<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/NCT03800394</url>
  </required_header>
  <id_info>
    <org_study_id>IRB201801820 - PKAdol</org_study_id>
    <secondary_id>2R01HD071779</secondary_id>
    <nct_id>NCT03800394</nct_id>
  </id_info>
  <brief_title>Pharmacokinetics of Intracellular TFV-DP and FTC-TP in HIV-infected Adolescents</brief_title>
  <official_title>Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Florida</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Florida</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Tenofovir (TFV) disoproxil fumarate (TDF) plus emtricitabine (FTC) or lamivudine (3TC) is the&#xD;
      preferred nucleoside backbone of first-line antiretroviral therapy (ART) for adolescents in&#xD;
      sub-Saharan Africa. In addition, TDF/FTC is recommended for preexposure prophylaxis (PrEP)&#xD;
      for human immunodeficiency virus (HIV) infection in adolescents at substantial risk of&#xD;
      acquisition of HIV infection, as well as for hepatitis B virus (HBV) treatment in those with&#xD;
      HBV/HIV coinfection. The efficacy TDF and FTC are dependent on intracellular concentrations&#xD;
      of the active phosphate anabolites, called TFV diphosphate (TFV-DP) and FTC triphosphate&#xD;
      (FTC-TP). However, the intracellular pharmacokinetics of TFV-DP and FTC-TP to examine the&#xD;
      adequacy of current dosages in African adolescents has not been previously studied. Thus,&#xD;
      examining the pharmacokinetics (PK) of these widely used antiretrovirals in African&#xD;
      adolescents is important as ART outcomes remain poor and the recommended dosages of these&#xD;
      drugs for children and adolescent were extrapolated from drug approval clinical trials in&#xD;
      adult in the United States and Europe.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study will evaluate the intracellular PK of TFV-DP and FTC-TP in Ghanaian HIV-infected&#xD;
      adolescents with and without TB coinfection. As the clinical effects of TDF and FTC are&#xD;
      related to the intracellular concentrations of the phosphate anabolites, called TFV-DP and&#xD;
      FTC-TP, there is a need to understand the cellular pharmacology of TDF interactions in&#xD;
      African HIV-infected adolescents with and without TB, as the study team cannot extrapolate&#xD;
      from US patients not on antituberculosis (anti-TB) drugs. This study will enroll HIV-infected&#xD;
      adolescents aged 10 to 18 years old with and without TB coinfection who are already&#xD;
      established on ART. The study team hypothesize that younger age, adenosine triphosphate&#xD;
      (ATP)-binding cassette subfamily C (ABCC) single nucleotide polymorphisms (SNPs) and anti-TB&#xD;
      therapy may influence the intracellular TFV-DP and FTC-TP concentrations in adolescents.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 28, 2019</start_date>
  <completion_date type="Anticipated">October 5, 2023</completion_date>
  <primary_completion_date type="Anticipated">October 5, 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Average concentration (Cav) of intracellular TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents.</measure>
    <time_frame>After at least 8 weeks of HIV therapy.</time_frame>
    <description>Mean and median Cav of intracellular TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Area under the time-concentration curve 0-24 hours (AUC0-24h) of intracellular TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents.</measure>
    <time_frame>After at least 8 weeks of HIV therapy.</time_frame>
    <description>Mean and median AUC0-24h of intracellular TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cav of TFV-DP and FTC-TP PK in HIV-infected adolescents with and without TB coinfection.</measure>
    <time_frame>After at least 8 weeks of HIV therapy.</time_frame>
    <description>Geometric mean intracellular TFV-DP and FTC-TP Cav in adolescents with TB/HIV coinfection compared to those only HIV infection.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC0-24h of TFV-DP and FTC-TP PK in HIV-infected adolescents with and without TB coinfection.</measure>
    <time_frame>After at least 8 weeks of HIV therapy.</time_frame>
    <description>Geometric mean of intracellular TFV-DP and FTC-TP AUC0-24h in adolescents with TB/HIV coinfection compared to those with only HIV infection.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Effect of age on TFV-DP and FTC-TP Cav.</measure>
    <time_frame>After at least 8 weeks of HIV therapy.</time_frame>
    <description>Geometric mean of intracellular TFV-DP and FTC-TP Cav in adolescents aged 10 - 14 years old compared to that in adolescents aged 15 - 19 years old.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of age on TFV-DP and FTC-TP AUC0-24h .</measure>
    <time_frame>After at least 8 weeks of HIV therapy.</time_frame>
    <description>Geometric mean of intracellular TFV-DP and FTC-TP AUC0-24h in adolescents aged 10 - 14 years old compared to that in adolescents aged 15 - 19 years old.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intracellular TFV-DP and FTC-TP Cav in adolescents compared to that in historical adult controls.</measure>
    <time_frame>After at least 8 weeks of HIV therapy.</time_frame>
    <description>Geometric mean of intracellular TFV-DP and FTC-TP Cav in Ghanaian HIV-infected adolescent compared to published values in adults treated with similar dosage.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intracellular TFV-DP and FTC-TP AUC0-24h in adolescents compared to that in historical adult controls.</measure>
    <time_frame>After at least 8 weeks of HIV therapy.</time_frame>
