<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/NCT02259855</url>
  </required_header>
  <id_info>
    <org_study_id>1182.59</org_study_id>
    <nct_id>NCT02259855</nct_id>
  </id_info>
  <brief_title>Pharmacokinetics (PK) of Tipranavir/Ritonavir, Ribavirin, Pegylated Interferon (Peg INF) in Hepatitis C (HCV) Subjects With Mild Hepatic Impairment and in HCV, Hepatitis B (HBV), Hepatitis D Infected Subjects or Alcoholic Cirrhosis With Moderate Hepatic Impairment</brief_title>
  <official_title>Open Label, Study to Determine the Pharmacokinetic Interactions of Steady State Tipranavir/Ritonavir (500/200 mg) and Steady State Ribavirin and Pegylated Interferon Alfa 2a in HIV Negative, HCV Infected Subjects With Mild Hepatic Impairment and the Pharmacokinetic Properties of Tipranavir/Ritonavir in HIV Negative, HCV, HBV, Hepatitis Delta Infected Subjects or Alcoholic Cirrhosis Subjects With Moderate Hepatic Impairment</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 primary objectives were:&#xD;
&#xD;
        -  To determine the effects of steady state TPV co-administered with low dose RTV on steady&#xD;
           state PegIFN and RBV in HIV negative subjects with mild hepatic impairment (scheme A)&#xD;
&#xD;
        -  To determine the effects of steady state of pegylated interferon (PegIFN) and RBV on&#xD;
           steady state pharmacokinetics of TPV co-administered with low dose RTV in HIV negative&#xD;
           subjects with mild hepatic impairment (scheme A)&#xD;
&#xD;
        -  To determine the pharmacokinetics of single dose and steady state TPV/r 500/200 mg in&#xD;
           subjects with moderate hepatic insufficiency (scheme B)&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>January 2006</start_date>
  <primary_completion_date type="Actual">October 2008</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Area under the concentration-time curve from 0 to 12 hours of ribavirin (RBV), tipranavir (TPV) and ritonavir (RTV) in the plasma (AUC0-12h)</measure>
    <time_frame>Pre-dose, up to 120 hours after start of treatment</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the concentration-time curve from 0 to 24 hours of pegylated interferon (Peg IFN) in the plasma (AUC0-24h)</measure>
    <time_frame>Pre-dose, up to 120 hours after start of treatment</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum measured concentration of RBV, Peg INF, TPV and RTV in the plasma (Cmax)</measure>
    <time_frame>Pre-dose, up to 120 hours after start of treatment</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Measured concentration of RBV, TPV and RTV in the plasma at 12 hours (Cp12h)</measure>
    <time_frame>Pre-dose, up to 120 hours after start of treatment</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Measured concentration of Peg INF in the plasma at 24 hours (Cp24h)</measure>
    <time_frame>Pre-dose, up to 120 hours after start of treatment</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the concentration-time curve from 0 extrapolated to infinity of TPV and RTV in the plasma (AUC0-∞)</measure>
    <time_frame>Pre-dose, up to 120 hours after start of treatment</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time from dosing to the maximum concentration of the analytes in the plasma (tmax)</measure>
    <time_frame>Pre-dose, up to 120 hours after start of treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Terminal half-life of the analytes in the plasma (t1/2)</measure>
    <time_frame>Pre-dose, up to 120 hours after start of treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent clearance of the analytes in the plasma after extra vascular administration (CL/F)</measure>
    <time_frame>Pre-dose, up to 120 hours after start of treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Apparent volume of distribution of the analytes in the plasma (Vz/F)</measure>
    <time_frame>Pre-dose, up to 120 hours after start of treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with clinically significant changes in laboratory values</measure>
    <time_frame>up to 3 weeks after start of treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with adverse events</measure>
    <time_frame>Up to 7 weeks</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with clinically significant changes in vital signs (seated blood pressure, pulse rate)</measure>
    <time_frame>up to 3 weeks after start of treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with clinically significant changes from baseline in 12-lead ECG</measure>
    <time_frame>3 weeks after start of treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of tolerability by the investigator</measure>
    <time_frame>Up to 3 weeks after start of treatment</time_frame>
    <description>verbal rating scale</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">36</enrollment>
  <condition>Hepatic Insufficiency</condition>
  <arm_group>
