<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/NCT03017495</url>
  </required_header>
  <id_info>
    <org_study_id>AC-078-104</org_study_id>
    <secondary_id>2016-003490-18</secondary_id>
    <nct_id>NCT03017495</nct_id>
  </id_info>
  <brief_title>A Clinical Study to Investigate the Potential Interactions Between Food and ACT-541468 and Between ACT-541468 and Midazolam</brief_title>
  <official_title>A Single-center, Open-label Study to Investigate the Food Effect on the Pharmacokinetics of ACT-541468 and the Effect of Single- and Multiple-dose ACT-541468 on the Pharmacokinetics of Midazolam and Its Metabolite 1-Hydroxymidazolam in Healthy Male Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Idorsia Pharmaceuticals Ltd.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Idorsia Pharmaceuticals Ltd.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The main objectives of this phase 1 trial are to evaluate the effect of food on the&#xD;
      pharmacokinetics (i.e. how long and how much a compound is present in the blood) of&#xD;
      ACT-541468 and to evaluate whether ACT-541468 can affect the pharmacokinetics of midazolam, a&#xD;
      CYP3A4 substrate.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Food effect will be assessed by comparing the pharmacokinetic (PK) parameters of a single&#xD;
      dose of ACT-541468 under fasted (Treatment B) and fed (Treatment C) conditions.&#xD;
&#xD;
      Potential CYP3A4 inhibiting / inducing effects of ACT-541468 will be assessed by comparing&#xD;
      the PK parameters of midazolam alone (Treatment A) and midazolam given with a single dose of&#xD;
      ACT-541468 (Treatment B) or with multiple doses of ACT-541468 (Treatment D).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 1, 2017</start_date>
  <completion_date type="Actual">February 1, 2017</completion_date>
  <primary_completion_date type="Actual">February 1, 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>Maximum plasma concentration (Cmax) of ACT-541468</measure>
    <time_frame>PK blood samples on Day 2, Day 4 and Day 8: before administration of ACT-541468 and up to 24 hours post-dose, and on Day 6 and Day 7: before ACT-541468 administration only</time_frame>
    <description>Cmax is directly determined from the plasma concentrations-time curves of ACT-541468</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time to reach Cmax (tmax) of ACT-541468</measure>
    <time_frame>PK blood samples on Day 2, Day 4 and Day 8: before administration of ACT-541468 and up to 24 hours post-dose, and on Day 6 and Day 7: before ACT-541468 administration only</time_frame>
    <description>Tmax is directly determined from the plasma concentrations-time curves of ACT-541468</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the plasma concentration-time curve [AUC(0-24)] of ACT-541468</measure>
    <time_frame>PK blood samples on Day 2, Day 4 and Day 8: before administration of ACT-541468 and up to 24 hours post-dose, and on Day 6 and Day 7: before ACT-541468 administration only</time_frame>
    <description>AUC is calculated from time zero to 24 hours post dose</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Terminal half-life (t1/2) of ACT-541468</measure>
    <time_frame>PK blood samples on Day 2, Day 4 and Day 8: before administration of ACT-541468 and up to 24 hours post-dose, and on Day 6 and Day 7: before ACT-541468 administration only</time_frame>
    <description>t1/2 is calculated from the plasma concentrations-time curves of ACT-541468</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum plasma concentration (Cmax) of midazolam</measure>
    <time_frame>PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose</time_frame>
    <description>Cmax is directly obtained from the plasma concentrations-time curves of midazolam</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time to reach Cmax (tmax) of midazolam</measure>
    <time_frame>PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose</time_frame>
    <description>Tmax is directly obtained from the plasma concentrations-time curves of midazolam</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the plasma concentration-time curve [AUC(0-24)] of midazolam</measure>
    <time_frame>PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose</time_frame>
    <description>AUC is calculated from time zero to 24 hours post dose</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Terminal half-life (t1/2) of midazolam</measure>
    <time_frame>PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose</time_frame>
    <description>t1/2 is calculated from the plasma concentrations-time curves of midazolam</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum plasma concentration (Cmax) of 1-hydroxymidazolam</measure>
    <time_frame>PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose</time_frame>
    <description>Cmax is directly determined from the plasma concentrations-time curves of 1-hydroxymidazolam</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Time to reach Cmax (tmax) of 1-hydroxymidazolam</measure>
    <time_frame>PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose</time_frame>
    <description>Tmax is directly determined from the plasma concentrations-time curves of 1-hydroxymidazolam</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the plasma concentration-time curve [AUC(0-24)] of 1-hydroxymidazolam</measure>
    <time_frame>PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose</time_frame>