    <description>Geometric mean of intracellular TFV-DP and FTC-TP AUC0-24h in Ghanaian HIV-infected adolescent compared to published values in adults treated with similar dosage.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relationship between Adenosine triphosphate (ATP)-binding cassette subfamily C, member 2 (ABCC2), member 4 (ABCC4) and member 10 (ABCC10) SNPs and TFV-DP and FTC-TP AUC0-24h.</measure>
    <time_frame>After at least 8 weeks of HIV therapy.</time_frame>
    <description>Relationship between ABCC2, ABCC4 and ABCC10 SNPs and intracellular TFV-DP and FTC-TP AUC0-24h.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prevalence and covariates of intracellular TFV-DP Cav &lt; 95 fmol/106 cells in adolescents.</measure>
    <time_frame>After at least 8 weeks of HIV therapy.</time_frame>
    <description>Proportion of Ghanaian adolescents and factors associated with intracellular TFV-DP average concentration &lt; 95 fmol/106 cells.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">382</enrollment>
  <condition>Human Immunodeficiency Virus (HIV)</condition>
  <condition>Tuberculosis</condition>
  <condition>Coinfection</condition>
  <arm_group>
    <arm_group_label>HIV only</arm_group_label>
    <description>Adolescents aged 10-19 years with HIV infection</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HIV/TB</arm_group_label>
    <description>Adolescents aged 10-19 years with HIV and TB coinfection</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Observational PK study</intervention_name>
    <description>Effect of antituberculosis treatment, age and genetic factors on intracellular TFV-DP and FTC-TP concentrations</description>
    <arm_group_label>HIV only</arm_group_label>
    <arm_group_label>HIV/TB</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Peripheral mononuclear cells (PBMCs) and deoxyribonucleic acid (DNA)&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Adolescents aged 10-19 years with HIV with or without TB co-infection.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  HIV-infected adolescents aged 10 to 19 years old who are stable on antiretroviral&#xD;
             regimen containing TDF/FTC (300/200 mg daily) for at least 8 weeks.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Unable to obtain informed signed consent from parent(s) or legal guardian.&#xD;
&#xD;
          -  Pregnant or breast feeding.&#xD;
&#xD;
          -  Require therapy for other opportunistic infections other than tuberculosis (TB).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>10 Years</minimum_age>
    <maximum_age>19 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Awewura Kwara, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Florida</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Awewura Kwara, MD</last_name>
    <phone>352-273-9501</phone>
    <email>awewura.kwara@medicine.ufl.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Oluwayemisi Ojewale, MBChB, MPH</last_name>
    <phone>3522739446</phone>
    <email>oawoyemi@ufl.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Kwame Nkrumah University of Science and Technology</name>
      <address>
        <city>Kumasi</city>
        <country>Ghana</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Sampson Antwi, MBChB</last_name>
      <phone>+233265812061</phone>
      <email>Kantwi@gmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Anthony Enimil, MBChB</last_name>
      <phone>+233208164433</phone>
      <email>Tenimil@live.com</email>
    </contact_backup>
    <investigator>
      <last_name>Sampson Antwi, MBChB</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Anthony Enimil, MBChB</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Ghana</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>January 3, 2019</study_first_submitted>
  <study_first_submitted_qc>January 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 11, 2019</study_first_posted>
  <last_update_submitted>June 14, 2023</last_update_submitted>
  <last_update_submitted_qc>June 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Pharmacokinetic</keyword>
  <keyword>Pharmacogenomic</keyword>
  <keyword>Tenofovir diphosphate</keyword>
  <keyword>Emtricitabine triphosphate</keyword>
  <keyword>Adolescents</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
    <mesh_term>Acquired Immunodeficiency Syndrome</mesh_term>
    <mesh_term>HIV Infections</mesh_term>
    <mesh_term>Coinfection</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03800394
org study id: IRB201801820 - PKAdol
secondary id: 2R01HD071779
nct id: NCT03800394
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: Yes
Tenofovir (TFV) disoproxil fumarate (TDF) plus emtricitabine (FTC) or lamivudine (3TC) is the
      preferred nucleoside backbone of first-line antiretroviral therapy (ART) for adolescents in
      sub-Saharan Africa. In addition, TDF/FTC is recommended for preexposure prophylaxis (PrEP)
      for human immunodeficiency virus (HIV) infection in adolescents at substantial risk of
      acquisition of HIV infection, as well as for hepatitis B virus (HBV) treatment in those with
      HBV/HIV coinfection. The efficacy TDF and FTC are dependent on intracellular concentrations
      of the active phosphate anabolites, called TFV diphosphate (TFV-DP) and FTC triphosphate
      (FTC-TP). However, the intracellular pharmacokinetics of TFV-DP and FTC-TP to examine the
      adequacy of current dosages in African adolescents has not been previously studied. Thus,
      examining the pharmacokinetics (PK) of these widely used antiretrovirals in African
      adolescents is important as ART outcomes remain poor and the recommended dosages of these
      drugs for children and adolescent were extrapolated from drug approval clinical trials in
      adult in the United States and Europe.
