<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/NCT02190708</url>
  </required_header>
  <id_info>
    <org_study_id>1002308-8302860</org_study_id>
    <secondary_id>2014-001883-36</secondary_id>
    <nct_id>NCT02190708</nct_id>
  </id_info>
  <brief_title>Effects of PQ912 on the Pharmacokinetics of Midazolam and Omeprazole</brief_title>
  <official_title>A Phase I, Open Label Study to Assess the Effects of PQ912 on the Pharmacokinetics of Midazolam and Omeprazole in Healthy Male Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vivoryon Therapeutics N.V.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Covance</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Vivoryon Therapeutics N.V.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Midazolam is a rapid-acting benzodiazepine, with a short half-life (approximately 1.9 hours)&#xD;
      and is primarily metabolised by CYP3A.&#xD;
&#xD;
      Omeprazole is a selective proton pump inhibitor substrate used to reduce gastric acid&#xD;
      secretion. Omeprazole is primarily metabolised by CYP2C19.&#xD;
&#xD;
      Midazolam and omeprazole are both used as probe drugs in clinical pharmacology studies to&#xD;
      evaluate clinical CYP3A and CYP2C19 drug interactions, respectively. Furthermore the EMA and&#xD;
      the FDA guidance on drug interactions recommend the use of these drugs for such evaluations.&#xD;
&#xD;
      The aim of this study is to assess the effect of PQ912 on the PK of midazolam and omeprazole.&#xD;
      In vitro studies have demonstrated that PQ912 inhibits several CYP enzymes, including CYP3A4&#xD;
      and CYP2C19 and at the expected exposure levels in patients, has the potential to inhibit&#xD;
      these enzymes in-vivo. This study is therefore planned to investigate the potential changes&#xD;
      in the PK of midazolam and omeprazole due to the effect of PQ912 at steady-state. In clinical&#xD;
      practice it is likely that co-administration of PQ912 with other drugs that are metabolised&#xD;
      via the CYP3A and/or CYP2C19 enzymes will occur. This study will provide important&#xD;
      information for the requirement of dose adjustments or contraindications in these&#xD;
      circumstances.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This will be an open-label, crossover, fixed sequence study in healthy male subjects. Thirty&#xD;
      six (36) subjects will participate in the study and will be enrolled as two groups of 18&#xD;
      (Groups 1 and 2).&#xD;
&#xD;
      If the PK data from Group 1 demonstrate a clinically important inhibition of the CYP3A4&#xD;
      and/or CYP2C19 enzymes then the second optional group (Group 2) might be studied at a lower&#xD;
      dose level of PQ912 .&#xD;
&#xD;
      Each subject will participate in one treatment period, residing at the CRU from Day -1 (the&#xD;
      day before dosing) to Day 7 (until after the last PK sampling occasion).&#xD;
&#xD;
      All subjects will return for a post study visit 5 to 7 days after their final dose.&#xD;
&#xD;
      Dose Regimen:&#xD;
&#xD;
      Each subject will receive single oral doses of midazolam and omeprazole on the morning of Day&#xD;
      1.&#xD;
&#xD;
      On the morning of Day 2, all subjects will commence the multiple dose regimen for PQ912,&#xD;
      which will continue for 5 days in total.&#xD;
&#xD;
      Subjects in Group 1 and (if it necessary) in Group 2 will receive PQ912 twice daily (bid) on&#xD;
      Days 2 to 6 inclusive and subjects in Group 2 will receive PQ912 bid on Days 2 to 6&#xD;
      inclusive.&#xD;
&#xD;
      On the morning of Day 6 subjects will be given single oral doses of midazolam and omeprazole&#xD;
      co-administered with PQ912.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>June 2014</start_date>
  <completion_date type="Actual">August 2014</completion_date>
  <primary_completion_date type="Actual">June 2014</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>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Effect of PQ912 at steady state on pharmacokinetic profile of Omeprazole and Midazolam</measure>
    <time_frame>from day 1 up to day 6</time_frame>
    <description>Serial blood samples on day 1 and day 6 from predose up to 24 hours postdose</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of PQ912 in terms of Adverse Events Assessments when coadministered with Midazolam and Omeprazol</measure>
    <time_frame>day-1 up to day 6 and post dose visit</time_frame>
    <description>Safety profile in terms of Adverse Events Assessments</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability in terms of vital signs (blood pressure, pulse rate, respiration rate, Body temperature)</measure>
