_group_label>
    <arm_group_label>Ondansetron with Tariquidar</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ondansetron 16mg with Saline &amp; Tariquidar</intervention_name>
    <description>Each participant will receive two IV infusions of ondansetron, 24 hours apart. In the first and second sessions, respectively, placebo (D5W) or tariquidar (4mg/kg dose in D5W) 22 will be administered IV over 60 minutes. Ondansetron will be diluted in 50mL 0.9% normal saline, and tariquidar will be diluted in 250mL D5W.</description>
    <arm_group_label>Ondansetron with Placebo</arm_group_label>
    <arm_group_label>Ondansetron with Tariquidar</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age 18-50;&#xD;
&#xD;
          2. Body mass index between 18.5 and 30;&#xD;
&#xD;
          3. Good general health with no remarkable medical conditions;&#xD;
&#xD;
          4. Able and willing to provide informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Current pregnancy or lactation;&#xD;
&#xD;
          2. Known history of hepatic, renal, or cardiac disease, including Long QT Syndrome,&#xD;
             cardiac arrhythmias or QTc interval &gt;450msec;&#xD;
&#xD;
          3. Known hypertension, endocrine disorders (such as diabetes mellitus), chronic pain,&#xD;
             hematologic disorders, or psychiatric conditions requiring medications;&#xD;
&#xD;
          4. Abnormal vital signs at screening visit, including:&#xD;
&#xD;
               -  HR &lt;40 or &gt;100&#xD;
&#xD;
               -  SBP &lt; 90mmHg or &gt;150mmHg&#xD;
&#xD;
               -  DBP &gt; 100mmHg&#xD;
&#xD;
          5. Abnormal troponin values at screening visit&#xD;
&#xD;
          6. Abnormal complete blood count (CBC) or comprehensive metabolic panel (CMP) values at&#xD;
             screening visit that could affect drug pharmacokinetics, or suggest undiagnosed&#xD;
             medical condition which would increase the risk of complications resulting from this&#xD;
             study.&#xD;
&#xD;
          7. Any contraindication for ondansetron administration;&#xD;
&#xD;
          8. Peri- or post-menopausal women experiencing symptoms such as hot flashes;&#xD;
&#xD;
          9. Contraindication to intrathecal catheter placement, such as known coagulopathy or&#xD;
             history of clotting disorders, history of scoliosis or lumbar fusion, current&#xD;
             infection or fever;&#xD;
&#xD;
         10. Ongoing use of any of the following medications with known effects on Pgp function:&#xD;
             carbamazepine, phenytoin, phenobarbital, cyclosporine, clarithromycin, erythromycin,&#xD;
             ritonavir, verapamil, rifampicin, St. John's wort;&#xD;
&#xD;
         11. Current treatment (or treatment within &lt; 5 half-lives) with any medication, including&#xD;
             QT-prolonging drugs and drugs known to have a significant interaction with ondansetron&#xD;
             or P-gp substrates (see below:)&#xD;
&#xD;
               -  Antiretrovirals of Protease inhibitor (e.g. Ritonavir, Saquinavir) or&#xD;
                  Non-nucleoside reverse transcriptase inhibitors (e.g. Efavirenz, Zidovudine)&#xD;
                  family.&#xD;
&#xD;
               -  Phenytoin, Carbamazepine, Oxcarbazepine, Rifampin&#xD;
&#xD;
               -  Amiodarone&#xD;
&#xD;
               -  Azole antifungals (e.g. Itraconazole, Fluconazole)&#xD;
&#xD;
               -  Macrolide antibiotics (Erythromycin, Clarithromycin)&#xD;
&#xD;
               -  Cimetidine&#xD;
&#xD;
               -  Non-DHP calcium channel blockers Verapamil and Diltiazem&#xD;
&#xD;
               -  First generation antipsychotic medications Thioridazine, Haloperidol,&#xD;
                  Chlorpromazine, and Pimozide&#xD;
&#xD;
