<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/NCT03813979</url>
  </required_header>
  <id_info>
    <org_study_id>UMCN-AKF-16.03</org_study_id>
    <nct_id>NCT03813979</nct_id>
  </id_info>
  <brief_title>Pharmacokinetics of Single-dose Dolutegravir in HIV-seronegative Subjects With Severe Hepatic Impairment Compared to Matched Controls.</brief_title>
  <acronym>POLO</acronym>
  <official_title>Pharmacokinetics of Single-dose Dolutegravir in HIV-seronegative Subjects With Severe Hepatic Impairment Compared to Matched Controls.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Radboud University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Erasmus Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Leiden University Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University Medical Center Groningen</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Radboud University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an open-label, parallel-group, nonrandomized, multi-centre, phase-IV, single dose&#xD;
      trial in 8 HIV-seronegative subjects with severe hepatic impairment and 8 matched controls to&#xD;
      assess the pharmacokinetics of a single dose of 50mg of dolutegravir in subjects with severe&#xD;
      hepatic impairment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open-label, parallel-group, nonrandomized, multi-centre, phase-IV, single dose&#xD;
      trial. The primary aim of this study is to assess the pharmacokinetics of a single dose of&#xD;
      50mg of dolutegravir in HIV-seronegative subjects with severe hepatic impairment (n=8) and&#xD;
      compare these with a single dose of 50mg of dolutegravir in matched controls (n=8). In both&#xD;
      groups a pharmacokinetic (PK) curve will be recorded for determination of dolutegravir (and&#xD;
      dolutegravir-glucuronide).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    difficult recruitment and delay due to COVID19&#xD;
  </why_stopped>
  <start_date type="Anticipated">November 15, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2021</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2021</primary_completion_date>
  <phase>Phase 4</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>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>area under the curve</measure>
    <time_frame>24 hours</time_frame>
    <description>dolutegravir area under the curve</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>adverse events</measure>
    <time_frame>7 days</time_frame>
    <description>number and severity of adverse events</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>HIV-1-infection</condition>
  <condition>Hepatic Impairment</condition>
  <arm_group>
    <arm_group_label>Hepatic impairment group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dolutegravir in HIV-seronegative subjects with severe hepatic impairment (child-Pugh score 10 or greater)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Matched controls</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Dolutegravir in control group matched for gender, age and BMI with subjects in hepatic impairment group</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dolutegravir</intervention_name>
    <description>Intake of a single-dose dolutegravir 50 mg tablet on an empty stomach</description>
    <arm_group_label>Hepatic impairment group</arm_group_label>
    <arm_group_label>Matched controls</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Subject is at least 18 and not older than 90 years at screening.&#xD;
&#xD;
          2. Subject is able and willing to sign the Informed Consent Form prior to screening&#xD;
             evaluations.&#xD;
&#xD;
          3. Child-Pugh score 10 or greater (Appendix A). Expected to be in clinical stable&#xD;
             condition for at least 4 weeks as assessed by the subject's own hepatologist. This&#xD;
             assessment takes into account the following aspects: MELD score, fibroscan results (if&#xD;
             available), life expectancy, recent history of decompensation events and the rate of&#xD;
             progression of hepatic insufficiency.&#xD;
&#xD;
        For healthy volunteers&#xD;
&#xD;
          1. Subject is at least 18 and not older than 90 years at screening.&#xD;
&#xD;
          2. Subject is able and willing to sign the Informed Consent Form prior to screening&#xD;
             evaluations.&#xD;
&#xD;
          3. Subject is in good age-appropriate health condition as established by medical history,&#xD;
             physical examination, electrocardiography, results of biochemistry, haematology and&#xD;
             urinalysis testing within 4 weeks prior to Day 1. Results of biochemistry, haematology&#xD;
             and urinalysis testing should be within the laboratory's reference ranges. If&#xD;
             laboratory results are not within the reference ranges, the subject is included on&#xD;
             condition that the Investigator judges that the deviations are not clinically&#xD;
             relevant. This should be clearly recorded.&#xD;
&#xD;
          4. Subject has a normal blood pressure and pulse rate, according to the Investigator's&#xD;
             judgement.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Inability to understand the nature and extent of the study and the procedures&#xD;
             required.&#xD;
&#xD;
          2. Gilbert's syndrome or other underlying disease (other than hepatic impairment) that&#xD;