    <arm_group_label>Mild hepatic insufficiency</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Moderate hepatic insufficiency</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy subjects</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tipranavir</intervention_name>
    <arm_group_label>Healthy subjects</arm_group_label>
    <arm_group_label>Mild hepatic insufficiency</arm_group_label>
    <arm_group_label>Moderate hepatic insufficiency</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ritonavir</intervention_name>
    <arm_group_label>Healthy subjects</arm_group_label>
    <arm_group_label>Mild hepatic insufficiency</arm_group_label>
    <arm_group_label>Moderate hepatic insufficiency</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pegylated interferon</intervention_name>
    <arm_group_label>Mild hepatic insufficiency</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ribavirin</intervention_name>
    <arm_group_label>Mild hepatic insufficiency</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥18 and Age ≤ 75 years&#xD;
&#xD;
          -  BMI ≥18 and BMI ≤ 29 kg/m2 (Body Mass Index) at screening visit&#xD;
&#xD;
          -  Signed and dated written informed consent prior to admission to the study in&#xD;
             accordance with good clinical practice (GCP) and the local legislation&#xD;
&#xD;
          -  Ability to swallow multiple large capsules without difficulty&#xD;
&#xD;
          -  Serologic evidence of chronic hepatitis C infection by an antibody test and HCV&#xD;
             branched DNA (bDNA) for subjects with mild hepatic impairment (Scheme A)&#xD;
&#xD;
          -  Serologic evidence of chronic hepatitis C, B and/or delta infection by an antibody&#xD;
             test and HCV bDNA, HBV RNA polymerase chain reaction (PCR) for subjects with moderate&#xD;
             hepatic impairment (Child Pugh B)&#xD;
&#xD;
          -  Alcoholic cirrhosis, for subjects with moderate hepatic impairment (Child Pugh B).&#xD;
             Patients had to stop the alcohol consumption at least 1 month before the screening&#xD;
             without any evidence of acute alcoholic hepatitis&#xD;
&#xD;
          -  Subjects HCV positive with mild hepatic insufficiency were to be on stable treatment&#xD;
             with PegIFN and ribavirin since at least 12 weeks prior to study entry&#xD;
&#xD;
          -  Subjects with mild hepatic insufficiency were to be viral non-responders with less&#xD;
             than a 2 log reduction in HCV RNA, compared to baseline (HCV treatment initiation) and&#xD;
             have positive HCV RNA after 12 weeks therapy with PegIFN/RBV&#xD;
&#xD;
          -  Subjects with:&#xD;
&#xD;
               -  stable mild hepatic insufficiency treated by PegIFN and RBV&#xD;
&#xD;
               -  moderate hepatic insufficiency [Child-Pugh Class B (score 7-9)]&#xD;
&#xD;
          -  All fertile males or females, and their respective partner(s) were to be using two&#xD;
             forms of effective contraception during ribavirin treatment and during the 6 months&#xD;
             after its end. All other women must agree to use an effective form of contraception&#xD;
             during the entire duration of the study. This may include condoms, diaphragms or&#xD;
             implants. This did not apply to those surgically sterilized or in a post menopausal&#xD;
             state&#xD;
&#xD;
          -  Laboratory values that indicated adequate baseline organ function were required at the&#xD;
             time of screening. All subjects with mild and moderate hepatic insufficiency should&#xD;
             have all laboratory values less than or equal to grade 2, based on division of aids&#xD;
             (DAIDS) Grading Scale. The following exceptions were made:&#xD;
&#xD;
               -  Alanine transaminase (ALT) and/or aspartate aminotransferase (AST) &lt; 3 x upper&#xD;
                  limit of normal (ULN)&#xD;
&#xD;
               -  Alkaline Phosphatase &lt; 2 x ULN&#xD;
&#xD;
               -  Haemoglobin &gt; 10.0 g/dL&#xD;
&#xD;
               -  Platelets &gt; 50.000 / μl And all healthy control subjects should have all&#xD;
                  laboratory values &lt; grade 1&#xD;
&#xD;
          -  Willingness to abstain from alcohol starting 2 days prior to administration of study&#xD;
             drug up to the end of the study, to abstain from over counter herbal medications for&#xD;
             the duration of the trial&#xD;
&#xD;
          -  Willingness to abstain from the following starting 14 days prior to administration of&#xD;
             study medication up until the end of the study: Grapefruit or grapefruit juice, red&#xD;
             wine, seville oranges (marmalade), St John's Wort or Milk Thistle&#xD;
&#xD;
          -  Willingness to abstain from the following 72 h prior to PK sampling: Garlic&#xD;
             supplements, Methylxanthine containing drinks (coffee, tea, cola, energy drinks,&#xD;
             chocolate, etc.)&#xD;
&#xD;
