<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/NCT02251795</url>
  </required_header>
  <id_info>
    <org_study_id>1182.117</org_study_id>
    <nct_id>NCT02251795</nct_id>
  </id_info>
  <brief_title>Effects of Steady State Tipranavir/Ritonavir or Darunavir/Ritonavir or Ritonavir on Platelet Function, Coagulation and Fibrinolysis Biomarkers in Healthy Subjects</brief_title>
  <official_title>Effects of Steady State Tipranavir/Ritonavir or Darunavir/Ritonavir or Ritonavir on Platelet Function, Coagulation and Fibrinolysis Biomarkers in Healthy Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Boehringer Ingelheim</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Boehringer Ingelheim</source>
  <brief_summary>
    <textblock>
      Study to determine the effect of steady-state plasma concentration of Tipranavir/ritonavir&#xD;
      (TPV/r) on platelet aggregation in healthy subjects and investigate the effect of TPV/r at&#xD;
      steady state plasma concentrations on other platelet functions and biomarkers of coagulation&#xD;
      and fibrinolysis.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>August 2007</start_date>
  <primary_completion_date type="Actual">June 2008</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percent change from baseline in the area under the curve (AUC) of platelet aggregation in response to arachidonic acid (AA)</measure>
    <time_frame>pre-dose, up to 48 h after drug administration</time_frame>
    <description>calculated as the ratio of the AUC at steady state TPV plasma concentrations and the baseline AUC</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in platelet aggregation in response to AA</measure>
    <time_frame>pre-dose, up to 48 h after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in platelet aggregation in response to collagen</measure>
    <time_frame>pre-dose, up to 48 h after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in platelet aggregation in response adenosine diphosphate (ADP)</measure>
    <time_frame>pre-dose, up to 48 h after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in closure Time (CT)</measure>
    <time_frame>pre-dose, up to 48 h after drug administration</time_frame>
    <description>Platelet Function Analyzer (PFA)-100 test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in urinary thromboxane B2 metabolites</measure>
    <time_frame>pre-dose, up to 48 h after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in bleeding time</measure>
    <time_frame>Baseline, up to day 30</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in activated partial thromboplastin time (aPTT)</measure>
    <time_frame>Baseline, up to day 30</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in prothrombin time (PT)</measure>
    <time_frame>Baseline, up to day 30</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in fibrinogen</measure>
    <time_frame>Baseline, up to day 30</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in von Willebrand antigen</measure>
    <time_frame>Baseline, up to day 30</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in von anti-thrombin III antigen</measure>
    <time_frame>Baseline, up to day 30</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in anti-thrombin III activity</measure>
    <time_frame>Baseline, up to day 30</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in factor II</measure>
    <time_frame>Baseline, up to day 30</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in factor VII</measure>
    <time_frame>Baseline, up to day 30</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in factor IX</measure>
    <time_frame>Baseline, up to day 30</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in factor X</measure>
    <time_frame>Baseline, up to day 30</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in plasminogen activity</measure>
    <time_frame>Baseline, up to day 30</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in alpha 2-antiplasmin</measure>
    <time_frame>Baseline, up to day 30</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in D-dimer</measure>
    <time_frame>Baseline, up to day 30</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Plasminogen Activator Inhibitor (PAI-1)</measure>
    <time_frame>Baseline, up to day 30</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum measured concentration of the analyte in plasma (Cmax)</measure>
    <time_frame>pre-dose, up to 48 h after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum concentration at 12 hours (Cp12h)</measure>
