<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/NCT04424264</url>
  </required_header>
  <id_info>
    <org_study_id>WRHI061</org_study_id>
    <nct_id>NCT04424264</nct_id>
  </id_info>
  <brief_title>The Effect of Rifampicin on the Pharmacokinetics of Intracellular Tenofovir-diphosphate and Tenofovir When Coadministered With Tenofovir Alafenamide Fumarate During the Maintenance Phase of Tuberculosis Treatment in TB/HIV-1 Coinfected Participants</brief_title>
  <acronym>EpiTAF</acronym>
  <official_title>The Effect of Rifampicin on the Pharmacokinetics of Intracellular Tenofovir-diphosphate and Tenofovir When Coadministered With Tenofovir Alafenamide Fumarate During the Maintenance Phase of Tuberculosis Treatment in TB/HIV-1 Coinfected Participants</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Professor Francois Venter</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Cape Town</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Witwatersrand, South Africa</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a pharmacokinetic study investigating the effect of rifampicin on the&#xD;
      pharmacokinetics of intracellular tenofovir-diphosphate and plasma tenofovir when&#xD;
      coadministered with tenofovir alafenamide fumarate during the maintenance phase of&#xD;
      tuberculosis treatment in TB/HIV-1 coinfected participants (EpiTAF)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open-label, sequential, single centre pharmacokinetic (PK) study investigating the&#xD;
      effect of rifampicin on the pharmacokinetics of intracellular tenofovir-diphosphate and&#xD;
      plasma tenofovir when coadministered with tenofovir alafenamide fumarate during the&#xD;
      maintenance phase of tuberculosis treatment in TB/HIV-1 coinfected participants (EpiTAF).&#xD;
&#xD;
      An open-label, sequential, pharmacokinetic (PK) drug-drug interaction study will be conducted&#xD;
      in medically stable virologically suppressed HIV-1 infected adults coinfected with TB, who&#xD;
      are in the maintenance phase of their TB treatment. After intensive PK evaluation of IC&#xD;
      TFV-DP and pTFV, participants will be switched from their standard-of-care tenofovir&#xD;
      disoproxil fumarate (TDF)/FTC/EFV regimen, to TAF + 3TC + EFV at the start of the study&#xD;
      treatment period. After 28 days each participant will have intensive PK evaluation of IC&#xD;
      TFV-DP and pTFV on TAF + 3TC + EFV with rifampicin (RIF). After the second intensive PK&#xD;
      assessment is completed, participants will be switched back to TDF/FTC/EFV, with a final&#xD;
      intensive PK evaluation of IC TFV-DP and pTFV 8 days after completion of TB treatment, at the&#xD;
      final study visit. Eighteen volunteers will be enrolled for a target of 13 participants&#xD;
      completing the study.&#xD;
&#xD;
      The study includes screening and enrolment visits, 1 visit on day 28 and an end of study&#xD;
      visit 28 days after the end of TB treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 5, 2019</start_date>
  <completion_date type="Actual">October 30, 2020</completion_date>
  <primary_completion_date type="Actual">October 30, 2020</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>IC TFV-DP concentrations during coadministration of TAF or TDF with RIF/INH in TB/HIV-1 coinfected participants</measure>
    <time_frame>56 days</time_frame>
    <description>Intracellular and plasma TFV-DP concentrations measured during coadministration of TAF or TDF with RIF/INH</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maintenance of irological suppression (HIV-1 RNA &lt; 50 copies/mL)</measure>
    <time_frame>At screening, day 28, completion of TB and EOS visits</time_frame>
    <description>Assessment of maintenance of virological suppression (HIV-1 RNA &lt; 50 copies/mL) while on TAF/RIF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison plasma concentrations of TAF with TDF</measure>
    <time_frame>56 days</time_frame>
    <description>Assessment to compare the plasma concentrations of tenofovir of TAF with TDF during coadministration of RIF/INH in TB/HIV-1 coinfected participants</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison of IC TFV-DP concentrations of TDF</measure>
    <time_frame>56 days</time_frame>
    <description>4. To compare the IC TFV-DP concentrations of TDF with and without coadministration with RIF/INH in TB/HIV-1 coinfected participants</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>HIV-1-infection</condition>
  <condition>Tuberculosis</condition>
  <arm_group>
    <arm_group_label>Tenofovir Alafenamide</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>TAF 25 mg once-daily administered with RIF/INH 600*/300mg</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Phase 1: Tenofovir disoproxil fumarate/Emtricitabine/Efavirenz coadministered with Rifampicin/Isoniazid</intervention_name>
    <description>TDF/FTC/EFV 300/200/600 mg once daily plus RIF/INH 600*/300 mg daily from screening until enrolment (days -15 to 0)</description>
    <arm_group_label>Tenofovir Alafenamide</arm_group_label>
    <other_name>Atripla</other_name>
    <other_name>Rifinah</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Phase 2: Tenofovir alafenamide/Lamivudine/Efavirenz coadministered with Rifampicin/Isoniazid</intervention_name>
    <description>TAF 25 mg + 3TC 300 mg + EFV 600 mg once daily plus RIF/INH 600/*300 mg daily (days 1 to ≤ 56)</description>
    <arm_group_label>Tenofovir Alafenamide</arm_group_label>
