<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/NCT02252731</url>
  </required_header>
  <id_info>
    <org_study_id>1517-CL-0509</org_study_id>
    <secondary_id>2013-001043-31</secondary_id>
    <nct_id>NCT02252731</nct_id>
  </id_info>
  <brief_title>A Study to Evaluate the Effects of Multiple Doses of FG-4592 on the Exposure, Safety and Tolerability and Effect of Warfarin in Healthy Subjects</brief_title>
  <official_title>A Phase 1, Open-label, One-sequence Crossover Study to Evaluate the Effect of Multiple Doses of FG 4592 on the Pharmacokinetics of Warfarin in Healthy Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Astellas Pharma Europe B.V.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>FibroGen</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Astellas Pharma Inc</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will determine the effect of multiple doses of FG-4592 on the pharmacokinetics&#xD;
      (PK) of a single dose of warfarin. It will evaluate the safety and tolerability of warfarin&#xD;
      alone and in combination with multiple doses of FG-4592, and will evaluate the effect of&#xD;
      multiple doses of FG-4592 on the pharmacodynamics (PD) of warfarin.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study consists of 2 periods, separated by a washout period (a minimum of 14 days after&#xD;
      warfarin dosing on Day 1, Period 1). Screening takes place from Day -22 to Day -2.&#xD;
&#xD;
      Subjects are admitted to the clinical unit on Day -1 of Period 1. On Day 1 of the first&#xD;
      period, subjects receive a single oral dose of warfarin. After completion of all assessments&#xD;
      on Day 8, subjects are discharged from the clinical unit on the condition that there are no&#xD;
      medical reasons for a prolonged stay. They return to the clinical unit on Day -1 of the&#xD;
      second period, after the washout period.&#xD;
&#xD;
      In Period 2, the subjects receive multiple doses of FG 4592. On Day 7 of Period 2, FG 4592 is&#xD;
      given concomitantly with warfarin. After completion of all assessments on Day 16 of Period 2,&#xD;
      subjects are discharged from the clinic on the condition that there are no medical reasons&#xD;
      for a prolonged stay. The subjects return for an End of Study Visit (ESV) 5 to 9 days after&#xD;
      the last assessment of Period 2 (or after early withdrawal).&#xD;
&#xD;
      Safety assessments are performed throughout the study. Blood and urine samples are collected&#xD;
      for PK and PD assessments.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2013</start_date>
  <completion_date type="Actual">November 2013</completion_date>
  <primary_completion_date type="Actual">November 2013</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>PK of S-warfarin and R-warfarin in plasma measured by area under the curve from the time of dosing extrapolated to time infinity (AUCinf)</measure>
    <time_frame>Period 1 (Day 1 to Day 8); Period 2 (Day 7 to Day 16)</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>PK of S-warfarin and R-warfarin in plasma measured by maximum concentration (Cmax)</measure>
    <time_frame>Period 1 (Day 1 to Day 8); Period 2 (Day 7 to Day 16)</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>PK profile of S-warfarin and R-warfarin in plasma</measure>
    <time_frame>Period 1 (Day 1 to Day 8); Period 2 (Day 7 to Day 16)</time_frame>
    <description>area under the concentration-time curve from the time of dosing to the last measurable concentration (Clast) (AUClast), unbound AUC from the time of dosing to Clast (AUClast,u), AUC from the time of dosing extrapolated to time infinity (AUCinf), unbound AUC extrapolated to infinity (AUCinf,u), maximum unbound plasma concentration (Cmax,u), apparent total body clearance after extra-vascular dosing (CL/F), unbound apparent total body clearance after extravascular dosing (CLu/F), fraction unbound (fu), time interval between the time of dosing and the first measurable concentration (tlag), time of the maximum concentration (tmax), terminal elimination half-life (t1/2), apparent volume of distribution during the terminal elimination phase after single extravascular dosing (Vz/F), unbound apparent volume of distribution during terminal phase after oral administration (Vz,u/F)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK profile of FG-4592 in plasma</measure>
    <time_frame>Period 2 (Day 1 to Day 15)</time_frame>
    <description>AUC from time point 0 to time point 24 hours (AUC0-24h), AUClast, AUCinf , Cmax, concentration at pre-dose for repeated dosing (Ctrough), tmax, t1/2, CL/F, and Vz/F</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>PK profile of FG-4592 in urine</measure>
    <time_frame>Period 2 (Day 7 to Day 8)</time_frame>
    <description>renal clearance (CLR), unbound CLR from time point 0 to 24 hours (CLR,0-24h), cumulative amount of drug excreted unchanged into urine from time of dosing extrapolated to time infinity (Aeinf), percent of drug excreted unchanged into urine from time of dosing extrapolated to time infinity in percent of dose (Aeinf%), cumulative amount of drug excreted unchanged into urine, from time of dosing up to the collection time of the last measurable concentration (Aelast), percent of drug excreted into urine from time of dosing up to the collection time of the last measurable concentration in percent of dose (Aelast%), cumulative amount of drug excreted unchanged into urine, from time of dosing up to the collection time of 24 hours (Ae0 24h), cumulative amount of drug excreted unchanged into urine, from time of dosing up to the collection time of 24 hours in percent of dose (Ae0-24h%)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamics profile of warfarin in plasma</measure>
