<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/NCT03796377</url>
  </required_header>
  <id_info>
    <org_study_id>Studien-Nr. 3459</org_study_id>
    <nct_id>NCT03796377</nct_id>
  </id_info>
  <brief_title>Rivaroxaban Hypericum Trial</brief_title>
  <official_title>Effects of Hypericum Perforatum (St. John's Wort) on the Pharmacokinetics and Pharmacodynamics of Rivaroxaban in Humans</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Insel Gruppe AG, University Hospital Bern</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bayer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Insel Gruppe AG, University Hospital Bern</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Single-center, open-label, sequential treatment study to investigate the influence of the&#xD;
      combined P-glycoprotein and CYP3A4 inducer hypericum perforatum on the pharmacokinetics and&#xD;
      pharmacodynamics of rivaroxaban in healthy volunteers.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Each session (one with and one without preceding CYP induction) will start with phenotyping&#xD;
      using 25 mg fexofenadine orally for P-gp phenotyping and 2 mg midazolam orally for cytochrome&#xD;
      P450 (CYP) 3A4 phenotyping. After a washout period of 5 days, subjects will receive a single&#xD;
      oral dose of 20 mg rivaroxaban, a dose currently approved for human use in clinical routine.&#xD;
      The same procedure will be repeated after pretreatment with St. John's wort extract (Jarsin®)&#xD;
      twice daily 450 mg po (dose usually used in clinical routine) for 2 weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 13, 2019</start_date>
  <completion_date type="Actual">April 9, 2019</completion_date>
  <primary_completion_date type="Actual">April 9, 2019</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>Sequential Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pharmacokinetic outcome measures: area under the curve (AUC).</measure>
    <time_frame>AUC will be calculated from the concentration-time plot (time points included: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions)</time_frame>
    <description>Effect of pretreatment with hypericum perforatum on geometric mean AUC.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacokinetic outcome measures: maximal concentration of rivaroxaban.</measure>
    <time_frame>Will be obtained from the individual plasma concentration data (time points included: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions)</time_frame>
    <description>Effect of pretreatment with hypericum perforatum on maximal concentration of rivaroxaban.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacodynamic outcome measures: Factor Xa activity</measure>
    <time_frame>Time points used for analysis: pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions</time_frame>
    <description>Displayed as maximal effect (Emax) and parametrized by calculating the area under the time-effect curves (AUEC)).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameters: Time to reach maximal concentration</measure>
    <time_frame>Time points used for analysis: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions</time_frame>
    <description>Time to reach maximal concentration of rivaroxaban</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameters: Plasma elimination half-life</measure>
    <time_frame>Time points used for analysis: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions</time_frame>
    <description>Plasma elimination half-life of rivaroxaban</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phenotyping metrics: AUC fexofenadine</measure>
    <time_frame>Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration</time_frame>
    <description>Estimated AUC of fexofenadine</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phenotyping metrics: AUC ratios midazolam</measure>
    <time_frame>Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration</time_frame>
    <description>AUC ratios of midazolam and 1'-hydroxymidazolam</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Phenotyping metrics: Single point metabolic ratios midazolam</measure>
    <time_frame>Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration</time_frame>
    <description>Single point metabolic ratios of midazolam and 1'-hydroxymidazolam</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">12</enrollment>
  <condition>Drug Interaction Study</condition>
  <arm_group>
    <arm_group_label>Rivaroxaban</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Single oral dose of 20 mg rivaroxaban</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Rivaroxaban after CYP- and P-gp induction</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Single oral dose of 20 mg rivaroxaban after pretreatment with St. John's wort extract (Jarsin®) twice daily 450 mg po for 2 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>St Johns Wort Extract</intervention_name>
    <description>20 mg rivaroxaban after supplementation with St. John's wort extract (Jarsin®) twice daily 450 mg po for 2 weeks.</description>
    <arm_group_label>Rivaroxaban after CYP- and P-gp induction</arm_group_label>
    <other_name>Inducer of CYP3A4 and P-gp</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rivaroxaban</intervention_name>
    <description>20 mg rivaroxaban.</description>
    <arm_group_label>Rivaroxaban</arm_group_label>
    <arm_group_label>Rivaroxaban after CYP- and P-gp induction</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men or women, age between 18 and 45 years (inclusive) at screening&#xD;
&#xD;
          -  BMI between 18 and 28 kg/m2 (inclusive) at screening&#xD;
&#xD;
          -  No clinically significant findings on the physical examination at screening&#xD;
&#xD;
          -  Hematology and clinical chemistry results not deviating from the normal range to a&#xD;
             clinically relevant extent at screening&#xD;
&#xD;
          -  Ability to communicate well with the investigator and to understand and comply with&#xD;
             the requirements of the study&#xD;
&#xD;
          -  Women of child-bearing age: willingness of using a double barrier contraception method&#xD;
             during the study, i.e. a hormonal method (oral contraceptive, intrauterine device) in&#xD;
             combination with a mechanical barrier (e.g. condom, diaphragm)&#xD;
&#xD;
          -  Signed informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known allergic reaction to any excipient of the drug formulations&#xD;
&#xD;
          -  Known photosensitivity&#xD;
&#xD;
          -  Smoking&#xD;
&#xD;
          -  History or clinical evidence of alcoholism or drug abuse within the 3-year period&#xD;
             prior to screening&#xD;
&#xD;
