<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/NCT03012607</url>
  </required_header>
  <id_info>
    <org_study_id>STUDY00000058</org_study_id>
    <secondary_id>R21AI127200-01</secondary_id>
    <nct_id>NCT03012607</nct_id>
  </id_info>
  <brief_title>Tenofovir Adherence to Rapidly Guide and Evaluate PrEP and HIV Therapy</brief_title>
  <acronym>TARGET</acronym>
  <official_title>Pharmacokinetics of Tenofovir in Blood, Plasma and Urine of Healthy Adults With Perfect, Median and Low Drug Adherence</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Washington</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Chiang Mai University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Washington</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Adherence to antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) are critical to&#xD;
      the success of HIV treatment and therapeutic prevention. No accurate, objective point-of-care&#xD;
      test is available to monitor adherence to either ART or PrEP. The inability to accurately&#xD;
      identify poorly adherent patients will lead to more HIV infections (from failed PrEP and&#xD;
      non-suppressive ART), more drug-resistant virus (selected by failing ART), and unnecessary&#xD;
      switching to costly second- or third-line ART (when first-line regimens with virologic&#xD;
      efficacy but non-adherence are stopped inappropriately). To address this critical knowledge&#xD;
      gap, the investigators have developed a novel point-of-care test to detect the presence of&#xD;
      tenofovir-the most common drug in both ART and PrEP treatments worldwide-in fingerprick blood&#xD;
      or urine as an objective measure of ART and PrEP adherence.&#xD;
&#xD;
      Our central hypothesis is that the pharmacokinetics of tenofovir in blood and urine will&#xD;
      support point-of-care tenofovir detection as an objective measure of adherence, and that our&#xD;
      point-of-care tenofovir assay will have the ability to discriminate different drug adherence&#xD;
      levels. The investigators will test our central hypotheses by pursuing the following two&#xD;
      specific aims: (1) To assess our novel point-of-care tenofovir (TFV) assay in whole blood and&#xD;
      urine specimens within a controlled pharmacokinetic study of HIV-negative adults receiving&#xD;
      tenofovir disoproxil fumarate (TDF) with low, moderate, and perfect adherence; and (2) To&#xD;
      validate our novel point-of-care tenofovir (TFV) assay on blood and urine specimens using an&#xD;
      existing biorepository from a real-world clinical HIV prevention study.&#xD;
&#xD;
      This work is innovative because it develops an entirely new category of rapid diagnostic&#xD;
      testing for monitoring ART and PrEP adherence at the clinical point of care. Our rapid assay&#xD;
      will help clinicians identify patients in need of more adherence counseling, which when&#xD;
      implemented will prevent HIV acquisition, emergence of drug resistant virus, and unnecessary&#xD;
      ART regimen switching-measures that will improve national HIV programs and help preserve the&#xD;
      global supply of an effective HIV medication.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Objectives of the Study&#xD;
&#xD;
      Primary Objective:&#xD;
&#xD;
      • To determine the pharmacokinetics of tenofovir (TFV) in blood, urine and plasma in adults&#xD;
      with perfect, median and low adherence to tenofovir disoproxil fumarate (TDF).&#xD;
&#xD;
      Secondary Objectives&#xD;
&#xD;
        -  To determine the rate of tenofovir washout in blood, plasma and urine among participants&#xD;
           with various levels of TDF adherence.&#xD;
&#xD;
        -  To determine the steady-state concentrations of TFV in blood and plasma among controlled&#xD;
           levels of TDF adherence.&#xD;
&#xD;
        -  To compare the agreement between TFV in blood, plasma and urine concentrations.&#xD;
&#xD;
        -  To determine the intracellular tenofovir-diphosphate (TFV-DP) trough concentrations in&#xD;
           peripheral blood mononuclear cells (PBMC) and dried blood spot (DBS) samples in adults&#xD;
           with perfect, median and low drug adherence.&#xD;
&#xD;
        -  To identify possible concentration thresholds for the clinical interpretation of a&#xD;
           binary point-of-care adherence test for measurement of TFV (and/or TFV-DP) in relation&#xD;
           to adherence to TDF.&#xD;
&#xD;
      Design:&#xD;
&#xD;
      The study design is a randomized, open-label pharmacokinetic study in healthy adult&#xD;
      volunteers. The study involves collection of clinical data and biological specimens, and&#xD;
      subjects will provide written informed consent to participate. Healthy adult volunteers (HIV&#xD;
