<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/NCT03801746</url>
  </required_header>
  <id_info>
    <org_study_id>AKB-6548-CI-0029</org_study_id>
    <nct_id>NCT03801746</nct_id>
  </id_info>
  <brief_title>Drug-Drug Interaction Study of Vadadustat With Cyclosporine, Probenecid and Rifampin</brief_title>
  <official_title>A Phase 1, Two-Part, Open-label Study in Healthy Adult Volunteers to Assess a Single Dose of Vadadustat as a Victim in Drug-Drug Interactions With Cyclosporine, Probenecid and Rifampin</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Akebia Therapeutics</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Akebia Therapeutics</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a Phase 1, two-part, open-label study to evaluate the interaction of cyclosporine,&#xD;
      probenecid, and rifampin as perpetrators with vadadustat (victim) in healthy male and female&#xD;
      subjects.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a Phase 1, two-part, open-label study to evaluate the interaction of cyclosporine,&#xD;
      probenecid, and rifampin as perpetrators with vadadustat (victim) in healthy male and female&#xD;
      subjects. Part 1 consists of 2 arms (cyclosporine and probenecid) and Part 2 consists of 1&#xD;
      arm (rifampin). Twenty (20) unique subjects will be enrolled into each study arm. The PK and&#xD;
      safety/tolerability data from Part 1 Arm 1 (cyclosporine) will determine if Part 2 (rifampin)&#xD;
      will proceed. Subjects will be on study for up to 72 days, including a 28-day screening&#xD;
      period, 6-10 day clinic period, and a 30-day follow-up period post last dose. Blood and/or&#xD;
      urine samples for PK analysis will be collected at pre-defined timepoints throughout the&#xD;
      study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 20, 2018</start_date>
  <completion_date type="Actual">August 15, 2018</completion_date>
  <primary_completion_date type="Actual">August 15, 2018</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>This is a 2 part study. Part 1 Arm 1 is a cross over design to assess the drug-drug interactions of cyclosporine with vadadustat. Part 1 Arm 2 is a fixed sequence design to assess the drug-drug interactions of probenecid with vadadustat. Part 2 is a crossover design to assess the drug-drug interaction of rifampin with vadadustat</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Area under plasma concentration-time curve from 0 to last quantifiable concentration (AUClast) of vadadustat</measure>
    <time_frame>Up to 10 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under plasma concentration-time curve from 0 to infinity (AUCinf) of vadadustat</measure>
    <time_frame>Up to 10 weeks</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum observed plasma concentration (Cmax) of vadadustat</measure>
    <time_frame>Up to 10 weeks</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to maximum observed plasma concentration (Tmax) of vadadustat</measure>
    <time_frame>Up to 10 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Elimination rate constant (Kel) of vadadustat</measure>
    <time_frame>Up to 10 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal half-life (t½) of vadadustat</measure>
    <time_frame>Up to 10 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent total body clearance (CL/F) of vadadustat</measure>
    <time_frame>Up to 10 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percent of extrapolated area under the curve from time t to infinity (%AUCextrap) of vadadustat</measure>
    <time_frame>Up to 10 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Renal clearance (CLr) of vadadustat and vadadustat 1-O-glucuronide excretion in urine for Part 1 Arm 2 (Probenecid) only</measure>
    <time_frame>Up to 10 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative amount excreted (Ae0-t) of vadadustat and vadadustat 1-O-glucuronide in urine for Part 1 Arm 2 (Probenecid) only</measure>
    <time_frame>Up to 10 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fraction (%) of the dose excreted (Fe%0-t) for Part 1 Arm 2 (Probenecid) only of vadadustat and vadadustat 1-O-glucuronide excretion in urine</measure>
    <time_frame>Up to 10 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under plasma concentration-time curve from 0 to last quantifiable concentration (AUClast) of vadadustat metabolites</measure>
    <time_frame>Up to 10 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under plasma concentration-time curve from 0 to infinity (AUCinf) of vadadustat metabolites</measure>
    <time_frame>Up to 10 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum observed plasma concentration (Cmax) of vadadustat metabolites</measure>
    <time_frame>Up to 10 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Reporting of treatment emergent adverse events as reported by the study subject</measure>