    <time_frame>Period 1 Day 1 to to ESV (5 to 9 days after the last protocol defined assessment of Period 2 (or after early withdrawal))</time_frame>
    <description>area under the Prothrombin Time (PT)-time curve from the time of dosing until the last sample collected (AUCPT,last), maximal PT (PTmax), time to reach PTmax (tPT,max), area under the International Normalized Ratio (INR)-time curve from the time of dosing until the last sample collected (AUCINR,last), maximal INR after Drug Administration (INRmax), time to reach the INRmax (tINR,max)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety profile</measure>
    <time_frame>Screening (Day -22 to Day -2) to ESV (5 to 9 days after the last protocol defined assessment of Period 2 (or after early withdrawal))</time_frame>
    <description>Safety profile includes Adverse Events (AEs), vital signs, physical examination, laboratory tests, electrocardiogram (ECG)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Pharmacokinetics of FG-4592</condition>
  <condition>Healthy Subjects</condition>
  <arm_group>
    <arm_group_label>warfarin and FG-4592</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Single dose of warfarin and Multiple doses of FG-4592 in combination with a single dose of warfarin</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Warfarin</intervention_name>
    <description>Oral</description>
    <arm_group_label>warfarin and FG-4592</arm_group_label>
    <other_name>Coumadin®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>FG-4592</intervention_name>
    <description>Oral</description>
    <arm_group_label>warfarin and FG-4592</arm_group_label>
    <other_name>ASP1517,</other_name>
    <other_name>roxadustat</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male subject and their female spouse/partners who are of childbearing potential must&#xD;
             be using highly effective contraception consisting of two forms of birth control.&#xD;
&#xD;
          -  Male subject must not donate sperm starting at screening and throughout the study&#xD;
             period and for 90 days after the final study drug administration.&#xD;
&#xD;
          -  Female subject must be either of non-childbearing potential or, if of childbearing&#xD;
             potential, must have a negative pregnancy test at screening and Day -1 and must use&#xD;
             two forms of birth control.&#xD;
&#xD;
          -  Female subject must not donate ova starting at screening and throughout the study&#xD;
             period and for 28 days after the final study drug administration.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subject has a known or suspected hypersensitivity to FG 4592, warfarin, or any&#xD;
             components of the formulations used.&#xD;
&#xD;
          -  Subject has/had febrile illness or symptomatic, viral, bacterial (including upper&#xD;
             respiratory infection), or fungal (non-cutaneous) infection within 1 week prior to&#xD;
             admission to the clinical unit [Day -1].&#xD;
&#xD;
          -  Subject is lactose intolerant.&#xD;
      </textblock>
    </criteria>
    <gender>All</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>Study Physician</last_name>
    <role>Study Director</role>
    <affiliation>Astellas Pharma Europe B.V.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Parexel International GmbH</name>
      <address>
        <city>Berlin</city>
        <zip>14050</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>September 2014</verification_date>
  <study_first_submitted>June 10, 2014</study_first_submitted>
  <study_first_submitted_qc>September 26, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 30, 2014</study_first_posted>
  <last_update_submitted>September 26, 2014</last_update_submitted>
  <last_update_submitted_qc>September 26, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 30, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Phase I</keyword>
  <keyword>FG-4592</keyword>
  <keyword>Warfarin</keyword>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Pharmacodynamics</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Warfarin</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/NCT02252731
org study id: 1517-CL-0509
secondary id: 2013-001043-31
nct id: NCT02252731
lead sponsor: 
collaborator: 
has dmc: No
This study will determine the effect of multiple doses of FG-4592 on the pharmacokinetics
      (PK) of a single dose of warfarin. It will evaluate the safety and tolerability of warfarin
      alone and in combination with multiple doses of FG-4592, and will evaluate the effect of
      multiple doses of FG-4592 on the pharmacodynamics (PD) of warfarin.
The study consists of 2 periods, separated by a washout period (a minimum of 14 days after
      warfarin dosing on Day 1, Period 1). Screening takes place from Day -22 to Day -2.

      Subjects are admitted to the clinical unit on Day -1 of Period 1. On Day 1 of the first
      period, subjects receive a single oral dose of warfarin. After completion of all assessments
      on Day 8, subjects are discharged from the clinical unit on the condition that there are no
      medical reasons for a prolonged stay. They return to the clinical unit on Day -1 of the
      second period, after the washout period.

