<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/NCT02251119</url>
  </required_header>
  <id_info>
    <org_study_id>1182.55</org_study_id>
    <nct_id>NCT02251119</nct_id>
  </id_info>
  <brief_title>The Pharmacodynamic/Pharmacokinetic Interaction of Tipranavir and Ritonavir With Loperamide in Healthy Volunteers</brief_title>
  <official_title>The Pharmacodynamic/Pharmacokinetic Interaction of Tipranavir and Ritonavir With Loperamide in Healthy Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boehringer Ingelheim</source>
  <brief_summary>
    <textblock>
      The objective of the study was to determine if the co-administration of loperamide (LOP) with&#xD;
      tipranavir (TPV), ritonavir (RTV), or TPV plus RTV (TPV/r) caused a clinically significant&#xD;
      change in the respiratory response to carbon dioxide (CO2), defined as a 10% decrease in the&#xD;
      area under the pharmacodynamic effect/time curve or at least a 25% decrease in at least one&#xD;
      pharmacodynamic time point.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>July 2002</start_date>
  <primary_completion_date type="Actual">January 2003</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum decrease in the percentage baseline CO2 response slope</measure>
    <time_frame>up to 6 hours on days 1, 9 and 22</time_frame>
    <description>rebreathing test</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Zero-to-six hour area under the curve for the percentage baseline CO2 response slope profile</measure>
    <time_frame>up to 6 hours on days 1, 9 and 22</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in the ratio between the diameter of the iris and pupil</measure>
    <time_frame>Pupillary resonse to loperamide</time_frame>
    <description>up to 6 hours on days 1, 9 and 22</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum plasma concentration</measure>
    <time_frame>up to 75 h after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimum plasma concentration</measure>
    <time_frame>up to 75 h after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to reach peak or maximum concentration</measure>
    <time_frame>up to 75 h after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal half life</measure>
    <time_frame>up to 75 h after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oral clearance</measure>
    <time_frame>up to 75 h after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration time curve</measure>
    <time_frame>up to 75 h after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of subjects with adverse events</measure>
    <time_frame>up to day 24</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>TPV</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Administration of LOP on days 1, 9 and 22&#xD;
Administration of TPV on days 4-9&#xD;
Administration of TPV/RTV on days 12-22</description>
  </arm_group>
  <arm_group>
    <arm_group_label>RTV</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Administration of LOP on days 1, 9 and 22&#xD;
Administration of RTV on days 4-9&#xD;
Administration of TPV/RTV on days 12-22</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tipranavir</intervention_name>
    <arm_group_label>RTV</arm_group_label>
    <arm_group_label>TPV</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ritonavir</intervention_name>
    <arm_group_label>RTV</arm_group_label>
    <arm_group_label>TPV</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Loperamide</intervention_name>
    <arm_group_label>RTV</arm_group_label>
    <arm_group_label>TPV</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Ability and willingness to give written informed consent in accordance with&#xD;
             institutional and federal guidelines and to comply with the investigational nature of&#xD;
             the study and the related requirements&#xD;
&#xD;
          2. Healthy males or females between 18 and 60 years of age inclusive&#xD;
&#xD;
          3. A body mass index (BMI) between 18 and 35 kg/m2&#xD;
&#xD;
          4. Ability to perform a respiratory depression test&#xD;
&#xD;
          5. Ability to swallow numerous large capsules without difficulty&#xD;
&#xD;
          6. In the opinion of the investigator, a reasonable probability for completion of the&#xD;
             study&#xD;
&#xD;
          7. Acceptable laboratory values that indicated adequate baseline organ function were&#xD;
             required at the time of screening. Laboratory values were considered to be acceptable&#xD;
             if their severity was ≤Grade 1 based on the AIDS Clinical Trials Group Division of&#xD;
             AIDS (DAIDS) Grading Scale. All abnormal laboratory values &gt;Grade 1 (e.g., creatinine&#xD;
             phosphokinase, amylase, triglycerides) were subject to approval by the clinical&#xD;
             monitor or designee&#xD;
&#xD;
          8. Acceptable medical history, physical examination, ECG, and chest x-ray were required&#xD;
             prior to entering the study&#xD;
&#xD;
          9. Willingness to abstain from alcohol from Day -2 to Day 24. In addition, red wine must&#xD;
             not have been ingested within 14 days prior to Day 1 (Visit 2)&#xD;
&#xD;
         10. Willingness to abstain from ingesting grapefruit, grapefruit juice, Seville oranges,&#xD;
             St. John's Wort and Milk Thistle, within 14 days of Day 1 (Visit 2) and for the&#xD;
             duration of the study&#xD;
&#xD;
         11. Willingness to abstain from ingesting garlic supplements, or methylxanthine containing&#xD;
             drinks or food (coffee, tea, cola, energy drinks, chocolate, etc) within 72 hours of&#xD;
             pharmacokinetic (PK) sampling days (Day 1 [Visit 2], Day 9 [Visit 3], Day 21-22 [Visit&#xD;
             4])&#xD;
&#xD;
         12. Willingness to abstain from the use of tobacco products for the duration of the study&#xD;
&#xD;
         13. Nonsmoker&#xD;
&#xD;
         14. Urine drug screen negative for illegal nonprescription drugs&#xD;
&#xD;
         15. Negative HIV serology&#xD;
&#xD;
