<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/NCT02249442</url>
  </required_header>
  <id_info>
    <org_study_id>1182.32</org_study_id>
    <nct_id>NCT02249442</nct_id>
  </id_info>
  <brief_title>Study to Determine the Pharmacokinetics on TPV/r in Subjects With Mild and Moderate Hepatic Insufficiency</brief_title>
  <official_title>An Open-label Study to Determine the Pharmacokinetics of Single-dose and/or Steady-state TPV/r 500/200 mg in Subjects With Mild and Moderate Hepatic Insufficiency</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boehringer Ingelheim</source>
  <brief_summary>
    <textblock>
      To determine the pharmacokinetics of single-dose and steady-state Tipranavir/Ritonavir&#xD;
      (TPV/r) 500/200 mg in subjects with mild to moderate hepatic insufficiency&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>October 2003</start_date>
  <primary_completion_date type="Actual">June 2004</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>AUC0-∞ (area under the concentration time curve of drug in plasma over the time interval from 0 extrapolated to infinity)</measure>
    <time_frame>Up to day 12 after first drug administration</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC0-12h (area under the concentration time curve of drug in plasma over the time interval from 0 to 12h)</measure>
    <time_frame>Up to 12 hours after drug administration</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Cmax (maximum concentration of drug in plasma)</measure>
    <time_frame>Up to day 12 after first drug administration</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Cp12h (drug concentration in plasma at 12 hours after administration) for the mild hepatic subjects</measure>
    <time_frame>Up to 12 hours (h) after drug administration</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>time from dosing to the maximum concentration (tmax)</measure>
    <time_frame>Up to day 12 after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>elimination half-life (t1/2)</measure>
    <time_frame>Up to day 12 after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>oral clearance (CL/F)</measure>
    <time_frame>Up to day 12 after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>volume of distribution (Vz/F)</measure>
    <time_frame>Up to day 12 after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relationship between pharmacokinetic parameters and baseline covariates</measure>
    <time_frame>Up to day 12 after first drug administration</time_frame>
    <description>Covariates = age, weight, race, cigarette smoking and hepatic impairment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relationship between pharmacokinetic parameters and baseline covariates</measure>
    <time_frame>Up to day 12 after first drug administration</time_frame>
    <description>Covariates = age, weight, race, cigarette smoking and the child-Pugh score as linear and quadratic terms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with abnormal changes in clinical laboratory parameters</measure>
    <time_frame>Up to day 12 after first drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with adverse events</measure>
    <time_frame>Up to day 12 after first drug administration</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Hepatic Insufficiency</condition>
  <arm_group>
    <arm_group_label>Scheme A, mild hepatic subjects</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>multi-dose</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Scheme B, moderate hepatic subjects</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>single dose</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tipranavir (TPV)</intervention_name>
    <arm_group_label>Scheme A, mild hepatic subjects</arm_group_label>
    <arm_group_label>Scheme B, moderate hepatic subjects</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ritonavir (r)</intervention_name>
    <arm_group_label>Scheme A, mild hepatic subjects</arm_group_label>
    <arm_group_label>Scheme B, moderate hepatic subjects</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Signed informed consent prior to trial participation.&#xD;
&#xD;
          2. Male and female subjects with:&#xD;
&#xD;
               -  Diagnostically established hepatic disease with mild hepatic insufficiency&#xD;
                  (defined as maximum ever Child-Pugh score ≤6) or&#xD;
&#xD;
               -  Diagnostically established hepatic disease with moderate hepatic insufficiency&#xD;
                  (defined as maximum ever Child-Pugh score ≤9) for less than 5 years. Current&#xD;
                  Child-Pugh score must be less than 9 or&#xD;
&#xD;
               -  Subjects matched by gender, race, age (±3 years), and weight (±3 kg) and&#xD;