    <time_frame>from baseline up to end of study visit (2 weeks after first treatment)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and Tolerability by assessing changes in electrocardiogram (ECG) parameters</measure>
    <time_frame>from baseline up to end of study visit (2 weeks after first treatment)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability in terms of lab tests assessment (hematology, Serum biochemistry, serology, urinalysis)</measure>
    <time_frame>from baseline up to end of study visit (2 weeks after first treatment)</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Healthy Volunteers</condition>
  <condition>Pharmacologic Action</condition>
  <arm_group>
    <arm_group_label>PQ912 &amp; Midazolam &amp; Omeprazole</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>day2 - day6 800mg PQ912 twice per day po day1 / day6 2.5 mg Midazolam once per day day1 / day6 20 mg Omeprazole once per day</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>PQ912</intervention_name>
    <description>from day2 up to day6 twice daily oral dose of PQ912</description>
    <arm_group_label>PQ912 &amp; Midazolam &amp; Omeprazole</arm_group_label>
    <other_name>Glutaminyl Cyclase Inhibitor</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Midazolam</intervention_name>
    <description>single oral dose on day1 and day 6</description>
    <arm_group_label>PQ912 &amp; Midazolam &amp; Omeprazole</arm_group_label>
    <other_name>benzodiazepine</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Omeprazole</intervention_name>
    <description>single oral dose on day1 and day6</description>
    <arm_group_label>PQ912 &amp; Midazolam &amp; Omeprazole</arm_group_label>
    <other_name>Proton pump inhibitor</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  males&#xD;
&#xD;
          -  of any ethnic origin&#xD;
&#xD;
          -  between 18 and 55 years of age&#xD;
&#xD;
          -  body mass index (BMI) between 18.0 and 32.0 kg/m2 inclusive&#xD;
&#xD;
          -  body weight between 50 kg and 100 kg inclusive&#xD;
&#xD;
          -  must be in good health,&#xD;
&#xD;
          -  will have given written informed consent and to abide by the study restrictions&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  history of any clinically significant disease or disorder which, in the opinion of the&#xD;
             Investigator, may put the subject at risk because of participation in the study, may&#xD;
             influence the results, or may limit the subject's ability to participate in the study&#xD;
&#xD;
          -  history or presence of gastrointestinal, hepatic or renal disease or any other&#xD;
             condition known to interfere with absorption, distribution, metabolism or excretion of&#xD;
             drugs&#xD;
&#xD;
          -  active participation in a clinical study or participation in a clinical study&#xD;
             investigating a new chemical entity within 3 months or 5 half-lives (whichever is&#xD;
             longer prior to first dose)&#xD;
&#xD;
          -  clinically significant illness within 4 weeks of the start of the dose administration&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Joseph Chiesa, MD, Dr</last_name>
    <role>Principal Investigator</role>
    <affiliation>Covance</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Covance Clinical Research Unit Ltd</name>
      <address>
        <city>Leeds</city>
        <zip>LS2 9LH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>July 2014</verification_date>
  <study_first_submitted>July 4, 2014</study_first_submitted>
  <study_first_submitted_qc>July 14, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 15, 2014</study_first_posted>
  <last_update_submitted>October 19, 2015</last_update_submitted>
  <last_update_submitted_qc>October 19, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 21, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>PQ912</keyword>
  <keyword>Midazolam</keyword>
  <keyword>Omeprazole</keyword>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Drug Interaction</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Midazolam</mesh_term>
    <mesh_term>Omeprazole</mesh_term>
    <mesh_term>Proton Pump Inhibitors</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/NCT02190708
org study id: 1002308-8302860
secondary id: 2014-001883-36
nct id: NCT02190708
lead sponsor: 
collaborator: 
has dmc: No
Midazolam is a rapid-acting benzodiazepine, with a short half-life (approximately 1.9 hours)
      and is primarily metabolised by CYP3A.