    <other_name>HepBest</other_name>
    <other_name>Stocrin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Phase 3: Tenofovir disoproxil fumarate/Emtricitabine/Efavirenz</intervention_name>
    <description>TDF/FTC/EFV 300/200/600 mg once daily. RIF/INH 600mg &lt;70kg, 750mg &gt;70kg</description>
    <arm_group_label>Tenofovir Alafenamide</arm_group_label>
    <other_name>Atripla</other_name>
    <other_name>Rifinah</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adult (≥ 18 years old) male or female&#xD;
&#xD;
          2. HIV-1 infected on TDF/FTC/EFV with HIV RNA &lt; 50 copies/mL in the last three months&#xD;
&#xD;
          3. On TB treatment in the maintenance phase (RIF/INH) with at least one month of TB&#xD;
             treatment needed for completion&#xD;
&#xD;
          4. Women of childbearing potential must not be pregnant or breastfeeding, with a negative&#xD;
             pregnancy test at screening&#xD;
&#xD;
          5. Women must be postmenopausal, surgically sterile or practicing an effective birth&#xD;
             control method (established before and maintained throughout the trial). Women who are&#xD;
             not sexually active must agree to use an effective birth control method if they become&#xD;
             heterosexually active during the trial&#xD;
&#xD;
          6. Understand the purpose of and procedures required for the study and having confirmed&#xD;
             they are willing to participate in the study by signing the informed consent document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Weight &lt; 40 kg&#xD;
&#xD;
          2. Estimated creatinine clearance &lt; 50 mL/min&#xD;
&#xD;
          3. Any active clinically significant or life-threatening disease (e.g. acute infections,&#xD;
             pancreatitis, hepatitis, cardiac dysfunction), medical or psychiatric condition, or&#xD;
             findings during screening, that in the investigator's opinion would compromise the&#xD;
             safety of the participant or the study outcome, or their ability to comply with the&#xD;
             study procedures&#xD;
&#xD;
          4. Chronic medical requirement for any drugs that are known to affect the PK of the study&#xD;
             drugs&#xD;
&#xD;
          5. Active drug/alcohol abuser&#xD;
&#xD;
          6. History of allergy or hypersensivity to any of the study drugs&#xD;
&#xD;
          7. Currently enrolled in an investigational drug study or has participated in an&#xD;
             investigational drug study within the 4 weeks before screening&#xD;
&#xD;
          8. Unable to comply with study protocol and study protocol restrictions&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Simiso Sokhela, MBBCh</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ezintsha, a subdivision of Wits Reproductive Health and HIV Institute (Wits RHI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Charlotte Maxeke Johannesburg Academic Hospital</name>
      <address>
        <city>Johannesburg</city>
        <state>Gauteng</state>
        <zip>2196</zip>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Wits RHI Yeoville Clinic</name>
      <address>
        <city>Johannesburg</city>
        <state>Gauteng</state>
        <country>South Africa</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>South Africa</country>
  </location_countries>
  <verification_date>June 2022</verification_date>
  <study_first_submitted>June 5, 2020</study_first_submitted>
  <study_first_submitted_qc>June 5, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 9, 2020</study_first_posted>
  <last_update_submitted>June 6, 2022</last_update_submitted>
  <last_update_submitted_qc>June 6, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">June 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Witwatersrand, South Africa</investigator_affiliation>
    <investigator_full_name>Professor Francois Venter</investigator_full_name>
    <investigator_title>Divisional Director of Ezintsha</investigator_title>
  </responsible_party>
  <keyword>Rifampicin, RIF/INH</keyword>
  <keyword>Tenofovir alafenamide fumarate (TAF)</keyword>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Intracellular tenofovir-diphosphate</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tuberculosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tenofovir</mesh_term>
    <mesh_term>Lamivudine</mesh_term>
    <mesh_term>Emtricitabine</mesh_term>
    <mesh_term>Efavirenz</mesh_term>
    <mesh_term>Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination</mesh_term>
    <mesh_term>Rifampin</mesh_term>
    <mesh_term>Isoniazid</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/NCT04424264
org study id: WRHI061
nct id: NCT04424264
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This is a pharmacokinetic study investigating the effect of rifampicin on the
      pharmacokinetics of intracellular tenofovir-diphosphate and plasma tenofovir when
      coadministered with tenofovir alafenamide fumarate during the maintenance phase of
      tuberculosis treatment in TB/HIV-1 coinfected participants (EpiTAF)
This is an open-label, sequential, single centre pharmacokinetic (PK) study investigating the
      effect of rifampicin on the pharmacokinetics of intracellular tenofovir-diphosphate and
      plasma tenofovir when coadministered with tenofovir alafenamide fumarate during the
      maintenance phase of tuberculosis treatment in TB/HIV-1 coinfected participants (EpiTAF).