      serology and hepatitis B surface Ag negative) will be enrolled. Once written consent is&#xD;
      obtained, the screening visit will be performed. The study team will obtain each&#xD;
      participant's phone number, address, and relevant contact information.&#xD;
&#xD;
      Screening Visit:&#xD;
&#xD;
      Participant screening will be performed within 14 days of enrollment. A detailed background&#xD;
      demographic and health questionnaire will be administered. Ten mL of blood will be drawn for&#xD;
      baseline assessments: complete blood count, HIV antibody testing, Hepatitis B surface Ag&#xD;
      testing, renal and liver function tests and storage of blood in the biorepository. The blood&#xD;
      and chemistry tests will be used to exclude subjects with any abnormal laboratory test among&#xD;
      neutrophil count, hemoglobin, platelets, AST, or ALT. An abnormal test will be defined as&#xD;
      Grade ≥3 by DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events,&#xD;
      Version 2.0 Nov. 2014). The results of the clinical examination and baseline laboratory&#xD;
      assessments will be reviewed for inclusion/exclusion criteria.&#xD;
&#xD;
      Entry:&#xD;
&#xD;
      All entry visits will begin on a Monday morning. After receiving in-depth information on the&#xD;
      study schedule, subjects meeting the inclusion criteria will be enrolled and randomized&#xD;
      (1:1:1) into one of 3 groups to receive a controlled number of doses of Truvada® (Gilead&#xD;
      Sciences Inc.), which contains tenofovir disoproxil fumarate (TDF, 300 mg) and emtricitabine&#xD;
      (FTC, 200 mg) for 6 weeks. The participant will be carefully explained about their&#xD;
      drug-dosing schedule, visit schedule and potential medication side effects.&#xD;
&#xD;
      We will enroll a total of 30 adults with evaluable PK samples (10 per group). All&#xD;
      participants will start TDF in the morning of the Entry visit. The 6-week treatment period&#xD;
      was chosen in order to ensure concentrations of tenofovir in the different matrices (i.e.&#xD;
      blood, plasma, urine, PBMCs) mimic the expected conditions in patients with chronic dosing of&#xD;
      perfect, median and low drug adherence. The blood/urine sampling schedule is based on the&#xD;
      reported tenofovir plasma half-life and results of previous PK studies.&#xD;
&#xD;
      Tenofovir concentrations will be determined in each participant during three study phases (1)&#xD;
      lead-in period, (2) intensive PK sampling, and (3) wash-out period.&#xD;
&#xD;
      Phase 1: Lead-in Period (Entry to 6 weeks) Visit Prior to 2nd Dose: Immediately prior to the&#xD;
      second dose (i.e. Group 1: 24 post-dose (Day #2; Tuesday Morning); Group 2: 48 hours&#xD;
      post-dose (Day #3; Wednesday Morning); and Group 3; 72 hours post-dose (Day #4; Thursday&#xD;
      Morning) the subject will return to the hospital. A single blood sample will be drawn (5 mL).&#xD;
      From this venous blood sample, 5 dried blood spots (50 µL/spot) will be prepared on a Whatman&#xD;
      903 filter paper card. The remaining blood will be centrifuged and the plasma stored. A&#xD;
      single fingerstick whole blood sample will be collected and on a second Whatman 903 filter&#xD;
      paper card 2 dried blood spots (50 µL/spot) will be prepared. A separate 10 mL blood drawn&#xD;
      will be taken to collect PBMCs for determination of intracellular tenofovir-DP&#xD;
      concentrations. Finally, a spot urine sample will be collected (5-10 mL). All samples will be&#xD;
      stored at -70°C to -80°C.&#xD;
&#xD;
      Weeks 3 and 5 (both Monday morning, pre-dose): A single blood sample will be drawn (5 mL)&#xD;
      prior to dose administration. From this venous blood sample, 5 dried blood spots (50 µL/spot)&#xD;
      will be prepared on a Whatman 903 filter paper card. The remaining blood will be centrifuged&#xD;
      and the plasma stored. A single fingerstick whole blood sample will be collected and 2 dried&#xD;
      blood spots (50 µL/spot) will be prepared on a second Whatman 903 filter paper card. A&#xD;
      separate 10 mL blood drawn will be taken to collect PBMCs for determination of intracellular&#xD;
      tenofovir-DP concentrations. Finally, a spot urine sample will be collected (5-10 mL). All&#xD;
      samples will be stored at -70°C to -80°C. Renal and liver function tests will be performed.&#xD;
&#xD;
      Phase 2: Intensive PK sampling (starting Monday morning of Week 7 for 24 hours) Week 7&#xD;
      Intensive PK visit: On the Monday morning of Week 7, subjects will return to the hospital in&#xD;
      the early morning. A medical officer will conduct a physical examination and blood will be&#xD;
      drawn for laboratory safety evaluations (AST, and ALT). Following their normal morning daily&#xD;