               -  Second generation antipsychotic medications Ziprasidone and Quetiapine&#xD;
&#xD;
               -  Antihistamine Terfenadine&#xD;
&#xD;
               -  Antidepressants Trazodone, Bupropion, monoamine oxidase inhibitors, Mirtazapine&#xD;
&#xD;
               -  Antiarrhythmics Propafenone, Flecainide, and Procainamide&#xD;
&#xD;
               -  Fluoroquinolone antibiotics Norfloxacin, Ofloxacin, and Ciprofloxacin&#xD;
&#xD;
               -  Cisapride&#xD;
&#xD;
               -  Fentanyl, Lithium, Tramadol&#xD;
&#xD;
               -  Intravenous Methylene blue&#xD;
&#xD;
               -  Other strong inhibitors or inducers of Cytochromes P450 2D6 or 3A4.&#xD;
&#xD;
               -  Other strong inhibitors or inducers of P-glycoprotein&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Simon Haroutounian, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Washington University School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Washington University in St. Louis</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Yawn BP, Wollan PC, Weingarten TN, Watson JC, Hooten WM, Melton LJ 3rd. The prevalence of neuropathic pain: clinical evaluation compared with screening tools in a community population. Pain Med. 2009 Apr;10(3):586-93. doi: 10.1111/j.1526-4637.2009.00588.x. Epub 2009 Mar 17. Erratum In: Pain Med. 2011 Aug;12(8):1294.</citation>
    <PMID>20849570</PMID>
  </reference>
  <reference>
    <citation>Smith BH, Torrance N. Epidemiology of neuropathic pain and its impact on quality of life. Curr Pain Headache Rep. 2012 Jun;16(3):191-8. doi: 10.1007/s11916-012-0256-0.</citation>
    <PMID>22395856</PMID>
  </reference>
  <reference>
    <citation>Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpaa M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015 Feb;14(2):162-73. doi: 10.1016/S1474-4422(14)70251-0. Epub 2015 Jan 7.</citation>
    <PMID>25575710</PMID>
  </reference>
  <reference>
    <citation>Dogrul A, Ossipov MH, Porreca F. Differential mediation of descending pain facilitation and inhibition by spinal 5HT-3 and 5HT-7 receptors. Brain Res. 2009 Jul 14;1280:52-9. doi: 10.1016/j.brainres.2009.05.001. Epub 2009 May 8.</citation>
    <PMID>19427839</PMID>
  </reference>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>January 14, 2019</study_first_submitted>
  <study_first_submitted_qc>January 15, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 18, 2019</study_first_posted>
  <last_update_submitted>March 28, 2022</last_update_submitted>
  <last_update_submitted_qc>March 28, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Washington University School of Medicine</investigator_affiliation>
    <investigator_full_name>simon.haroutounian</investigator_full_name>
    <investigator_title>Assistant Professor of Anesthsiology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neuralgia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ondansetron</mesh_term>
  </intervention_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/NCT03809234
org study id: 201811167
nct id: NCT03809234
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
To determine the time-course of plasma and CSF concentrations of intravenous (IV) ondansetron
      in healthy subjects, with and without selective inhibition of Pgp efflux transporter.
The study hypothesis is that inhibition of Pgp efflux transporters will increase the CNS
      bio-distribution of the 5-HT3R antagonist ondansetron.

      Specifically:

        1. Intravenous administration of ondansetron is expected to yield low CSF exposure.

        2. Co-administration of ondansetron with intravenous tariquidar, an inhibitor of Pgp efflux
           transporters, will result in increased CSF exposure of ondansetron.