             causes alterations in the Child-Pugh class components (bilirubin, albumin,&#xD;
             prothrombin, encephalopathy and ascites).&#xD;
&#xD;
          3. Therapy with strong inducers or inhibitors of UGT1A1 or drugs that are&#xD;
             contra-indicated with concomitant use of dolutegravir (see appendix B). (NB. there are&#xD;
             restrictions for intake of magnesium/aluminium-containing antacids, iron and calcium&#xD;
             supplements, multivitamins and other cation-containing supplements (see appendix B and&#xD;
             section 5.2)).&#xD;
&#xD;
          4. Positive HIV test.&#xD;
&#xD;
          5. Participation in a drug study within 60 days prior to Day 1.&#xD;
&#xD;
          6. Febrile illness within 3 days before Day 1.&#xD;
&#xD;
        For healthy volunteers&#xD;
&#xD;
          1. Documented history of sensitivity/idiosyncrasy to medicinal products or excipients.&#xD;
&#xD;
          2. Positive HIV test.&#xD;
&#xD;
          3. Positive hepatitis B or C test.&#xD;
&#xD;
          4. Pregnant female (as confirmed by an hCG test performed less than 4 weeks before Day 1)&#xD;
             or breast-feeding female. Female subjects of childbearing potential without adequate&#xD;
             contraception.&#xD;
&#xD;
          5. Therapy with strong inducers or inhibitors of UGT1A1 or drugs that are&#xD;
             contra-indicated with concomitant use of dolutegravir (see appendix B). (NB. there are&#xD;
             restrictions for intake of magnesium/aluminium-containing antacids, iron and calcium&#xD;
             supplements, multivitamins and other cation-containing supplements (see appendix B and&#xD;
             section 5.2)).&#xD;
&#xD;
          6. Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular&#xD;
             disorders, neurological disorders (especially seizures and migraine), psychiatric&#xD;
             disorders, gastro-intestinal disorders, renal and hepatic disorders, hormonal&#xD;
             disorders (especially diabetes mellitus), coagulation disorders.&#xD;
&#xD;
          7. Relevant history or current condition that might interfere with drug absorption,&#xD;
             distribution, metabolism or excretion.&#xD;
&#xD;
          8. History of or current abuse of drugs, alcohol or solvents.&#xD;
&#xD;
          9. Inability to understand the nature and extent of the study and the procedures&#xD;
             required.&#xD;
&#xD;
         10. Participation in a drug study within 60 days prior to Day 1.&#xD;
&#xD;
         11. Donation of blood within 60 days prior to Day 1.&#xD;
&#xD;
         12. Febrile illness within 3 days before Day 1&#xD;
&#xD;
         13. UGT1A1 polymorphism (at least one *28, *37 or *6 allele) -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <removed_countries>
    <country>Netherlands</country>
  </removed_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>January 21, 2019</study_first_submitted>
  <study_first_submitted_qc>January 21, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 23, 2019</study_first_posted>
  <last_update_submitted>June 7, 2021</last_update_submitted>
  <last_update_submitted_qc>June 7, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 10, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>pharmacokinetics</keyword>
  <keyword>dolutegravir</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Liver Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dolutegravir</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/NCT03813979
org study id: UMCN-AKF-16.03
nct id: NCT03813979
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
This is an open-label, parallel-group, nonrandomized, multi-centre, phase-IV, single dose
      trial in 8 HIV-seronegative subjects with severe hepatic impairment and 8 matched controls to
      assess the pharmacokinetics of a single dose of 50mg of dolutegravir in subjects with severe
      hepatic impairment.
This is an open-label, parallel-group, nonrandomized, multi-centre, phase-IV, single dose
      trial. The primary aim of this study is to assess the pharmacokinetics of a single dose of
      50mg of dolutegravir in HIV-seronegative subjects with severe hepatic impairment (n=8) and
      compare these with a single dose of 50mg of dolutegravir in matched controls (n=8). In both
      groups a pharmacokinetic (PK) curve will be recorded for determination of dolutegravir (and
      dolutegravir-glucuronide).
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: None (Open Label)
measure: area under the curve
time frame: 24 hours
description: dolutegravir area under the curve
measure: adverse events
time frame: 7 days
description: number and severity of adverse events
arm group label: Hepatic impairment group
arm group type: Experimental
description: Dolutegravir in HIV-seronegative subjects with severe hepatic impairment (child-Pugh score 10 or greater)
arm group label: Matched controls
arm group type: Active Comparator
description: Dolutegravir in control group matched for gender, age and BMI with subjects in hepatic impairment group
intervention type: Drug
intervention name: Dolutegravir
description: Intake of a single-dose dolutegravir 50 mg tablet on an empty stomach
arm group label: Hepatic impairment group
arm group label: Matched controls
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: Accepts Healthy Volunteers
country: Netherlands
responsible party type: Sponsor
mesh term: Liver Diseases
mesh term: Dolutegravir