      schedule of drug intake, a pre-dose blood sample will be drawn and a single Truvada® tablet&#xD;
      will be administered on an empty stomach (at least 6 hour fast beforehand). This will be the&#xD;
      last dose of Truvada® for all subjects. Venous blood (3 mL/time point) will be collected at&#xD;
      1, 2, 4, 6, 8, 10, 12, and 24 hours post-dose. At each time point, a venous blood DBS (5&#xD;
      spots) and fingerstick (2 spots) will be collected. Renal and liver function tests will be&#xD;
      performed.&#xD;
&#xD;
      Urine samples will be collected pre-dose and over the intervals of 0-4 hours, 4-8 hours, 8-12&#xD;
      hours, and 12-24 hours. Subjects will have an additional 10 mL blood drawn pre-dose and PBMCs&#xD;
      will be collected and stored at -70°C to -80°C. After 24 hours, the participant will be&#xD;
      discharged from the hospital. The subject will be asked to collect all their urine until&#xD;
      their next study visit in 24 hours.&#xD;
&#xD;
      Phase 3: Wash-out PK sampling (Weeks 7 to Week 10) Week 7 (Wednesday to Saturday): After the&#xD;
      intensive PK sampling is complete, participants will return to the clinic once a day for the&#xD;
      next 4 days (i.e. until the Saturday of Week 7) for a single venous blood draw (5mL),&#xD;
      fingerprick sample collection for dried blood spot, and a spot urine sample (5-10 mL). The&#xD;
      subject will be asked to collect all their urine until their next clinic visit.&#xD;
&#xD;
      Week 8 (Monday and Thursday): A single venous blood draw, fingerprick sample collection for&#xD;
      dried blood spot, and a spot urine sample (5-10 mL) will be drawn on Monday and Thursday of&#xD;
      Week 8. A single PBMC sample (10 mL blood) will be collected on Monday morning of week 8&#xD;
      (i.e. 1 week since last TDF dose).&#xD;
&#xD;
      Week 9 (Monday): A single venous blood draw, fingerprick sample collection for dried blood&#xD;
      spot, and a spot urine sample (5-10 mL) will be drawn on Monday. A single PBMC sample (10 mL&#xD;
      blood) will also be collected on Monday (i.e. 2 weeks since last TDF dose).&#xD;
&#xD;
      Week 10 (Monday): A single venous blood draw, fingerprick sample collection for dried blood&#xD;
      spot, and a spot urine sample (5-10 mL) will be drawn on Monday. A single PBMC sample (10 mL&#xD;
      blood) will also be collected on Monday morning (i.e. 3 weeks since last TDF dose).&#xD;
&#xD;
      End of Study visit (i.e. end of Week 10):&#xD;
&#xD;
      A single venous blood draw, fingerprick sample collection for dried blood spot, and a spot&#xD;
      urine test (5-10 mL) will be drawn on Monday. A single PBMC sample (10 mL blood) will also be&#xD;
      collected on Monday (i.e. 4 weeks since last TDF dose). A renal and liver function tests will&#xD;
      be performed.&#xD;
&#xD;
      At this time the participants will have completed the study and no additional evaluations&#xD;
      will be performed.&#xD;
&#xD;
      Tenofovir concentrations will be measured using validated liquid chromatography-triple&#xD;
      quadrupole mass spectrometry (LC-MS/MS) assays at the Faculty of Associated Medical Sciences&#xD;
      at Chiang Mai University. Intracellular tenofovir-diphosphate (TFV-DP) concentrations will be&#xD;
      determined using a validated a LC-MS based assay.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 2017</start_date>
  <completion_date type="Actual">March 2018</completion_date>
  <primary_completion_date type="Actual">March 2018</primary_completion_date>
  <phase>N/A</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>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Area under the plasma concentration versus time curve (AUC) of Truvada concentration</measure>
    <time_frame>24, 48, 72 hours post-dose</time_frame>
    <description>Area under the plasma concentration versus time curve (AUC) of Truvada concentration</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximum plasma concentration of Truvada</measure>
    <time_frame>24, 48, 72 hours post-dose</time_frame>
    <description>Maximum plasma concentration of Truvada</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Renal clearance of Truvada</measure>
    <time_frame>24, 48, 72 hours post-dose</time_frame>
    <description>Renal clearance of Truvada</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Maximum Plasma Concentration(Cmax) of Truvada</measure>
    <time_frame>24, 48, 72 hours post-dose</time_frame>
    <description>Time to Maximum Plasma Concentration(Cmax) of Truvada</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Hiv</condition>
  <arm_group>