      An open-label, sequential, pharmacokinetic (PK) drug-drug interaction study will be conducted
      in medically stable virologically suppressed HIV-1 infected adults coinfected with TB, who
      are in the maintenance phase of their TB treatment. After intensive PK evaluation of IC
      TFV-DP and pTFV, participants will be switched from their standard-of-care tenofovir
      disoproxil fumarate (TDF)/FTC/EFV regimen, to TAF + 3TC + EFV at the start of the study
      treatment period. After 28 days each participant will have intensive PK evaluation of IC
      TFV-DP and pTFV on TAF + 3TC + EFV with rifampicin (RIF). After the second intensive PK
      assessment is completed, participants will be switched back to TDF/FTC/EFV, with a final
      intensive PK evaluation of IC TFV-DP and pTFV 8 days after completion of TB treatment, at the
      final study visit. Eighteen volunteers will be enrolled for a target of 13 participants
      completing the study.

      The study includes screening and enrolment visits, 1 visit on day 28 and an end of study
      visit 28 days after the end of TB treatment.
allocation: N/A
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: IC TFV-DP concentrations during coadministration of TAF or TDF with RIF/INH in TB/HIV-1 coinfected participants
time frame: 56 days
description: Intracellular and plasma TFV-DP concentrations measured during coadministration of TAF or TDF with RIF/INH
measure: Maintenance of irological suppression (HIV-1 RNA < 50 copies/mL)
time frame: At screening, day 28, completion of TB and EOS visits
description: Assessment of maintenance of virological suppression (HIV-1 RNA < 50 copies/mL) while on TAF/RIF
measure: Comparison plasma concentrations of TAF with TDF
time frame: 56 days
description: Assessment to compare the plasma concentrations of tenofovir of TAF with TDF during coadministration of RIF/INH in TB/HIV-1 coinfected participants
measure: Comparison of IC TFV-DP concentrations of TDF
time frame: 56 days
description: 4. To compare the IC TFV-DP concentrations of TDF with and without coadministration with RIF/INH in TB/HIV-1 coinfected participants
arm group label: Tenofovir Alafenamide
arm group type: Experimental
description: TAF 25 mg once-daily administered with RIF/INH 600*/300mg
intervention type: Drug
intervention name: Phase 1: Tenofovir disoproxil fumarate/Emtricitabine/Efavirenz coadministered with Rifampicin/Isoniazid
description: TDF/FTC/EFV 300/200/600 mg once daily plus RIF/INH 600*/300 mg daily from screening until enrolment (days -15 to 0)
arm group label: Tenofovir Alafenamide
other name: Atripla
other name: Rifinah
intervention type: Drug
intervention name: Phase 2: Tenofovir alafenamide/Lamivudine/Efavirenz coadministered with Rifampicin/Isoniazid
description: TAF 25 mg + 3TC 300 mg + EFV 600 mg once daily plus RIF/INH 600/*300 mg daily (days 1 to ≤ 56)
arm group label: Tenofovir Alafenamide
other name: HepBest
other name: Stocrin
intervention type: Drug
intervention name: Phase 3: Tenofovir disoproxil fumarate/Emtricitabine/Efavirenz
description: TDF/FTC/EFV 300/200/600 mg once daily. RIF/INH 600mg <70kg, 750mg >70kg
arm group label: Tenofovir Alafenamide
other name: Atripla
other name: Rifinah
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Simiso Sokhela, MBBCh
role: Principal Investigator
affiliation: Ezintsha, a subdivision of Wits Reproductive Health and HIV Institute (Wits RHI)
facility: 
facility: 
country: South Africa
responsible party type: Sponsor-Investigator
investigator affiliation: University of Witwatersrand, South Africa
investigator full name: Professor Francois Venter
investigator title: Divisional Director of Ezintsha
mesh term: Tuberculosis
mesh term: Tenofovir
mesh term: Lamivudine
mesh term: Emtricitabine
mesh term: Efavirenz
mesh term: Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
mesh term: Rifampin
mesh term: Isoniazid