          -  Acceptable medical history, physical examination were required prior to entering the&#xD;
             treatment phase of the trial&#xD;
&#xD;
          -  Reasonable probability for completion of the study, including dosing requirements of&#xD;
             TPV/r and acceptance of the risk for hepatic decompensation&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Use of any medication listed in the protocol within 30 days prior to Day 1&#xD;
&#xD;
          -  Participation in another trial with an investigational medicine within 2 months prior&#xD;
             to Day 1&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &lt; 750 cells/mm³ at screening&#xD;
&#xD;
          -  Serum creatine level &gt; 1.5 times upper the limit of normal at screening&#xD;
&#xD;
          -  History of acute illness within 60 days prior to Day 1&#xD;
&#xD;
          -  Subject with mild hepatic impairment (scheme A), HIV, HBV, hepatitis Delta positive&#xD;
             and/or alcoholic cirrhosis&#xD;
&#xD;
          -  Subject with moderate hepatic impairment (CPB), HIV positive&#xD;
&#xD;
          -  Subject control, HIV hepatitis positive and alcoholic cirrhosis&#xD;
&#xD;
          -  Subjects HIV positive, HBV positive and, for subjects controls HCV positive&#xD;
&#xD;
          -  Active bleeding from oesophageal varices or other conditions consistent with active&#xD;
             decompensated liver disease, active spontaneous bacterial peritonitis, active&#xD;
             oesophageal variceal disease or active liver encephalopathy&#xD;
&#xD;
          -  Subjects with Child-Pugh Class C (score &gt; 9)&#xD;
&#xD;
          -  Alcohol abuse within 1 month prior to screening or during the study&#xD;
&#xD;
          -  Other substance abuse within 6 months prior to screening or during the study&#xD;
&#xD;
          -  Subjects with a history of any illness or allergy (including drug allergy) that, in&#xD;
             the opinion of the investigator, might confound the results of the study or pose&#xD;
             additional risk in administering TPV and RTV&#xD;
&#xD;
          -  Subjects who have taken (within 7 days prior to Day 1) any over-the-counter or&#xD;
             prescription medication that, in the opinion of the investigator in consultation with&#xD;
             the Boehringer Ingelheim France (BIF) clinical monitor, might interfere with&#xD;
             absorption, distribution, or metabolism of the study medications&#xD;
&#xD;
          -  Known hypersensitivity to sulphonamide class of drugs&#xD;
&#xD;
          -  Known hypersensitivity to TPV, RTV or antiretroviral drugs (marketed or experimental&#xD;
             use as part of clinical research studies)&#xD;
&#xD;
          -  Known elevated liver enzymes in past clinical trials with any compounds&#xD;
&#xD;
          -  Inability to adhere to the protocol&#xD;
&#xD;
          -  Cautions or warnings in the RTV, PegIFN and RBV package insert which, in the opinion&#xD;
             of the investigator, constituted grounds for subject exclusion&#xD;
&#xD;
          -  History or other evidence of severe illness, malignancy or any other conditions which&#xD;
             would have made the patients, in the opinion of the investigator, unsuitable for the&#xD;
             trial&#xD;
&#xD;
          -  History of any systemic antineoplasic or immunomodulatory treatment (including&#xD;
             supraphysiologic doses of steroids and radiation) ≤ 6 months prior to study entry or&#xD;
             expectation that such treatment would be needed at any time during the study&#xD;
&#xD;
          -  Use of hormone replacement therapy with oestrogen-based preparations for at least 1&#xD;
             month prior to screening and for the duration of the study&#xD;
&#xD;
          -  Administration of antimicrobial agents within 10 days prior to Day 1 (Visit 2)&#xD;
&#xD;
          -  Subjects with evidence of hepatocellular carcinoma, or who tested positive for serum&#xD;
             alpha foeto protein &gt; 5μg/l or suspected tumour based on ultrasonography examination,&#xD;
             - Patients with history of stroke, intracranial aneurysm, neurosurgery and skull&#xD;
             traumatism within 4 weeks prior to screening&#xD;
&#xD;
          -  History of intracranial, intraocular, spinal, retroperitoneal or atraumatic&#xD;
             intraarticular bleeding&#xD;
&#xD;
          -  Gastrointestinal hemorrhage within the past year&#xD;
&#xD;
          -  Endoscopically documented gastro-duodenal ulcer disease in the previous 30 days&#xD;
&#xD;
          -  Hemorrhagic disorder or bleeding diathesis&#xD;
&#xD;
          -  Need for anticoagulant treatment for disorders&#xD;
&#xD;
          -  Uncontrolled hypertension (systolic blood pressure (SBP) &gt;180 mmHg and/or diastolic&#xD;
             blood pressure (DBP) &gt;100 mmHg)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 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>October 2014</verification_date>