                  cigarette smoking (matched where possible by +/- .25 pack years) to subjects with&#xD;
                  mild or moderate hepatic impairment already enrolled in the study.&#xD;
&#xD;
          3. Body Mass Index (BMI) between 18 and 29 kg/m2&#xD;
&#xD;
          4. Subjects ≥18 and ≤75 years old.&#xD;
&#xD;
          5. Ability to swallow multiple large capsules without difficulty.&#xD;
&#xD;
          6. Laboratory values that indicate adequate baseline organ function are required at the&#xD;
             time of screening. All subjects (including healthy controls) should have all&#xD;
             laboratory values less than or equal to Grade 1, based on the AIDS Clinical Trial&#xD;
             Group (ACTG) Grading Scale.The following exceptions will be made only for subjects&#xD;
             with mild or moderate hepatic insufficiency:&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) &lt;5 x upper&#xD;
                  limit normal (ULN) (≤ Grade 2)&#xD;
&#xD;
               -  Alkaline Phosphatase &lt;2 x ULN&#xD;
&#xD;
               -  Hemoglobin &gt;10.0 g / dL&#xD;
&#xD;
               -  Platelets &gt;75,000 / μl&#xD;
&#xD;
          7. Willingness to abstain from alcohol starting 2 days prior to administration of study&#xD;
             drug up to the end of the study.&#xD;
&#xD;
          8. Willingness to abstain from the following 72 hours prior to pharmacokinetic (PK)&#xD;
             sampling: Garlic supplements, methylxanthine containing drinks (coffee, tea, cola,&#xD;
             energy drinks, chocolate, etc.).&#xD;
&#xD;
          9. Willingness to abstain from over the counter herbal medications for the duration of&#xD;
             the study.&#xD;
&#xD;
         10. Acceptable medical history, physical examination and chest X-ray (at investigator's&#xD;
             discretion) are required prior to entering the treatment phase of the study.&#xD;
&#xD;
         11. Willingness to abstain from the following starting 14 days prior to administration of&#xD;
             study drug up until the end of the study: Grapefruit or grapefruit juice; Red wine;&#xD;
             Seville oranges (marmalade); St. John's Wort or Milk Thistle.&#xD;
&#xD;
         12. Willingness to abstain from vigorous physical exercise during intense PK study days&#xD;
             (Days 1 and 7).&#xD;
&#xD;
         13. Reasonable probability for completion of the study, including dosing requirements of&#xD;
             TPV/r and risk for hepatic decompensation among subjects with mild and moderate&#xD;
             hepatic insufficiency.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Female subjects who are of reproductive potential who:&#xD;
&#xD;
               -  Have positive serum β-hCG (Human chorionic gonadotropin test for pregnancy) at&#xD;
                  Visit 1 or on Day 0.&#xD;
&#xD;
               -  Have not been using a barrier contraceptive method for at least 3 months prior to&#xD;
                  Day 0 (Visit 2).&#xD;
&#xD;
               -  Are not willing to use a reliable method of at least barrier contraception,&#xD;
                  during the trial and 60 days after completion/termination.&#xD;
&#xD;
               -  Are breast-feeding.&#xD;
&#xD;
          2. Participation in another trial with an investigational medicine within 60 days prior&#xD;
             to Day 0 (Visit 2).&#xD;
&#xD;
          3. Use of any medication listed in the protocol within 30 days prior to Day 0 (Visit 2).&#xD;
&#xD;
          4. Use of any pharmacological contraceptive (including oral or patch) for one month prior&#xD;
             to study initiation and for the duration of the study. Use of implantable or&#xD;
             injectable contraceptive agents is excluded for at least six months prior to study&#xD;
             start.&#xD;
&#xD;
          5. Use of hormone replacement therapy with estrogen-based preparations for at least 1&#xD;
             month prior to study initiation and for the duration of the study.&#xD;
&#xD;
          6. Administration of antimicrobial agents within 10 days prior to Day 0 (Visit 2) or&#xD;
             during the trial.&#xD;
&#xD;
          7. Subjects with a history of spontaneous bacterial peritonitis, advanced hepatic&#xD;
             cirrhosis (including Child's-Pugh score &gt;8), active esophageal variceal disease, or&#xD;
             asterixis.&#xD;
&#xD;
          8. Subjects with active or untreated hepatocellular carcinoma or who test positive for&#xD;
             serum alpha fetoprotein (&gt;10mg/dL).&#xD;
&#xD;
          9. Subjects with active coagulopathy.&#xD;
&#xD;
         10. Have serological evidence of exposure to, or infection with, HIV.&#xD;
&#xD;
         11. Recent history of alcohol or substance abuse (within 6 months of study period).&#xD;
&#xD;