allocation: Non-Randomized
intervention model: Crossover Assignment
primary purpose: Other
masking: Single (Participant)
measure: CSF penetration of ondansetron with and without tariquidar - area under the curve (AUC)
time frame: 48 hours
description: CSF penetration of intravenous ondansetron will be determined as AUCCSF0-∞ of ondansetron, and compared between the two sessions, with and without tariquidar
measure: Cmax CSF
time frame: 48 hours
description: Maximum CSF concentration (Cmax CSF) of ondansetron, compared between the sessions
measure: CSF:plasma concentration ratio
time frame: 48 hours
description: CSF:plasma concentration ratio of ondansetron, compared between the two sessions
measure: Plasma Cmax
time frame: 48 hours
description: Maximum plasma concentration (Cmax) of ondansetron, compared between the sessions
measure: Evaluation of analgesic effect of ondansetron in an experimental heat pain model
time frame: 48 hours
description: Comparison of analgesic effect of ondansetron in an experimental heat pain model: HPTT (as Δ°C from baseline) will be compared between the sessions at 30 min and 50 min after ondansetron infusion completion
measure: Assessment of analgesic effect of ondansetron in an experimental cold pain model
time frame: 48 hours
description: Comparison of analgesic effect of ondansetron in an experimental cold pain model duration of tolerance and pain rating after 120 second (or maximum tolerable) hand submersion in 3-5°C water will be compared between the sessions at 40 minutes.
arm group label: Ondansetron with Tariquidar
arm group type: Experimental
description: The participants will receive an IV ondansetron infusion with tariquidar. Participants will receive either 8mg or 16 mg of iv ondansetron, with 4mg/kg tariguidar.
arm group label: Ondansetron with Placebo
arm group type: Placebo Comparator
description: The participants will receive an IV ondansetron infusion with D5W as placebo. Participants will receive either 8mg or 16 mg of iv ondansetron.
intervention type: Drug
intervention name: Ondansetron 8mg with Saline & Tariquidar
description: Each participant will receive two IV infusions of ondansetron, 24 hours apart. In the first and second sessions, respectively, placebo (D5W) or tariquidar (4mg/kg dose in D5W) 22 will be administered IV over 60 minutes. Ondansetron will be diluted in 50mL 0.9% normal saline, and tariquidar will be diluted in 250mL D5W.
arm group label: Ondansetron with Placebo
arm group label: Ondansetron with Tariquidar
intervention type: Drug
intervention name: Ondansetron 16mg with Saline & Tariquidar
description: Each participant will receive two IV infusions of ondansetron, 24 hours apart. In the first and second sessions, respectively, placebo (D5W) or tariquidar (4mg/kg dose in D5W) 22 will be administered IV over 60 minutes. Ondansetron will be diluted in 50mL 0.9% normal saline, and tariquidar will be diluted in 250mL D5W.
arm group label: Ondansetron with Placebo
arm group label: Ondansetron with Tariquidar
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Simon Haroutounian, PhD
role: Principal Investigator
affiliation: Washington University School of Medicine
facility: 
country: United States
citation: Yawn BP, Wollan PC, Weingarten TN, Watson JC, Hooten WM, Melton LJ 3rd. The prevalence of neuropathic pain: clinical evaluation compared with screening tools in a community population. Pain Med. 2009 Apr;10(3):586-93. doi: 10.1111/j.1526-4637.2009.00588.x. Epub 2009 Mar 17. Erratum In: Pain Med. 2011 Aug;12(8):1294.
PMID: 20849570
citation: Smith BH, Torrance N. Epidemiology of neuropathic pain and its impact on quality of life. Curr Pain Headache Rep. 2012 Jun;16(3):191-8. doi: 10.1007/s11916-012-0256-0.
PMID: 22395856
citation: Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpaa M, Hansson P, Jensen TS, Kamerman PR, Lund K, Moore A, Raja SN, Rice AS, Rowbotham M, Sena E, Siddall P, Smith BH, Wallace M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015 Feb;14(2):162-73. doi: 10.1016/S1474-4422(14)70251-0. Epub 2015 Jan 7.
PMID: 25575710
citation: Dogrul A, Ossipov MH, Porreca F. Differential mediation of descending pain facilitation and inhibition by spinal 5HT-3 and 5HT-7 receptors. Brain Res. 2009 Jul 14;1280:52-9. doi: 10.1016/j.brainres.2009.05.001. Epub 2009 May 8.
PMID: 19427839
responsible party type: Principal Investigator
investigator affiliation: Washington University School of Medicine
investigator full name: simon.haroutounian
investigator title: Assistant Professor of Anesthsiology
mesh term: Neuralgia
mesh term: Ondansetron