    <arm_group_label>Perfect Adherence</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive a single tablet of TENOFOVIR DISOPROXIL FUMARATE 300 Mg / EMTRICITABINE 200 Mg ORAL TABLET [TRUVADA] once daily for 6 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Moderate Adherence</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive a single tablet of TENOFOVIR DISOPROXIL FUMARATE 300 Mg / EMTRICITABINE 200 Mg ORAL TABLET [TRUVADA] 4 times per week (Monday, Wednesday, Friday, and Saturday) for 6 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Poor Adherence</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will receive a single tablet of TENOFOVIR DISOPROXIL FUMARATE 300 Mg / EMTRICITABINE 200 Mg ORAL TABLET [TRUVADA] 2 times per week (Monday, Thursday) for 6 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Truvada</intervention_name>
    <description>Participants will be randomized into 1 of 3 groups (10 participants/group) to receive a controlled number of doses of tenofovir disoproxil fumarate (TDF, 300mg) in a combination pill with emtricitabine (FTC, 200mg) (Truvada®)</description>
    <arm_group_label>Moderate Adherence</arm_group_label>
    <arm_group_label>Perfect Adherence</arm_group_label>
    <arm_group_label>Poor Adherence</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥18 and &lt;50 years old&#xD;
&#xD;
          -  HIV and Hepatitis B surface Ag negative&#xD;
&#xD;
          -  Normal renal function (estimated GFR &gt;60 mL/min by the Cockcroft-Gault equation)&#xD;
&#xD;
          -  Willing/able to provided written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant female&#xD;
&#xD;
          -  Any significant lab abnormality of neutrophil count, hemoglobin, platelets, AST, or&#xD;
             ALT (Defined as Grade ≥3 by DAIDS Table for Grading the Severity of Adult and&#xD;
             Pediatric Adverse Events, Version 2.0, Nov. 2014)&#xD;
&#xD;
          -  History of using PrEP or thought to be eligible to receive PrEP.&#xD;
&#xD;
          -  Any clinically significant diseases or clinically significant findings during the&#xD;
             screening medical history or physical examination that, in the investigator's opinion,&#xD;
             might compromise participation in this study&#xD;
&#xD;
          -  Any concurrent participation in another clinical trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>49 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paul Drain, MD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Washington</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Tim R Cressey, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Chiang Mai University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Oraphan Siriprakaisil, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sanpatong Hospital, Chiang Mai</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Virat Klinbuayaem, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sanpatong Hospital, Chiang Mai</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sanpatong Hospital</name>
      <address>
        <city>Chiang Mai</city>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Thailand</country>
  </location_countries>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>January 4, 2017</study_first_submitted>
  <study_first_submitted_qc>January 5, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 6, 2017</study_first_posted>
  <last_update_submitted>February 5, 2020</last_update_submitted>
  <last_update_submitted_qc>February 5, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 7, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Washington</investigator_affiliation>
    <investigator_full_name>Paul Drain</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>PrEP</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
    <ipd_description>We will make decisions to share IPD on case by case basis</ipd_description>
  </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/NCT03012607
org study id: STUDY00000058
secondary id: R21AI127200-01
nct id: NCT03012607
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
Adherence to antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) are critical to
      the success of HIV treatment and therapeutic prevention. No accurate, objective point-of-care
      test is available to monitor adherence to either ART or PrEP. The inability to accurately
      identify poorly adherent patients will lead to more HIV infections (from failed PrEP and
      non-suppressive ART), more drug-resistant virus (selected by failing ART), and unnecessary
      switching to costly second- or third-line ART (when first-line regimens with virologic
      efficacy but non-adherence are stopped inappropriately). To address this critical knowledge
      gap, the investigators have developed a novel point-of-care test to detect the presence of
      tenofovir-the most common drug in both ART and PrEP treatments worldwide-in fingerprick blood
      or urine as an objective measure of ART and PrEP adherence.

