<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/NCT03237416</url>
  </required_header>
  <id_info>
    <org_study_id>18860</org_study_id>
    <secondary_id>2017-001116-11</secondary_id>
    <nct_id>NCT03237416</nct_id>
  </id_info>
  <brief_title>Drug-drug-interaction Study to Assess the Effect of Darolutamide on the Pharmacokinetics of Probe Substrates of CYP3A4 and P-gp in Healthy Male Volunteers</brief_title>
  <official_title>A Phase I, Non-randomized, Open-label, Fixed-sequence Study to Investigate the Effect of Darolutamide (ODM-201) on the Pharmacokinetics of a Probe Substrate of CYP3A4 and P-gp in Healthy Male Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bayer</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Orion Corporation, Orion Pharma</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Bayer</source>
  <oversight_info>
    <has_dmc>No</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>
      Evaluate the effect of darolutamide on the pharmacokinetics of a probe CYP3A4 substrate and&#xD;
      Pgp substrate&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 2, 2017</start_date>
  <completion_date type="Actual">December 18, 2017</completion_date>
  <primary_completion_date type="Actual">October 5, 2017</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>AUC in plasma of non-conjugated dabigatran (AUC(0-tlast), if AUC cannot be calculated)</measure>
    <time_frame>Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing</time_frame>
    <description>Exposure of non-conjugated dabigatran in plasma following a single administration of dabigatran etexilate AUC: area under the concentration vs. time curve from zero to infinity after single (first) dose AUC(0-tlast): AUC from time 0 to the last data point &gt; LLOQ</description>
  </primary_outcome>
  <primary_outcome>
    <measure>C(max) in plasma of non-conjugated dabigatran</measure>
    <time_frame>Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing</time_frame>
    <description>Maximum plasma concentration of non-conjugated dabigatran in plasma following a single administration of dabigatran etexilate Cmax: maximum observed drug concentration in measured matrix after single dose administration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC in plasma of midazolam (AUC(0-tlast), if AUC cannot be calculated)</measure>
    <time_frame>PPeriod 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing</time_frame>
    <description>Exposure of midazolam in plasma following a single administration of midazolam</description>
  </primary_outcome>
  <primary_outcome>
    <measure>C(max) in plasma of midazolam</measure>
    <time_frame>Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing</time_frame>
    <description>Maximum plasma concentration of midazolam in plasma following a single administration of midazolam</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of subjects with study drug-related treatment-emergent Adverse Event (TEAE)</measure>
    <time_frame>30 days following last intake of Investigational Product</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC in plasma of total dabigatran (AUC(0-tlast), if AUC cannot be calculated)</measure>
    <time_frame>Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing</time_frame>
    <description>Exposure of total dabigatran in plasma following a single administration of dabigatran etexilate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>C(max) in plasma of total dabigatran</measure>
    <time_frame>Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing</time_frame>
    <description>Maximum plasma concentration of total dabigatran in plasma following a single administration of dabigatran etexilate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC in plasma of 1-OH midazolam (AUC(0-tlast), if AUC cannot be calculated)</measure>
    <time_frame>Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing</time_frame>
    <description>Exposure of 1-OH midazolam in plasma following a single administration of midazolam</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>C(max) in plasma of 1-OH midazolam</measure>
    <time_frame>PPeriod 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing</time_frame>
    <description>Maximum plasma concentration of 1-OH midazolam in plasma following a single administration of midazolam</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">15</enrollment>
  <condition>Prostatic Neoplasms</condition>
  <arm_group>
    <arm_group_label>BAY1841788/Healthy subjects</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Period 1: intake of Midazolam and Dabigatran etexilate at day 1 followed by Period 2: intake of Darolutamide at days 1-11 (twice daily), intake of dabigatran etexilate at days 3 and 9, intake of Midazolam at day 9</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dabigatran etexilate</intervention_name>