    <time_frame>Up to 10 weeks</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">40</enrollment>
  <condition>Drug Interaction Potentiation</condition>
  <arm_group>
    <arm_group_label>Vadadustat, Cyclosporine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Part 1: Arm 1: Subjects will receive vadadustat 300 mg alone and vadadustat 300 mg in combination with oral cyclosporine 500 mg in a crossover design</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Vadadustat; Probenecid</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Part 1: Arm 2: Subjects will receive vadadustat 300 mg alone and vadadustat 300 mg in combination with oral Probenecid 500 mg Q12h in a fixed sequence design</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Vadadustat and Rifampin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Part 2: Subjects will receive vadadustat 300 mg alone and vadadustat 300 mg in combination with IV rifampin 600 mg in a cross-over design</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>vadadustat</intervention_name>
    <description>Oral dose 300 mg</description>
    <arm_group_label>Vadadustat and Rifampin</arm_group_label>
    <arm_group_label>Vadadustat, Cyclosporine</arm_group_label>
    <arm_group_label>Vadadustat; Probenecid</arm_group_label>
    <other_name>AKB 6548</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rifampin</intervention_name>
    <description>IV Rifampin</description>
    <arm_group_label>Vadadustat and Rifampin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Probenecid</intervention_name>
    <description>Oral Probenecid</description>
    <arm_group_label>Vadadustat; Probenecid</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclosporins</intervention_name>
    <description>Oral Cyclosporine</description>
    <arm_group_label>Vadadustat, Cyclosporine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy Male or female between 18 and 55 years of age, inclusive, at time of informed&#xD;
             consent&#xD;
&#xD;
          -  Body mass index between 18.0 and 30.0 kg/m2, with a minimum body weight of 45 kg for&#xD;
             females and 50 kg for males, inclusive.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Current or past clinically significant history of cardiovascular, cerebrovascular,&#xD;
             pulmonary, gastrointestinal, hematologic, renal, hepatic, immunologic, metabolic,&#xD;
             urologic, neurologic, dermatologic, psychiatric, or other major disease. History of&#xD;
             cancer (except treated non-melanoma skin cancer) or history of chemotherapy use within&#xD;
             5 years prior to Screening; History of latent or active tuberculosis (TB).&#xD;
&#xD;
          -  Positive test results for human immunodeficiency virus (HIV) antibody; Positive test&#xD;
             results of hepatitis B surface antigen (HBsAg), or positive hepatitis C virus antibody&#xD;
             (HCVab) within 3 months prior to screening , or positive test results for human&#xD;
             immunodeficiency virus antibody (HIVab) at Screening.&#xD;
&#xD;
          -  Taking any prescription medication or over the counter multi-vitamin supplement, or&#xD;
             any non-prescription products (including herbal-containing preparations but excluding&#xD;
             acetaminophen) within 14 days prior to Day -1.&#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>Akebia Inc</last_name>
    <role>Study Director</role>
    <affiliation>Sponsor GmbH</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>inVentiv Health Clinique Inc.</name>
      <address>
        <city>Québec City</city>
        <state>Quebec</state>
        <zip>G1P A02</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>March 2019</verification_date>
  <study_first_submitted>December 27, 2018</study_first_submitted>
  <study_first_submitted_qc>January 9, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 11, 2019</study_first_posted>
  <last_update_submitted>March 20, 2019</last_update_submitted>
  <last_update_submitted_qc>March 20, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">March 22, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Healthy volunteers</keyword>
  <keyword>vadadustat</keyword>
  <keyword>drug interactions</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cyclosporine</mesh_term>
    <mesh_term>Rifampin</mesh_term>
    <mesh_term>Probenecid</mesh_term>
    <mesh_term>Cyclosporins</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03801746
org study id: AKB-6548-CI-0029
nct id: NCT03801746
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This is a Phase 1, two-part, open-label study to evaluate the interaction of cyclosporine,
      probenecid, and rifampin as perpetrators with vadadustat (victim) in healthy male and female
      subjects.