      Omeprazole is a selective proton pump inhibitor substrate used to reduce gastric acid
      secretion. Omeprazole is primarily metabolised by CYP2C19.

      Midazolam and omeprazole are both used as probe drugs in clinical pharmacology studies to
      evaluate clinical CYP3A and CYP2C19 drug interactions, respectively. Furthermore the EMA and
      the FDA guidance on drug interactions recommend the use of these drugs for such evaluations.

      The aim of this study is to assess the effect of PQ912 on the PK of midazolam and omeprazole.
      In vitro studies have demonstrated that PQ912 inhibits several CYP enzymes, including CYP3A4
      and CYP2C19 and at the expected exposure levels in patients, has the potential to inhibit
      these enzymes in-vivo. This study is therefore planned to investigate the potential changes
      in the PK of midazolam and omeprazole due to the effect of PQ912 at steady-state. In clinical
      practice it is likely that co-administration of PQ912 with other drugs that are metabolised
      via the CYP3A and/or CYP2C19 enzymes will occur. This study will provide important
      information for the requirement of dose adjustments or contraindications in these
      circumstances.
This will be an open-label, crossover, fixed sequence study in healthy male subjects. Thirty
      six (36) subjects will participate in the study and will be enrolled as two groups of 18
      (Groups 1 and 2).

      If the PK data from Group 1 demonstrate a clinically important inhibition of the CYP3A4
      and/or CYP2C19 enzymes then the second optional group (Group 2) might be studied at a lower
      dose level of PQ912 .

      Each subject will participate in one treatment period, residing at the CRU from Day -1 (the
      day before dosing) to Day 7 (until after the last PK sampling occasion).

      All subjects will return for a post study visit 5 to 7 days after their final dose.

      Dose Regimen:

      Each subject will receive single oral doses of midazolam and omeprazole on the morning of Day
      1.

      On the morning of Day 2, all subjects will commence the multiple dose regimen for PQ912,
      which will continue for 5 days in total.

      Subjects in Group 1 and (if it necessary) in Group 2 will receive PQ912 twice daily (bid) on
      Days 2 to 6 inclusive and subjects in Group 2 will receive PQ912 bid on Days 2 to 6
      inclusive.

      On the morning of Day 6 subjects will be given single oral doses of midazolam and omeprazole
      co-administered with PQ912.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Effect of PQ912 at steady state on pharmacokinetic profile of Omeprazole and Midazolam
time frame: from day 1 up to day 6
description: Serial blood samples on day 1 and day 6 from predose up to 24 hours postdose
measure: Safety and tolerability of PQ912 in terms of Adverse Events Assessments when coadministered with Midazolam and Omeprazol
time frame: day-1 up to day 6 and post dose visit
description: Safety profile in terms of Adverse Events Assessments
measure: Safety and tolerability in terms of vital signs (blood pressure, pulse rate, respiration rate, Body temperature)
time frame: from baseline up to end of study visit (2 weeks after first treatment)
measure: Safety and Tolerability by assessing changes in electrocardiogram (ECG) parameters
time frame: from baseline up to end of study visit (2 weeks after first treatment)
measure: Safety and tolerability in terms of lab tests assessment (hematology, Serum biochemistry, serology, urinalysis)
time frame: from baseline up to end of study visit (2 weeks after first treatment)
arm group label: PQ912 & Midazolam & Omeprazole
arm group type: Experimental
description: day2 - day6 800mg PQ912 twice per day po day1 / day6 2.5 mg Midazolam once per day day1 / day6 20 mg Omeprazole once per day
intervention type: Drug
intervention name: PQ912
description: from day2 up to day6 twice daily oral dose of PQ912
arm group label: PQ912 & Midazolam & Omeprazole
other name: Glutaminyl Cyclase Inhibitor
intervention type: Drug
intervention name: Midazolam
description: single oral dose on day1 and day 6
arm group label: PQ912 & Midazolam & Omeprazole
other name: benzodiazepine
intervention type: Drug
intervention name: Omeprazole
description: single oral dose on day1 and day6
arm group label: PQ912 & Midazolam & Omeprazole
other name: Proton pump inhibitor
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Joseph Chiesa, MD, Dr
role: Principal Investigator
affiliation: Covance
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Midazolam
mesh term: Omeprazole
mesh term: Proton Pump Inhibitors