    <description>In Period 1, Day 1 a single dose of 75 mg will be administered after breakfast In Period 2, Day 3 a single dose of 75 mg will be administered prior to breakfast In Period 2, Day 9 a single dose of 75 mg will be administered after breakfast</description>
    <arm_group_label>BAY1841788/Healthy subjects</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Midazolam</intervention_name>
    <description>In Period 1, Day 1 a single dose of 1 mg will be administered after breakfast In Period 2, Day 9 a single dose of 1 mg will be administered after breakfast</description>
    <arm_group_label>BAY1841788/Healthy subjects</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>BAY1841788 (darolutamide)</intervention_name>
    <description>In Period 2, Days 1-11 600 mg twice a day (as 2 x 300 mg tablets) will be administered after breakfast</description>
    <arm_group_label>BAY1841788/Healthy subjects</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy subject - as determined by the investigator or medically qualified designee&#xD;
             based on medical evaluations including medical history, physical examination,&#xD;
             laboratory tests and cardiac monitoring.&#xD;
&#xD;
          -  Gender: Male.&#xD;
&#xD;
          -  Age: 45 to 65 years (inclusive) at the screening visit.&#xD;
&#xD;
          -  Race: White.&#xD;
&#xD;
          -  Body mass index (BMI): ≥18.0 and ≤30.0 kg/m2.&#xD;
&#xD;
          -  Agree to use condoms as an effective contraception barrier method and refrain from&#xD;
             sperm donation during the whole study (starting after informed consent) and for 3&#xD;
             months after the end of treatment with darolutamide.&#xD;
&#xD;
        In addition, participants must agree to utilize a second reliable method of contraception&#xD;
        simultaneously. The second method which has to be used by a female partner of childbearing&#xD;
        potential can be one of the following methods: diaphragm or cervical cap with spermicide or&#xD;
        intra-uterine device or hormone-based contraception. Therefore, contraception methods to be&#xD;
        used by male subjects and female partners are in line with clinical trial facilitation&#xD;
        group recommendations related to contraception in clinical trials.&#xD;
&#xD;
          -  Ability to understand and follow study-related instructions.&#xD;
&#xD;
          -  Results of alcohol tests are negative at screening and on Study Day -1.&#xD;
&#xD;
          -  Confirmation of the subject's health insurance coverage prior to the first screening&#xD;
             examination/visit.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Existing relevant diseases of vital organs (e.g. liver diseases, heart diseases),&#xD;
             central nervous system (for example seizures) or other organs (e.g. diabetes&#xD;
             mellitus).&#xD;
&#xD;
          -  Incompletely cured pre-existing diseases for which it can be assumed that the&#xD;
             absorption, distribution, metabolism, elimination and effects of the study drugs will&#xD;
             not be normal.&#xD;
&#xD;
          -  Known history of hypersensitivity (or known allergic reaction) to medications&#xD;
             including any ingredient of midazolam, benzodiazepines, dabigatran etexilate, or&#xD;
             darolutamide.&#xD;
&#xD;
          -  Relevant hepatic disorders like cholestasis, disturbances of bilirubin metabolism, any&#xD;
             progressive liver disease.&#xD;
&#xD;
          -  Relevant renal disorders like recurrent glomerulonephritis, renal injury, and renal&#xD;
             insufficiency. However, a history of a single episode of uncomplicated nephrolithiasis&#xD;
             will not prevent participation.&#xD;
&#xD;
          -  CYP3A4 inhibitors within 1 week or 5 drug half-lives, whichever is longer, before&#xD;
             start of study treatment or during the study.&#xD;
&#xD;
          -  CYP3A4 inducers as well as St John's Wort within 28 days or 5 drug half-lives,&#xD;
             whichever is longer, before start of study treatment or during the study.&#xD;
&#xD;
          -  Known BCRP and OATP substrates within 28 days or 5 drug half-lives, whichever is&#xD;
             longer, before start of study treatment or during the study.&#xD;
&#xD;
          -  P-gp inducers (e.g. rifampin) within 28 days or 5 drug half-lives, whichever is&#xD;
             longer, before start of study treatment or during the study.&#xD;
&#xD;
          -  P-gp inhibitors within 1 week or 5 drug half-lives, whichever is longer, before start&#xD;
             of study treatment or during the study.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>45 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bayer Study Director</last_name>
    <role>Study Director</role>
    <affiliation>Bayer</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>CRS Clinical-Research-Services Mannheim GmbH</name>
      <address>
        <city>Mannheim</city>
        <state>Baden-Württemberg</state>
        <zip>68167</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <link>