This study will evaluate the intracellular PK of TFV-DP and FTC-TP in Ghanaian HIV-infected
      adolescents with and without TB coinfection. As the clinical effects of TDF and FTC are
      related to the intracellular concentrations of the phosphate anabolites, called TFV-DP and
      FTC-TP, there is a need to understand the cellular pharmacology of TDF interactions in
      African HIV-infected adolescents with and without TB, as the study team cannot extrapolate
      from US patients not on antituberculosis (anti-TB) drugs. This study will enroll HIV-infected
      adolescents aged 10 to 18 years old with and without TB coinfection who are already
      established on ART. The study team hypothesize that younger age, adenosine triphosphate
      (ATP)-binding cassette subfamily C (ABCC) single nucleotide polymorphisms (SNPs) and anti-TB
      therapy may influence the intracellular TFV-DP and FTC-TP concentrations in adolescents.
observational model: Cohort
time perspective: Cross-Sectional
measure: Average concentration (Cav) of intracellular TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents.
time frame: After at least 8 weeks of HIV therapy.
description: Mean and median Cav of intracellular TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents.
measure: Area under the time-concentration curve 0-24 hours (AUC0-24h) of intracellular TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents.
time frame: After at least 8 weeks of HIV therapy.
description: Mean and median AUC0-24h of intracellular TFV-DP and FTC-TP in Ghanaian HIV-infected adolescents.
measure: Cav of TFV-DP and FTC-TP PK in HIV-infected adolescents with and without TB coinfection.
time frame: After at least 8 weeks of HIV therapy.
description: Geometric mean intracellular TFV-DP and FTC-TP Cav in adolescents with TB/HIV coinfection compared to those only HIV infection.
measure: AUC0-24h of TFV-DP and FTC-TP PK in HIV-infected adolescents with and without TB coinfection.
time frame: After at least 8 weeks of HIV therapy.
description: Geometric mean of intracellular TFV-DP and FTC-TP AUC0-24h in adolescents with TB/HIV coinfection compared to those with only HIV infection.
measure: Effect of age on TFV-DP and FTC-TP Cav.
time frame: After at least 8 weeks of HIV therapy.
description: Geometric mean of intracellular TFV-DP and FTC-TP Cav in adolescents aged 10 - 14 years old compared to that in adolescents aged 15 - 19 years old.
measure: Effect of age on TFV-DP and FTC-TP AUC0-24h .
time frame: After at least 8 weeks of HIV therapy.
description: Geometric mean of intracellular TFV-DP and FTC-TP AUC0-24h in adolescents aged 10 - 14 years old compared to that in adolescents aged 15 - 19 years old.
measure: Intracellular TFV-DP and FTC-TP Cav in adolescents compared to that in historical adult controls.
time frame: After at least 8 weeks of HIV therapy.
description: Geometric mean of intracellular TFV-DP and FTC-TP Cav in Ghanaian HIV-infected adolescent compared to published values in adults treated with similar dosage.
measure: Intracellular TFV-DP and FTC-TP AUC0-24h in adolescents compared to that in historical adult controls.
time frame: After at least 8 weeks of HIV therapy.
description: Geometric mean of intracellular TFV-DP and FTC-TP AUC0-24h in Ghanaian HIV-infected adolescent compared to published values in adults treated with similar dosage.
measure: Relationship between Adenosine triphosphate (ATP)-binding cassette subfamily C, member 2 (ABCC2), member 4 (ABCC4) and member 10 (ABCC10) SNPs and TFV-DP and FTC-TP AUC0-24h.
time frame: After at least 8 weeks of HIV therapy.
description: Relationship between ABCC2, ABCC4 and ABCC10 SNPs and intracellular TFV-DP and FTC-TP AUC0-24h.
measure: Prevalence and covariates of intracellular TFV-DP Cav < 95 fmol/106 cells in adolescents.
time frame: After at least 8 weeks of HIV therapy.
description: Proportion of Ghanaian adolescents and factors associated with intracellular TFV-DP average concentration < 95 fmol/106 cells.
arm group label: HIV only
description: Adolescents aged 10-19 years with HIV infection
arm group label: HIV/TB
description: Adolescents aged 10-19 years with HIV and TB coinfection
intervention type: Other
intervention name: Observational PK study
description: Effect of antituberculosis treatment, age and genetic factors on intracellular TFV-DP and FTC-TP concentrations
arm group label: HIV only
arm group label: HIV/TB
Peripheral mononuclear cells (PBMCs) and deoxyribonucleic acid (DNA)
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 10 Years
maximum age: 19 Years
healthy volunteers: No
last name: Awewura Kwara, MD
role: Principal Investigator
affiliation: University of Florida
last name: Awewura Kwara, MD
phone: 352-273-9501
email: awewura.kwara@medicine.ufl.edu
last name: Oluwayemisi Ojewale, MBChB, MPH
phone: 3522739446
email: oawoyemi@ufl.edu
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
country: Ghana
responsible party type: Sponsor
mesh term: Tuberculosis
mesh term: Acquired Immunodeficiency Syndrome
mesh term: HIV Infections
mesh term: Coinfection
sharing ipd: Undecided