This is a Phase 1, two-part, open-label study to evaluate the interaction of cyclosporine,
      probenecid, and rifampin as perpetrators with vadadustat (victim) in healthy male and female
      subjects. Part 1 consists of 2 arms (cyclosporine and probenecid) and Part 2 consists of 1
      arm (rifampin). Twenty (20) unique subjects will be enrolled into each study arm. The PK and
      safety/tolerability data from Part 1 Arm 1 (cyclosporine) will determine if Part 2 (rifampin)
      will proceed. Subjects will be on study for up to 72 days, including a 28-day screening
      period, 6-10 day clinic period, and a 30-day follow-up period post last dose. Blood and/or
      urine samples for PK analysis will be collected at pre-defined timepoints throughout the
      study.
allocation: Randomized
intervention model: Sequential Assignment
intervention model description: This is a 2 part study. Part 1 Arm 1 is a cross over design to assess the drug-drug interactions of cyclosporine with vadadustat. Part 1 Arm 2 is a fixed sequence design to assess the drug-drug interactions of probenecid with vadadustat. Part 2 is a crossover design to assess the drug-drug interaction of rifampin with vadadustat
primary purpose: Basic Science
masking: None (Open Label)
measure: Area under plasma concentration-time curve from 0 to last quantifiable concentration (AUClast) of vadadustat
time frame: Up to 10 weeks
measure: Area under plasma concentration-time curve from 0 to infinity (AUCinf) of vadadustat
time frame: Up to 10 weeks
measure: Maximum observed plasma concentration (Cmax) of vadadustat
time frame: Up to 10 weeks
measure: Time to maximum observed plasma concentration (Tmax) of vadadustat
time frame: Up to 10 weeks
measure: Elimination rate constant (Kel) of vadadustat
time frame: Up to 10 weeks
measure: Terminal half-life (t½) of vadadustat
time frame: Up to 10 weeks
measure: Apparent total body clearance (CL/F) of vadadustat
time frame: Up to 10 weeks
measure: Percent of extrapolated area under the curve from time t to infinity (%AUCextrap) of vadadustat
time frame: Up to 10 weeks
measure: Renal clearance (CLr) of vadadustat and vadadustat 1-O-glucuronide excretion in urine for Part 1 Arm 2 (Probenecid) only
time frame: Up to 10 weeks
measure: Cumulative amount excreted (Ae0-t) of vadadustat and vadadustat 1-O-glucuronide in urine for Part 1 Arm 2 (Probenecid) only
time frame: Up to 10 weeks
measure: Fraction (%) of the dose excreted (Fe%0-t) for Part 1 Arm 2 (Probenecid) only of vadadustat and vadadustat 1-O-glucuronide excretion in urine
time frame: Up to 10 weeks
measure: Area under plasma concentration-time curve from 0 to last quantifiable concentration (AUClast) of vadadustat metabolites
time frame: Up to 10 weeks
measure: Area under plasma concentration-time curve from 0 to infinity (AUCinf) of vadadustat metabolites
time frame: Up to 10 weeks
measure: Maximum observed plasma concentration (Cmax) of vadadustat metabolites
time frame: Up to 10 weeks
measure: Reporting of treatment emergent adverse events as reported by the study subject
time frame: Up to 10 weeks
arm group label: Vadadustat, Cyclosporine
arm group type: Experimental
description: Part 1: Arm 1: Subjects will receive vadadustat 300 mg alone and vadadustat 300 mg in combination with oral cyclosporine 500 mg in a crossover design
arm group label: Vadadustat; Probenecid
arm group type: Experimental
description: Part 1: Arm 2: Subjects will receive vadadustat 300 mg alone and vadadustat 300 mg in combination with oral Probenecid 500 mg Q12h in a fixed sequence design
arm group label: Vadadustat and Rifampin
arm group type: Experimental
description: Part 2: Subjects will receive vadadustat 300 mg alone and vadadustat 300 mg in combination with IV rifampin 600 mg in a cross-over design
intervention type: Drug
intervention name: vadadustat
description: Oral dose 300 mg
arm group label: Vadadustat and Rifampin
arm group label: Vadadustat, Cyclosporine
arm group label: Vadadustat; Probenecid
other name: AKB 6548
intervention type: Drug
intervention name: Rifampin
description: IV Rifampin
arm group label: Vadadustat and Rifampin
intervention type: Drug
intervention name: Probenecid
description: Oral Probenecid
arm group label: Vadadustat; Probenecid
intervention type: Drug
intervention name: Cyclosporins
description: Oral Cyclosporine
arm group label: Vadadustat, Cyclosporine
criteria: 
gender: All
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Akebia Inc
role: Study Director
affiliation: Sponsor GmbH
facility: 
country: Canada
responsible party type: Sponsor
mesh term: Cyclosporine
mesh term: Rifampin
mesh term: Probenecid
mesh term: Cyclosporins
sharing ipd: Undecided