    <url>https://clinicaltrials.bayer.com/</url>
    <description>Click here to find results for studies related to Bayer Healthcare products.</description>
  </link>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>July 26, 2017</study_first_submitted>
  <study_first_submitted_qc>July 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 2, 2017</study_first_posted>
  <last_update_submitted>November 5, 2018</last_update_submitted>
  <last_update_submitted_qc>November 5, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">November 6, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Drug-drug interaction</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Midazolam</mesh_term>
    <mesh_term>Dabigatran</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/NCT03237416
org study id: 18860
secondary id: 2017-001116-11
nct id: NCT03237416
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Evaluate the effect of darolutamide on the pharmacokinetics of a probe CYP3A4 substrate and
      Pgp substrate
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: AUC in plasma of non-conjugated dabigatran (AUC(0-tlast), if AUC cannot be calculated)
time frame: Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing
description: Exposure of non-conjugated dabigatran in plasma following a single administration of dabigatran etexilate AUC: area under the concentration vs. time curve from zero to infinity after single (first) dose AUC(0-tlast): AUC from time 0 to the last data point > LLOQ
measure: C(max) in plasma of non-conjugated dabigatran
time frame: Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing
description: Maximum plasma concentration of non-conjugated dabigatran in plasma following a single administration of dabigatran etexilate Cmax: maximum observed drug concentration in measured matrix after single dose administration
measure: AUC in plasma of midazolam (AUC(0-tlast), if AUC cannot be calculated)
time frame: PPeriod 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing
description: Exposure of midazolam in plasma following a single administration of midazolam
measure: C(max) in plasma of midazolam
time frame: Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing
description: Maximum plasma concentration of midazolam in plasma following a single administration of midazolam
measure: Number of subjects with study drug-related treatment-emergent Adverse Event (TEAE)
time frame: 30 days following last intake of Investigational Product
measure: AUC in plasma of total dabigatran (AUC(0-tlast), if AUC cannot be calculated)
time frame: Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing
description: Exposure of total dabigatran in plasma following a single administration of dabigatran etexilate
measure: C(max) in plasma of total dabigatran
time frame: Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing
description: Maximum plasma concentration of total dabigatran in plasma following a single administration of dabigatran etexilate
measure: AUC in plasma of 1-OH midazolam (AUC(0-tlast), if AUC cannot be calculated)
time frame: Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing
description: Exposure of 1-OH midazolam in plasma following a single administration of midazolam
measure: C(max) in plasma of 1-OH midazolam
time frame: PPeriod 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing
description: Maximum plasma concentration of 1-OH midazolam in plasma following a single administration of midazolam
arm group label: BAY1841788/Healthy subjects
arm group type: Experimental
description: Period 1: intake of Midazolam and Dabigatran etexilate at day 1 followed by Period 2: intake of Darolutamide at days 1-11 (twice daily), intake of dabigatran etexilate at days 3 and 9, intake of Midazolam at day 9
intervention type: Drug
intervention name: Dabigatran etexilate
description: In Period 1, Day 1 a single dose of 75 mg will be administered after breakfast In Period 2, Day 3 a single dose of 75 mg will be administered prior to breakfast In Period 2, Day 9 a single dose of 75 mg will be administered after breakfast
arm group label: BAY1841788/Healthy subjects
intervention type: Drug
intervention name: Midazolam
description: In Period 1, Day 1 a single dose of 1 mg will be administered after breakfast In Period 2, Day 9 a single dose of 1 mg will be administered after breakfast
arm group label: BAY1841788/Healthy subjects
intervention type: Drug
intervention name: BAY1841788 (darolutamide)
description: In Period 2, Days 1-11 600 mg twice a day (as 2 x 300 mg tablets) will be administered after breakfast
arm group label: BAY1841788/Healthy subjects
criteria: 
gender: Male
minimum age: 45 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Bayer Study Director
role: Study Director
affiliation: Bayer
facility: 
country: Germany
url: https://clinicaltrials.bayer.com/
description: Click here to find results for studies related to Bayer Healthcare products.
responsible party type: Sponsor
mesh term: Prostatic Neoplasms
mesh term: Midazolam
mesh term: Dabigatran