    <time_frame>12 hours after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the curve from 0-12 hours (AUC0-12h)</measure>
    <time_frame>up to 12 hours after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time from dosing to the maximum measured concentration of the analyte in plasma (Tmax)</measure>
    <time_frame>up to 48 h after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total clearance of the analyte in plasma (CL/F)</measure>
    <time_frame>pre-dose, up to 48 h after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent volume of distribution (V/F)</measure>
    <time_frame>pre-dose, up to 48 h after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal half-life (t1/2)</measure>
    <time_frame>pre-dose, up to 48 h after drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of subjects with abnormal findings in laboratory tests</measure>
    <time_frame>up to day 61</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of subjects with treatment-emergent adverse events</measure>
    <time_frame>up to 96 days</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">52</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Tipranavir/Ritonavir</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>500 mg Tipranavir / 200 mg Ritonavir 10 days BID</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Darunavir/Ritonavir</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>600 mg Darunavir /100 mg Ritonavir 10 days BID</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Ritonavir</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>100 mg Ritonavir 10 days BID</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tipranavir</intervention_name>
    <arm_group_label>Tipranavir/Ritonavir</arm_group_label>
    <other_name>APTIVUS®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ritonavir</intervention_name>
    <arm_group_label>Darunavir/Ritonavir</arm_group_label>
    <arm_group_label>Ritonavir</arm_group_label>
    <arm_group_label>Tipranavir/Ritonavir</arm_group_label>
    <other_name>Norvir®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Darunavir</intervention_name>
    <arm_group_label>Darunavir/Ritonavir</arm_group_label>
    <other_name>PREZISTA®</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Aspirin</intervention_name>
    <description>single dose on day 2</description>
    <arm_group_label>Darunavir/Ritonavir</arm_group_label>
    <arm_group_label>Ritonavir</arm_group_label>
    <arm_group_label>Tipranavir/Ritonavir</arm_group_label>
    <other_name>Acetylsalicylic acid</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Ability and willingness to give written informed consent to participate in this study&#xD;
             (i.e., prior to any study-specific procedures)&#xD;
&#xD;
          2. Age ≥18 years and ≤50 years&#xD;
&#xD;
          3. Female subjects of child-bearing potential were eligible if:&#xD;
&#xD;
               -  They had used a barrier contraceptive method for at least 12 weeks before&#xD;
                  administration of study medication and had a negative serum pregnancy test result&#xD;
                  during the screening period (Day - 35 to Day -3); or,&#xD;
&#xD;
               -  Were abstinent for more than 12 weeks before screening and had a negative serum&#xD;
                  pregnancy test result during the screening period (Day -35 to Day -3); or,&#xD;
&#xD;
               -  Had a documented tubal ligation and had a negative serum pregnancy test result&#xD;
                  during the screening period (Day -35 to Day -3)&#xD;
&#xD;
          4. Ability to swallow capsules without difficulty&#xD;
&#xD;
          5. Reasonable probability of completing the study&#xD;
&#xD;
          6. Findings from medical history, physical examination and 12-lead ECG indicating subject&#xD;
             was healthy and suitable for the trial in the opinion of the investigator&#xD;
&#xD;
          7. Agreement to abstain from alcohol consumption or drugs of abuse during the study&#xD;
&#xD;
          8. Agreement to abstain from ingestion of grapefruit, grapefruit juice, Seville oranges,&#xD;
             or orange marmalade from screening period to the end of the study&#xD;
&#xD;
          9. Negative urine drug screen for drugs of abuse&#xD;
&#xD;
         10. Non smoker&#xD;
&#xD;
         11. Agreement to abstain from use of tobacco products from screening period to the end of&#xD;
             the study&#xD;
&#xD;
         12. Negative HIV-1 serology by ELISA testing&#xD;
&#xD;
         13. Negative Hepatitis B surface Antigen test (HBsAg)&#xD;
&#xD;