         16. Negative serology for hepatitis B surface antigen and hepatitis C&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Female subjects who were of reproductive potential who:&#xD;
&#xD;
               -  Had a positive serum β-human chorionic gonadotropin test at Visit 1, or&#xD;
&#xD;
               -  Had not been using a barrier contraceptive method for at least 3 months prior to&#xD;
                  Visit 2 (Day 1), or&#xD;
&#xD;
               -  Were not willing to use a reliable method of double-barrier contraception (such&#xD;
                  as a diaphragm with spermicidal cream/jelly or condoms with spermicidal foam)&#xD;
                  during the trial and 30 days after completion/termination of the trial, or&#xD;
&#xD;
               -  Were breast-feeding&#xD;
&#xD;
          2. Participation in another trial with an investigational medicine for 30 days prior to&#xD;
             Day 1 (Visit 2)&#xD;
&#xD;
          3. Ingestion of any known enzyme-altering drug listed in the protocol 30 days prior to&#xD;
             Day 1 (Visit 2)&#xD;
&#xD;
          4. Ingestion of grapefruit, grapefruit juice, St. John's Wort, Milk Thistle, Seville&#xD;
             oranges and red wine within 14 days prior to Day 1 (Visit 2)&#xD;
&#xD;
          5. Ingestion of garlic supplements or methylxanthine-containing drinks or food (coffee,&#xD;
             tea, cola, energy drinks, chocolate, etc) within 72 hours of PK sampling days (Day 1&#xD;
             [Visit 2], Day 9 [Visit 3], Day 21-22 [Visit 4])&#xD;
&#xD;
          6. Ingestion of antibiotics within 10 days prior to Day 1 (Visit 2)&#xD;
&#xD;
          7. Inability to comply with investigator's instructions&#xD;
&#xD;
          8. History of gastrointestinal, hepatic, or renal disorders within 60 days of study entry&#xD;
&#xD;
          9. Recent or active alcohol abuse&#xD;
&#xD;
         10. Current use of tobacco products&#xD;
&#xD;
         11. Blood or plasma donations within 30 days prior to Day 1 (Visit 2)&#xD;
&#xD;
         12. Seated systolic blood pressure either &lt;100 mm Hg or &gt;150 mm Hg; resting heart rate&#xD;
             either &lt;50 beats/min or &gt;90 beats/min&#xD;
&#xD;
         13. A history of any illness or allergy that, in the opinion of the investigator, might&#xD;
             confound the results of the study or pose an additional risk in administering TPV or&#xD;
             RTV or LOP to the subject&#xD;
&#xD;
         14. An acute illness within 2 weeks prior to Day 1 (Visit 2)&#xD;
&#xD;
         15. Current taking of any over-the-counter drug within 7 days prior to Day 1 (Visit 2) or&#xD;
             current taking of any prescription drug that, in the opinion of the investigator in&#xD;
             consultation with the clinical monitor and pharmacokineticist, might interfere with&#xD;
             either the absorption, distribution or metabolism of the test substances&#xD;
&#xD;
         16. Hypersensitivity to TPV, RTV, or LOP&#xD;
&#xD;
         17. Administration of any antidiarrheal agent within 7 days of Day 1 (Visit 2)&#xD;
&#xD;
         18. Hypersensitivity to sulfonamide drugs&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</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 25, 2014</study_first_submitted>
  <study_first_submitted_qc>September 25, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 29, 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 29, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ritonavir</mesh_term>
    <mesh_term>Tipranavir</mesh_term>
    <mesh_term>Loperamide</mesh_term>
    <mesh_term>Antidiarrheals</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/NCT02251119
org study id: 1182.55
nct id: NCT02251119
lead sponsor: 
The objective of the study was to determine if the co-administration of loperamide (LOP) with
      tipranavir (TPV), ritonavir (RTV), or TPV plus RTV (TPV/r) caused a clinically significant
      change in the respiratory response to carbon dioxide (CO2), defined as a 10% decrease in the
      area under the pharmacodynamic effect/time curve or at least a 25% decrease in at least one
      pharmacodynamic time point.
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum decrease in the percentage baseline CO2 response slope
time frame: up to 6 hours on days 1, 9 and 22
description: rebreathing test
measure: Zero-to-six hour area under the curve for the percentage baseline CO2 response slope profile
time frame: up to 6 hours on days 1, 9 and 22
measure: Change in the ratio between the diameter of the iris and pupil
time frame: Pupillary resonse to loperamide
description: up to 6 hours on days 1, 9 and 22
measure: Maximum plasma concentration
time frame: up to 75 h after drug administration
measure: Minimum plasma concentration
time frame: up to 75 h after drug administration
measure: Time to reach peak or maximum concentration
time frame: up to 75 h after drug administration
measure: Terminal half life
time frame: up to 75 h after drug administration
measure: Oral clearance
time frame: up to 75 h after drug administration
measure: Area under the plasma concentration time curve
time frame: up to 75 h after drug administration
measure: Number of subjects with adverse events
time frame: up to day 24
arm group label: TPV
arm group type: Experimental
description: Administration of LOP on days 1, 9 and 22
Administration of TPV on days 4-9
Administration of TPV/RTV on days 12-22
arm group label: RTV
arm group type: Experimental
description: Administration of LOP on days 1, 9 and 22
Administration of RTV on days 4-9
Administration of TPV/RTV on days 12-22
intervention type: Drug
intervention name: Tipranavir
arm group label: RTV
arm group label: TPV
intervention type: Drug
intervention name: Ritonavir
arm group label: RTV
arm group label: TPV
intervention type: Drug
intervention name: Loperamide
arm group label: RTV
arm group label: TPV
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: Accepts Healthy Volunteers
url: http://trials.boehringer-ingelheim.com
description: Related Info
responsible party type: Sponsor
mesh term: Ritonavir
mesh term: Tipranavir
mesh term: Loperamide
mesh term: Antidiarrheals