      Our central hypothesis is that the pharmacokinetics of tenofovir in blood and urine will
      support point-of-care tenofovir detection as an objective measure of adherence, and that our
      point-of-care tenofovir assay will have the ability to discriminate different drug adherence
      levels. The investigators will test our central hypotheses by pursuing the following two
      specific aims: (1) To assess our novel point-of-care tenofovir (TFV) assay in whole blood and
      urine specimens within a controlled pharmacokinetic study of HIV-negative adults receiving
      tenofovir disoproxil fumarate (TDF) with low, moderate, and perfect adherence; and (2) To
      validate our novel point-of-care tenofovir (TFV) assay on blood and urine specimens using an
      existing biorepository from a real-world clinical HIV prevention study.

      This work is innovative because it develops an entirely new category of rapid diagnostic
      testing for monitoring ART and PrEP adherence at the clinical point of care. Our rapid assay
      will help clinicians identify patients in need of more adherence counseling, which when
      implemented will prevent HIV acquisition, emergence of drug resistant virus, and unnecessary
      ART regimen switching-measures that will improve national HIV programs and help preserve the
      global supply of an effective HIV medication.
Objectives of the Study

      Primary Objective:

      • To determine the pharmacokinetics of tenofovir (TFV) in blood, urine and plasma in adults
      with perfect, median and low adherence to tenofovir disoproxil fumarate (TDF).

      Secondary Objectives

        -  To determine the rate of tenofovir washout in blood, plasma and urine among participants
           with various levels of TDF adherence.

        -  To determine the steady-state concentrations of TFV in blood and plasma among controlled
           levels of TDF adherence.

        -  To compare the agreement between TFV in blood, plasma and urine concentrations.

        -  To determine the intracellular tenofovir-diphosphate (TFV-DP) trough concentrations in
           peripheral blood mononuclear cells (PBMC) and dried blood spot (DBS) samples in adults
           with perfect, median and low drug adherence.

        -  To identify possible concentration thresholds for the clinical interpretation of a
           binary point-of-care adherence test for measurement of TFV (and/or TFV-DP) in relation
           to adherence to TDF.

      Design:

      The study design is a randomized, open-label pharmacokinetic study in healthy adult
      volunteers. The study involves collection of clinical data and biological specimens, and
      subjects will provide written informed consent to participate. Healthy adult volunteers (HIV
      serology and hepatitis B surface Ag negative) will be enrolled. Once written consent is
      obtained, the screening visit will be performed. The study team will obtain each
      participant's phone number, address, and relevant contact information.