  <study_first_submitted>September 24, 2014</study_first_submitted>
  <study_first_submitted_qc>October 7, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 9, 2014</study_first_posted>
  <last_update_submitted>October 7, 2014</last_update_submitted>
  <last_update_submitted_qc>October 7, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 9, 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>Hepatitis</mesh_term>
    <mesh_term>Hepatic Insufficiency</mesh_term>
    <mesh_term>Liver Failure</mesh_term>
    <mesh_term>Liver Cirrhosis, Alcoholic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Interferons</mesh_term>
    <mesh_term>Ritonavir</mesh_term>
    <mesh_term>Ribavirin</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/NCT02259855
org study id: 1182.59
nct id: NCT02259855
lead sponsor: 
The primary objectives were:

        -  To determine the effects of steady state TPV co-administered with low dose RTV on steady
           state PegIFN and RBV in HIV negative subjects with mild hepatic impairment (scheme A)

        -  To determine the effects of steady state of pegylated interferon (PegIFN) and RBV on
           steady state pharmacokinetics of TPV co-administered with low dose RTV in HIV negative
           subjects with mild hepatic impairment (scheme A)

        -  To determine the pharmacokinetics of single dose and steady state TPV/r 500/200 mg in
           subjects with moderate hepatic insufficiency (scheme B)
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Area under the concentration-time curve from 0 to 12 hours of ribavirin (RBV), tipranavir (TPV) and ritonavir (RTV) in the plasma (AUC0-12h)
time frame: Pre-dose, up to 120 hours after start of treatment
measure: Area under the concentration-time curve from 0 to 24 hours of pegylated interferon (Peg IFN) in the plasma (AUC0-24h)
time frame: Pre-dose, up to 120 hours after start of treatment
measure: Maximum measured concentration of RBV, Peg INF, TPV and RTV in the plasma (Cmax)
time frame: Pre-dose, up to 120 hours after start of treatment
measure: Measured concentration of RBV, TPV and RTV in the plasma at 12 hours (Cp12h)
time frame: Pre-dose, up to 120 hours after start of treatment
measure: Measured concentration of Peg INF in the plasma at 24 hours (Cp24h)
time frame: Pre-dose, up to 120 hours after start of treatment
measure: Area under the concentration-time curve from 0 extrapolated to infinity of TPV and RTV in the plasma (AUC0-∞)
time frame: Pre-dose, up to 120 hours after start of treatment
measure: Time from dosing to the maximum concentration of the analytes in the plasma (tmax)
time frame: Pre-dose, up to 120 hours after start of treatment
measure: Terminal half-life of the analytes in the plasma (t1/2)
time frame: Pre-dose, up to 120 hours after start of treatment
measure: Apparent clearance of the analytes in the plasma after extra vascular administration (CL/F)
time frame: Pre-dose, up to 120 hours after start of treatment
measure: Apparent volume of distribution of the analytes in the plasma (Vz/F)
time frame: Pre-dose, up to 120 hours after start of treatment
measure: Number of patients with clinically significant changes in laboratory values
time frame: up to 3 weeks after start of treatment
measure: Number of patients with adverse events
time frame: Up to 7 weeks
measure: Number of patients with clinically significant changes in vital signs (seated blood pressure, pulse rate)
time frame: up to 3 weeks after start of treatment
measure: Number of patients with clinically significant changes from baseline in 12-lead ECG
time frame: 3 weeks after start of treatment
measure: Assessment of tolerability by the investigator
time frame: Up to 3 weeks after start of treatment
description: verbal rating scale
arm group label: Mild hepatic insufficiency
arm group type: Experimental
arm group label: Moderate hepatic insufficiency
arm group type: Experimental
arm group label: Healthy subjects
arm group type: Experimental
intervention type: Drug
intervention name: Tipranavir
arm group label: Healthy subjects
arm group label: Mild hepatic insufficiency
arm group label: Moderate hepatic insufficiency
intervention type: Drug
intervention name: Ritonavir
arm group label: Healthy subjects
arm group label: Mild hepatic insufficiency
arm group label: Moderate hepatic insufficiency
intervention type: Drug
intervention name: Pegylated interferon
arm group label: Mild hepatic insufficiency
intervention type: Drug
intervention name: Ribavirin
arm group label: Mild hepatic insufficiency
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: Accepts Healthy Volunteers
url: http://trials.boehringer-ingelheim.com
description: Related Info
responsible party type: Sponsor
mesh term: Hepatitis
mesh term: Hepatic Insufficiency
mesh term: Liver Failure
mesh term: Liver Cirrhosis, Alcoholic
mesh term: Interferons
mesh term: Ritonavir
mesh term: Ribavirin
mesh term: Tipranavir