      In Period 2, the subjects receive multiple doses of FG 4592. On Day 7 of Period 2, FG 4592 is
      given concomitantly with warfarin. After completion of all assessments on Day 16 of Period 2,
      subjects are discharged from the clinic on the condition that there are no medical reasons
      for a prolonged stay. The subjects return for an End of Study Visit (ESV) 5 to 9 days after
      the last assessment of Period 2 (or after early withdrawal).

      Safety assessments are performed throughout the study. Blood and urine samples are collected
      for PK and PD assessments.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: PK of S-warfarin and R-warfarin in plasma measured by area under the curve from the time of dosing extrapolated to time infinity (AUCinf)
time frame: Period 1 (Day 1 to Day 8); Period 2 (Day 7 to Day 16)
measure: PK of S-warfarin and R-warfarin in plasma measured by maximum concentration (Cmax)
time frame: Period 1 (Day 1 to Day 8); Period 2 (Day 7 to Day 16)
measure: PK profile of S-warfarin and R-warfarin in plasma
time frame: Period 1 (Day 1 to Day 8); Period 2 (Day 7 to Day 16)
description: area under the concentration-time curve from the time of dosing to the last measurable concentration (Clast) (AUClast), unbound AUC from the time of dosing to Clast (AUClast,u), AUC from the time of dosing extrapolated to time infinity (AUCinf), unbound AUC extrapolated to infinity (AUCinf,u), maximum unbound plasma concentration (Cmax,u), apparent total body clearance after extra-vascular dosing (CL/F), unbound apparent total body clearance after extravascular dosing (CLu/F), fraction unbound (fu), time interval between the time of dosing and the first measurable concentration (tlag), time of the maximum concentration (tmax), terminal elimination half-life (t1/2), apparent volume of distribution during the terminal elimination phase after single extravascular dosing (Vz/F), unbound apparent volume of distribution during terminal phase after oral administration (Vz,u/F)
measure: PK profile of FG-4592 in plasma
time frame: Period 2 (Day 1 to Day 15)
description: AUC from time point 0 to time point 24 hours (AUC0-24h), AUClast, AUCinf , Cmax, concentration at pre-dose for repeated dosing (Ctrough), tmax, t1/2, CL/F, and Vz/F
measure: PK profile of FG-4592 in urine
time frame: Period 2 (Day 7 to Day 8)
description: renal clearance (CLR), unbound CLR from time point 0 to 24 hours (CLR,0-24h), cumulative amount of drug excreted unchanged into urine from time of dosing extrapolated to time infinity (Aeinf), percent of drug excreted unchanged into urine from time of dosing extrapolated to time infinity in percent of dose (Aeinf%), cumulative amount of drug excreted unchanged into urine, from time of dosing up to the collection time of the last measurable concentration (Aelast), percent of drug excreted into urine from time of dosing up to the collection time of the last measurable concentration in percent of dose (Aelast%), cumulative amount of drug excreted unchanged into urine, from time of dosing up to the collection time of 24 hours (Ae0 24h), cumulative amount of drug excreted unchanged into urine, from time of dosing up to the collection time of 24 hours in percent of dose (Ae0-24h%)
measure: Pharmacodynamics profile of warfarin in plasma
time frame: Period 1 Day 1 to to ESV (5 to 9 days after the last protocol defined assessment of Period 2 (or after early withdrawal))
description: area under the Prothrombin Time (PT)-time curve from the time of dosing until the last sample collected (AUCPT,last), maximal PT (PTmax), time to reach PTmax (tPT,max), area under the International Normalized Ratio (INR)-time curve from the time of dosing until the last sample collected (AUCINR,last), maximal INR after Drug Administration (INRmax), time to reach the INRmax (tINR,max)
measure: Safety profile
time frame: Screening (Day -22 to Day -2) to ESV (5 to 9 days after the last protocol defined assessment of Period 2 (or after early withdrawal))
description: Safety profile includes Adverse Events (AEs), vital signs, physical examination, laboratory tests, electrocardiogram (ECG)
arm group label: warfarin and FG-4592
arm group type: Experimental
description: Single dose of warfarin and Multiple doses of FG-4592 in combination with a single dose of warfarin
intervention type: Drug
intervention name: Warfarin
description: Oral
arm group label: warfarin and FG-4592
other name: Coumadin®
intervention type: Drug
intervention name: FG-4592
description: Oral
arm group label: warfarin and FG-4592
other name: ASP1517,
other name: roxadustat
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Study Physician
role: Study Director
affiliation: Astellas Pharma Europe B.V.
facility: 
country: Germany
responsible party type: Sponsor
mesh term: Warfarin