          -  Loss of ≥ 250 ml of blood within 3 months prior to screening, including blood donation&#xD;
&#xD;
          -  Treatment with an investigational drug within 30 days prior to screening&#xD;
&#xD;
          -  Previous treatment with any prescribed or over-the-counter medications (including&#xD;
             herbal medicines such as St. John's wort) within 2 weeks prior to screening&#xD;
&#xD;
          -  Pregnant (positive results from urine drug screen at screening) or lactating women&#xD;
&#xD;
          -  History or clinical evidence of any disease (e.g. gastrointestinal tract disease)&#xD;
             and/or existence of any surgical or medical condition, which might interfere with the&#xD;
             absorption, distribution, metabolism or excretion of the study drugs, or which might&#xD;
             increase the risk for toxicity&#xD;
&#xD;
          -  Legal incapacity or limited legal capacity at screening&#xD;
&#xD;
          -  Any circumstances or conditions, which, in the opinion of the investigator, may affect&#xD;
             full participation in the study or compliance with the protocol&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Inselpital</last_name>
    <role>Study Director</role>
    <affiliation>Sponsor: Inselspital, Bern University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Inselspital</name>
      <address>
        <city>Bern</city>
        <country>Switzerland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Switzerland</country>
  </location_countries>
  <results_reference>
    <citation>Scholz I, Liakoni E, Hammann F, Grafinger KE, Duthaler U, Nagler M, Krahenbuhl S, Haschke M. Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans. Br J Clin Pharmacol. 2021 Mar;87(3):1466-1474. doi: 10.1111/bcp.14553. Epub 2020 Oct 25.</citation>
    <PMID>32959922</PMID>
  </results_reference>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>January 4, 2019</study_first_submitted>
  <study_first_submitted_qc>January 4, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 8, 2019</study_first_posted>
  <last_update_submitted>October 30, 2020</last_update_submitted>
  <last_update_submitted_qc>October 30, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 3, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rivaroxaban</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/NCT03796377
org study id: Studien-Nr. 3459
nct id: NCT03796377
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Single-center, open-label, sequential treatment study to investigate the influence of the
      combined P-glycoprotein and CYP3A4 inducer hypericum perforatum on the pharmacokinetics and
      pharmacodynamics of rivaroxaban in healthy volunteers.
Each session (one with and one without preceding CYP induction) will start with phenotyping
      using 25 mg fexofenadine orally for P-gp phenotyping and 2 mg midazolam orally for cytochrome
      P450 (CYP) 3A4 phenotyping. After a washout period of 5 days, subjects will receive a single
      oral dose of 20 mg rivaroxaban, a dose currently approved for human use in clinical routine.
      The same procedure will be repeated after pretreatment with St. John's wort extract (Jarsin®)
      twice daily 450 mg po (dose usually used in clinical routine) for 2 weeks.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Other
masking: None (Open Label)
measure: Pharmacokinetic outcome measures: area under the curve (AUC).
time frame: AUC will be calculated from the concentration-time plot (time points included: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions)
description: Effect of pretreatment with hypericum perforatum on geometric mean AUC.
measure: Pharmacokinetic outcome measures: maximal concentration of rivaroxaban.
time frame: Will be obtained from the individual plasma concentration data (time points included: pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions)
description: Effect of pretreatment with hypericum perforatum on maximal concentration of rivaroxaban.
measure: Pharmacodynamic outcome measures: Factor Xa activity
time frame: Time points used for analysis: pre-dose, 0.5, 1, 2, 4, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions
description: Displayed as maximal effect (Emax) and parametrized by calculating the area under the time-effect curves (AUEC)).
measure: Pharmacokinetic parameters: Time to reach maximal concentration
time frame: Time points used for analysis: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions
description: Time to reach maximal concentration of rivaroxaban
measure: Pharmacokinetic parameters: Plasma elimination half-life
time frame: Time points used for analysis: 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 36, and 48 hours (post-dose) during both sessions
description: Plasma elimination half-life of rivaroxaban
measure: Phenotyping metrics: AUC fexofenadine
time frame: Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration
description: Estimated AUC of fexofenadine
measure: Phenotyping metrics: AUC ratios midazolam
time frame: Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration
description: AUC ratios of midazolam and 1'-hydroxymidazolam
measure: Phenotyping metrics: Single point metabolic ratios midazolam
time frame: Time points used for analysis: Before dosing and 0.5, 2, 3, 6 h after administration
description: Single point metabolic ratios of midazolam and 1'-hydroxymidazolam
arm group label: Rivaroxaban
arm group type: Other
description: Single oral dose of 20 mg rivaroxaban
arm group label: Rivaroxaban after CYP- and P-gp induction
arm group type: Other
description: Single oral dose of 20 mg rivaroxaban after pretreatment with St. John's wort extract (Jarsin®) twice daily 450 mg po for 2 weeks.
intervention type: Drug
intervention name: St Johns Wort Extract
description: 20 mg rivaroxaban after supplementation with St. John's wort extract (Jarsin®) twice daily 450 mg po for 2 weeks.
arm group label: Rivaroxaban after CYP- and P-gp induction
other name: Inducer of CYP3A4 and P-gp
intervention type: Drug
intervention name: Rivaroxaban
description: 20 mg rivaroxaban.
arm group label: Rivaroxaban
arm group label: Rivaroxaban after CYP- and P-gp induction
criteria: 
gender: All
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Inselpital
role: Study Director
affiliation: Sponsor: Inselspital, Bern University Hospital
facility: 
country: Switzerland
citation: Scholz I, Liakoni E, Hammann F, Grafinger KE, Duthaler U, Nagler M, Krahenbuhl S, Haschke M. Effects of Hypericum perforatum (St John's wort) on the pharmacokinetics and pharmacodynamics of rivaroxaban in humans. Br J Clin Pharmacol. 2021 Mar;87(3):1466-1474. doi: 10.1111/bcp.14553. Epub 2020 Oct 25.
PMID: 32959922
responsible party type: Sponsor
mesh term: Rivaroxaban
sharing ipd: No