    <description>AUC is calculated from time zero to 24 hours post dose</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Terminal half-life (t1/2) of 1-hydroxymidazolam</measure>
    <time_frame>PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose</time_frame>
    <description>t1/2 is calculated from the plasma concentrations-time curves of 1-hydroxymidazolam</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of subjects with treatment-emergent adverse events and serious adverse events</measure>
    <time_frame>From baseline to end-of-study, i.e.,maximum 5 days after Day 8</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum plasma concentration (Cmax) of ACT-541468 metabolites</measure>
    <time_frame>PK blood samples on Day 8, before administration of ACT-541468 and up to 24 hours post dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to reach Cmax (tmax) of ACT-541468 metabolites</measure>
    <time_frame>PK blood samples on Day 8, before administration of ACT-541468 and up to 24 hours post dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration-time curve [AUC(0-24)] of ACT-541468 metabolites</measure>
    <time_frame>PK blood samples on Day 8, before administration of ACT-541468 and up to 24 hours post dose</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal half-life (t1/2) of ACT-541468 metabolites</measure>
    <time_frame>PK blood samples on Day 8, before administration of ACT-541468 and up to 24 hours post dose</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Healthy Subjects</condition>
  <arm_group>
    <arm_group_label>Food effect and Drug-Drug interaction</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Treatments will be given to all subjects in the same fixed sequence: Treatment A (Day 1, single dose of midazolam, fasted), Treatment B (Day 2, single dose of ACT-541468 followed by single dose of midazolam, fasted), Treatment C (Day 4, single dose ACT-541468, fed), Treatment D (multiple doses of ACT-541468 from Day 5 to Day 8 + single dose of midazolam on Day 8, fasted).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Midazolam</intervention_name>
    <description>2 mg/mL oral solution</description>
    <arm_group_label>Food effect and Drug-Drug interaction</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ACT-541468</intervention_name>
    <description>Hard gelatin capsules for oral use at a strength of 25 mg</description>
    <arm_group_label>Food effect and Drug-Drug interaction</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed informed consent form&#xD;
&#xD;
          -  Male subjects aged from 18 to 45 years (inclusive) at screening&#xD;
&#xD;
          -  Body mass index (BMI) from 18.0 to 30.0 kg/m2 (inclusive) at screening&#xD;
&#xD;
          -  Healthy on the basis of physical examination, cardiovascular assessments and&#xD;
             laboratory tests&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any contraindication to the study treatments&#xD;
&#xD;
          -  History or clinical evidence of any disease or medical / surgical condition or&#xD;
             treatment, which may put the subject at risk of participation in the study or may&#xD;
             interfere with the absorption, distribution, metabolism or excretion of the study&#xD;
             treatments&#xD;
&#xD;
          -  History of narcolepsy or cataplexy or modified Swiss narcolepsy scale total score &lt; 0&#xD;
&#xD;
          -  Any circumstances or conditions, which, in the opinion of the investigator, may affect&#xD;
             the subject's full participation in the study or compliance with the protocol&#xD;
      </textblock>
    </criteria>
    <gender>Male</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>Marie-Laure Boof, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Actelion</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Investigator Site</name>
      <address>
        <city>Kiel</city>
        <zip>24105</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>July 2018</verification_date>
  <study_first_submitted>January 10, 2017</study_first_submitted>
  <study_first_submitted_qc>January 10, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 11, 2017</study_first_posted>
  <last_update_submitted>July 6, 2018</last_update_submitted>
  <last_update_submitted_qc>July 6, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">July 10, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>food-drug interaction</keyword>
  <keyword>drug-drug interaction</keyword>
  <keyword>pharmacokinetics</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Midazolam</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/NCT03017495
org study id: AC-078-104
secondary id: 2016-003490-18
nct id: NCT03017495
lead sponsor: 
has dmc: No
The main objectives of this phase 1 trial are to evaluate the effect of food on the
      pharmacokinetics (i.e. how long and how much a compound is present in the blood) of
      ACT-541468 and to evaluate whether ACT-541468 can affect the pharmacokinetics of midazolam, a
      CYP3A4 substrate.
Food effect will be assessed by comparing the pharmacokinetic (PK) parameters of a single
      dose of ACT-541468 under fasted (Treatment B) and fed (Treatment C) conditions.

      Potential CYP3A4 inhibiting / inducing effects of ACT-541468 will be assessed by comparing
      the PK parameters of midazolam alone (Treatment A) and midazolam given with a single dose of
      ACT-541468 (Treatment B) or with multiple doses of ACT-541468 (Treatment D).