         12. Blood or plasma donations within 30 days prior to Day 0 (Visit 2).&#xD;
&#xD;
         13. Subjects with a seated systolic blood pressure either &lt;100 mm Hg or &gt;150 mm Hg;&#xD;
             resting heart rate either &lt;50 beats/min or &gt;90 beats/min. For subjects with a resting&#xD;
             heart rate below 50, or above 90, the investigator could discuss exclusion with the&#xD;
             medical monitor on a case-by-case basis.&#xD;
&#xD;
         14. Subjects with a history of any illness or allergy that, in the opinion of the&#xD;
             investigator, might confound the results of the study or pose additional risk in&#xD;
             administering TPV and ritonavir (RTV).&#xD;
&#xD;
         15. Subjects who have had an acute illness within 2 weeks prior to Day 0 (Visit 2).&#xD;
&#xD;
         16. Current use of any medications to control symptoms of hepatic disease within 30 days&#xD;
             prior to Day 0, (Visit 2) or for the duration of the trial.&#xD;
&#xD;
         17. Known hypersensitivity to TPV, Ritonavir or the sulphonamide class of drugs.&#xD;
&#xD;
         18. Inability to adhere to the requirements of the protocol.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <link>
    <url>http://trials.boehringer-ingelheim.com</url>
    <description>Related Info</description>
  </link>
  <verification_date>September 2014</verification_date>
  <study_first_submitted>September 23, 2014</study_first_submitted>
  <study_first_submitted_qc>September 23, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 25, 2014</study_first_posted>
  <last_update_submitted>September 25, 2014</last_update_submitted>
  <last_update_submitted_qc>September 25, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 26, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatic Insufficiency</mesh_term>
    <mesh_term>Liver Failure</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ritonavir</mesh_term>
    <mesh_term>Tipranavir</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/NCT02249442
org study id: 1182.32
nct id: NCT02249442
lead sponsor: 
To determine the pharmacokinetics of single-dose and steady-state Tipranavir/Ritonavir
      (TPV/r) 500/200 mg in subjects with mild to moderate hepatic insufficiency
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: AUC0-∞ (area under the concentration time curve of drug in plasma over the time interval from 0 extrapolated to infinity)
time frame: Up to day 12 after first drug administration
measure: AUC0-12h (area under the concentration time curve of drug in plasma over the time interval from 0 to 12h)
time frame: Up to 12 hours after drug administration
measure: Cmax (maximum concentration of drug in plasma)
time frame: Up to day 12 after first drug administration
measure: Cp12h (drug concentration in plasma at 12 hours after administration) for the mild hepatic subjects
time frame: Up to 12 hours (h) after drug administration
measure: time from dosing to the maximum concentration (tmax)
time frame: Up to day 12 after first drug administration
measure: elimination half-life (t1/2)
time frame: Up to day 12 after first drug administration
measure: oral clearance (CL/F)
time frame: Up to day 12 after first drug administration
measure: volume of distribution (Vz/F)
time frame: Up to day 12 after first drug administration
measure: Relationship between pharmacokinetic parameters and baseline covariates
time frame: Up to day 12 after first drug administration
description: Covariates = age, weight, race, cigarette smoking and hepatic impairment
measure: Relationship between pharmacokinetic parameters and baseline covariates
time frame: Up to day 12 after first drug administration
description: Covariates = age, weight, race, cigarette smoking and the child-Pugh score as linear and quadratic terms
measure: Number of patients with abnormal changes in clinical laboratory parameters
time frame: Up to day 12 after first drug administration
measure: Number of patients with adverse events
time frame: Up to day 12 after first drug administration
arm group label: Scheme A, mild hepatic subjects
arm group type: Experimental
description: multi-dose
arm group label: Scheme B, moderate hepatic subjects
arm group type: Experimental
description: single dose
intervention type: Drug
intervention name: Tipranavir (TPV)
arm group label: Scheme A, mild hepatic subjects
arm group label: Scheme B, moderate hepatic subjects
intervention type: Drug
intervention name: Ritonavir (r)
arm group label: Scheme A, mild hepatic subjects
arm group label: Scheme B, moderate hepatic subjects
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
url: http://trials.boehringer-ingelheim.com
description: Related Info
responsible party type: Sponsor
mesh term: Hepatic Insufficiency
mesh term: Liver Failure
mesh term: Ritonavir
mesh term: Tipranavir