         14. Negative Hepatitis C Virus antibody (anti-HCV) test by Enzyme Immunoassay&#xD;
&#xD;
         15. Platelet count ≥125,000/mm3&#xD;
&#xD;
         16. Hemoglobin ≥11.0 g/dL&#xD;
&#xD;
         17. Prothrombin time ≤1.0 x upper limit of normal (ULN)&#xD;
&#xD;
         18. Activated Partial thromboplastin time ≤1.0 x ULN&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Female subjects who:&#xD;
&#xD;
               -  had a positive serum pregnancy test during the screening period (Day -35 to Day&#xD;
                  -3) or during the study&#xD;
&#xD;
               -  were breast feeding or planing to breast feed at any time from the screening&#xD;
                  period through 30 days after the last dose of the study drug&#xD;
&#xD;
               -  were not willing to use a barrier method of contraception at any time from&#xD;
                  screening period through 30 days after the last dose of the study drug&#xD;
&#xD;
               -  were taking any hormonal therapy for any reason such as birth control or&#xD;
                  replacement therapy&#xD;
&#xD;
          2. Had used any investigational agent within 30 days prior to Visit 2&#xD;
&#xD;
          3. Blood or plasma donations (&gt;100 mL total) for research or altruistic reasons within 30&#xD;
             days prior to Visit 2&#xD;
&#xD;
          4. Had used aspirin or any non-steroidal anti-inflammatory agent (NSAID), and including&#xD;
             COX-2 inhibitors, dipyridamole, clopidogrel, ticlopidine or other antiplatelet drugs&#xD;
             within 14 days prior to Visit 2 or during the study&#xD;
&#xD;
          5. Active peptic ulceration or history of peptic ulcer disease&#xD;
&#xD;
          6. Known history of or suspected hypersensitivity to aspirin, any NSAID or any other&#xD;
             component of the test drugs (Tipranavir, Darunavir, Ritonavir)&#xD;
&#xD;
          7. Known hypersensitivity to antiretroviral drugs (marketed or experimental drug in&#xD;
             clinical research studies)&#xD;
&#xD;
          8. Active bleeding disorder or history of active bleeding disorder&#xD;
&#xD;
          9. Active Intra cranial hemorrhage (ICH) or history of ICH&#xD;
&#xD;
         10. Active coronary artery disease or history of coronary artery disease&#xD;
&#xD;
         11. Alcohol abuse (more than 60 g/day)&#xD;
&#xD;
         12. Any indication for current use of aspirin or any NSAID or indication for such use from&#xD;
             Visit 2 to Visit 18&#xD;
&#xD;
         13. Had used any over-the-counter medication within 7 days prior to Visit 2, or current&#xD;
             use of any prescription drug&#xD;
&#xD;
         14. Subjects who had an abnormal laboratory result of Grade 1 or greater, as defined by&#xD;
             the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse&#xD;
             Events (DAIDS), (result must have been available at least 3 days prior to Visit 2-Day&#xD;
             1), except the following screening laboratory values:&#xD;
&#xD;
               -  serum potassium, serum sodium, serum phosphate and uric acid, where central&#xD;
                  laboratory reference ranges will be used to determine eligibility rather than&#xD;
                  DAIDS table; or,&#xD;
&#xD;
               -  amylase or creatinine results of Grade 1 on DAIDS table if these results are&#xD;
                  considered clinically not significant by investigator; or&#xD;
&#xD;
               -  other marginally abnormal laboratory values not considered clinically significant&#xD;
                  by investigator and approved by clinical monitor&#xD;
&#xD;
         15. History of any illness that in the opinion of the investigator might confound the&#xD;
             results of the study or pose additional risks in administering aspirin, Tipranavir,&#xD;
             Darunavir, or Ritonavir&#xD;
&#xD;
         16. Hypersensitivity to sulphonamide drugs&#xD;
&#xD;
         17. Had used proton pump inhibitors during 14 days prior to Visit 2&#xD;
&#xD;
         18. Vitamin E intake in excess of 60 mg/day within 30 days prior to Visit 2&#xD;
&#xD;
         19. Vitamin E supplementation in excess of 60 mg/day during the study (Vitamin E content&#xD;
             of multivitamin tablets is allowed)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 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>Aspirin</mesh_term>
    <mesh_term>Ritonavir</mesh_term>
    <mesh_term>Darunavir</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/NCT02251795
org study id: 1182.117
nct id: NCT02251795
lead sponsor: 