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Maximum plasma concentration (Cmax) of ACT-541468
time frame: PK blood samples on Day 2, Day 4 and Day 8: before administration of ACT-541468 and up to 24 hours post-dose, and on Day 6 and Day 7: before ACT-541468 administration only
description: Cmax is directly determined from the plasma concentrations-time curves of ACT-541468
measure: Time to reach Cmax (tmax) of ACT-541468
time frame: PK blood samples on Day 2, Day 4 and Day 8: before administration of ACT-541468 and up to 24 hours post-dose, and on Day 6 and Day 7: before ACT-541468 administration only
description: Tmax is directly determined from the plasma concentrations-time curves of ACT-541468
measure: Area under the plasma concentration-time curve [AUC(0-24)] of ACT-541468
time frame: PK blood samples on Day 2, Day 4 and Day 8: before administration of ACT-541468 and up to 24 hours post-dose, and on Day 6 and Day 7: before ACT-541468 administration only
description: AUC is calculated from time zero to 24 hours post dose
measure: Terminal half-life (t1/2) of ACT-541468
time frame: PK blood samples on Day 2, Day 4 and Day 8: before administration of ACT-541468 and up to 24 hours post-dose, and on Day 6 and Day 7: before ACT-541468 administration only
description: t1/2 is calculated from the plasma concentrations-time curves of ACT-541468
measure: Maximum plasma concentration (Cmax) of midazolam
time frame: PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose
description: Cmax is directly obtained from the plasma concentrations-time curves of midazolam
measure: Time to reach Cmax (tmax) of midazolam
time frame: PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose
description: Tmax is directly obtained from the plasma concentrations-time curves of midazolam
measure: Area under the plasma concentration-time curve [AUC(0-24)] of midazolam
time frame: PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose
description: AUC is calculated from time zero to 24 hours post dose
measure: Terminal half-life (t1/2) of midazolam
time frame: PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose
description: t1/2 is calculated from the plasma concentrations-time curves of midazolam
measure: Maximum plasma concentration (Cmax) of 1-hydroxymidazolam
time frame: PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose
description: Cmax is directly determined from the plasma concentrations-time curves of 1-hydroxymidazolam
measure: Time to reach Cmax (tmax) of 1-hydroxymidazolam
time frame: PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose
description: Tmax is directly determined from the plasma concentrations-time curves of 1-hydroxymidazolam
measure: Area under the plasma concentration-time curve [AUC(0-24)] of 1-hydroxymidazolam
time frame: PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose
description: AUC is calculated from time zero to 24 hours post dose
measure: Terminal half-life (t1/2) of 1-hydroxymidazolam
time frame: PK blood samples on Day 1, Day 2, Day 8: before administration of midazolam and up to 24 hours post dose
description: t1/2 is calculated from the plasma concentrations-time curves of 1-hydroxymidazolam
measure: Number of subjects with treatment-emergent adverse events and serious adverse events
time frame: From baseline to end-of-study, i.e.,maximum 5 days after Day 8
measure: Maximum plasma concentration (Cmax) of ACT-541468 metabolites
time frame: PK blood samples on Day 8, before administration of ACT-541468 and up to 24 hours post dose
measure: Time to reach Cmax (tmax) of ACT-541468 metabolites
time frame: PK blood samples on Day 8, before administration of ACT-541468 and up to 24 hours post dose
measure: Area under the plasma concentration-time curve [AUC(0-24)] of ACT-541468 metabolites
time frame: PK blood samples on Day 8, before administration of ACT-541468 and up to 24 hours post dose
measure: Terminal half-life (t1/2) of ACT-541468 metabolites
time frame: PK blood samples on Day 8, before administration of ACT-541468 and up to 24 hours post dose
arm group label: Food effect and Drug-Drug interaction
arm group type: Experimental
description: Treatments will be given to all subjects in the same fixed sequence: Treatment A (Day 1, single dose of midazolam, fasted), Treatment B (Day 2, single dose of ACT-541468 followed by single dose of midazolam, fasted), Treatment C (Day 4, single dose ACT-541468, fed), Treatment D (multiple doses of ACT-541468 from Day 5 to Day 8 + single dose of midazolam on Day 8, fasted).
intervention type: Drug
intervention name: Midazolam
description: 2 mg/mL oral solution
arm group label: Food effect and Drug-Drug interaction
intervention type: Drug
intervention name: ACT-541468
description: Hard gelatin capsules for oral use at a strength of 25 mg
arm group label: Food effect and Drug-Drug interaction
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Marie-Laure Boof, PhD
role: Study Director
affiliation: Actelion
facility: 
country: Germany
responsible party type: Sponsor
mesh term: Midazolam