Study to determine the effect of steady-state plasma concentration of Tipranavir/ritonavir
      (TPV/r) on platelet aggregation in healthy subjects and investigate the effect of TPV/r at
      steady state plasma concentrations on other platelet functions and biomarkers of coagulation
      and fibrinolysis.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Percent change from baseline in the area under the curve (AUC) of platelet aggregation in response to arachidonic acid (AA)
time frame: pre-dose, up to 48 h after drug administration
description: calculated as the ratio of the AUC at steady state TPV plasma concentrations and the baseline AUC
measure: Changes in platelet aggregation in response to AA
time frame: pre-dose, up to 48 h after drug administration
measure: Changes in platelet aggregation in response to collagen
time frame: pre-dose, up to 48 h after drug administration
measure: Changes in platelet aggregation in response adenosine diphosphate (ADP)
time frame: pre-dose, up to 48 h after drug administration
measure: Changes in closure Time (CT)
time frame: pre-dose, up to 48 h after drug administration
description: Platelet Function Analyzer (PFA)-100 test
measure: Changes in urinary thromboxane B2 metabolites
time frame: pre-dose, up to 48 h after drug administration
measure: Changes in bleeding time
time frame: Baseline, up to day 30
measure: Changes in activated partial thromboplastin time (aPTT)
time frame: Baseline, up to day 30
measure: Changes in prothrombin time (PT)
time frame: Baseline, up to day 30
measure: Changes in fibrinogen
time frame: Baseline, up to day 30
measure: Changes in von Willebrand antigen
time frame: Baseline, up to day 30
measure: Changes in von anti-thrombin III antigen
time frame: Baseline, up to day 30
measure: Changes in anti-thrombin III activity
time frame: Baseline, up to day 30
measure: Changes in factor II
time frame: Baseline, up to day 30
measure: Changes in factor VII
time frame: Baseline, up to day 30
measure: Changes in factor IX
time frame: Baseline, up to day 30
measure: Changes in factor X
time frame: Baseline, up to day 30
measure: Changes in plasminogen activity
time frame: Baseline, up to day 30
measure: Changes in alpha 2-antiplasmin
time frame: Baseline, up to day 30
measure: Changes in D-dimer
time frame: Baseline, up to day 30
measure: Changes in Plasminogen Activator Inhibitor (PAI-1)
time frame: Baseline, up to day 30
measure: Maximum measured concentration of the analyte in plasma (Cmax)
time frame: pre-dose, up to 48 h after drug administration
measure: Serum concentration at 12 hours (Cp12h)
time frame: 12 hours after drug administration
measure: Area under the curve from 0-12 hours (AUC0-12h)
time frame: up to 12 hours after drug administration
measure: Time from dosing to the maximum measured concentration of the analyte in plasma (Tmax)
time frame: up to 48 h after drug administration
measure: Total clearance of the analyte in plasma (CL/F)
time frame: pre-dose, up to 48 h after drug administration
measure: Apparent volume of distribution (V/F)
time frame: pre-dose, up to 48 h after drug administration
measure: Terminal half-life (t1/2)
time frame: pre-dose, up to 48 h after drug administration
measure: Number of subjects with abnormal findings in laboratory tests
time frame: up to day 61
measure: Number of subjects with treatment-emergent adverse events
time frame: up to 96 days
arm group label: Tipranavir/Ritonavir
arm group type: Experimental
description: 500 mg Tipranavir / 200 mg Ritonavir 10 days BID
arm group label: Darunavir/Ritonavir
arm group type: Active Comparator
description: 600 mg Darunavir /100 mg Ritonavir 10 days BID
arm group label: Ritonavir
arm group type: Active Comparator
description: 100 mg Ritonavir 10 days BID
intervention type: Drug
intervention name: Tipranavir
arm group label: Tipranavir/Ritonavir
other name: APTIVUS®
intervention type: Drug
intervention name: Ritonavir
arm group label: Darunavir/Ritonavir
arm group label: Ritonavir
arm group label: Tipranavir/Ritonavir
other name: Norvir®
intervention type: Drug
intervention name: Darunavir
arm group label: Darunavir/Ritonavir
other name: PREZISTA®
intervention type: Drug
intervention name: Aspirin
description: single dose on day 2
arm group label: Darunavir/Ritonavir
arm group label: Ritonavir
arm group label: Tipranavir/Ritonavir
other name: Acetylsalicylic acid
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
url: http://trials.boehringer-ingelheim.com
description: Related Info
responsible party type: Sponsor
mesh term: Aspirin
mesh term: Ritonavir
mesh term: Darunavir
mesh term: Tipranavir