      Screening Visit:

      Participant screening will be performed within 14 days of enrollment. A detailed background
      demographic and health questionnaire will be administered. Ten mL of blood will be drawn for
      baseline assessments: complete blood count, HIV antibody testing, Hepatitis B surface Ag
      testing, renal and liver function tests and storage of blood in the biorepository. The blood
      and chemistry tests will be used to exclude subjects with any abnormal laboratory test among
      neutrophil count, hemoglobin, platelets, AST, or ALT. An abnormal test will be defined as
      Grade ≥3 by DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events,
      Version 2.0 Nov. 2014). The results of the clinical examination and baseline laboratory
      assessments will be reviewed for inclusion/exclusion criteria.

      Entry:

      All entry visits will begin on a Monday morning. After receiving in-depth information on the
      study schedule, subjects meeting the inclusion criteria will be enrolled and randomized
      (1:1:1) into one of 3 groups to receive a controlled number of doses of Truvada® (Gilead
      Sciences Inc.), which contains tenofovir disoproxil fumarate (TDF, 300 mg) and emtricitabine
      (FTC, 200 mg) for 6 weeks. The participant will be carefully explained about their
      drug-dosing schedule, visit schedule and potential medication side effects.

      We will enroll a total of 30 adults with evaluable PK samples (10 per group). All
      participants will start TDF in the morning of the Entry visit. The 6-week treatment period
      was chosen in order to ensure concentrations of tenofovir in the different matrices (i.e.
      blood, plasma, urine, PBMCs) mimic the expected conditions in patients with chronic dosing of
      perfect, median and low drug adherence. The blood/urine sampling schedule is based on the
      reported tenofovir plasma half-life and results of previous PK studies.

      Tenofovir concentrations will be determined in each participant during three study phases (1)
      lead-in period, (2) intensive PK sampling, and (3) wash-out period.

      Phase 1: Lead-in Period (Entry to 6 weeks) Visit Prior to 2nd Dose: Immediately prior to the
      second dose (i.e. Group 1: 24 post-dose (Day #2; Tuesday Morning); Group 2: 48 hours
      post-dose (Day #3; Wednesday Morning); and Group 3; 72 hours post-dose (Day #4; Thursday
      Morning) the subject will return to the hospital. A single blood sample will be drawn (5 mL).
      From this venous blood sample, 5 dried blood spots (50 µL/spot) will be prepared on a Whatman
      903 filter paper card. The remaining blood will be centrifuged and the plasma stored. A
      single fingerstick whole blood sample will be collected and on a second Whatman 903 filter
      paper card 2 dried blood spots (50 µL/spot) will be prepared. A separate 10 mL blood drawn
      will be taken to collect PBMCs for determination of intracellular tenofovir-DP
      concentrations. Finally, a spot urine sample will be collected (5-10 mL). All samples will be
      stored at -70°C to -80°C.

      Weeks 3 and 5 (both Monday morning, pre-dose): A single blood sample will be drawn (5 mL)
      prior to dose administration. From this venous blood sample, 5 dried blood spots (50 µL/spot)
      will be prepared on a Whatman 903 filter paper card. The remaining blood will be centrifuged
      and the plasma stored. A single fingerstick whole blood sample will be collected and 2 dried
      blood spots (50 µL/spot) will be prepared on a second Whatman 903 filter paper card. A
      separate 10 mL blood drawn will be taken to collect PBMCs for determination of intracellular
      tenofovir-DP concentrations. Finally, a spot urine sample will be collected (5-10 mL). All
      samples will be stored at -70°C to -80°C. Renal and liver function tests will be performed.

      Phase 2: Intensive PK sampling (starting Monday morning of Week 7 for 24 hours) Week 7
      Intensive PK visit: On the Monday morning of Week 7, subjects will return to the hospital in
      the early morning. A medical officer will conduct a physical examination and blood will be
      drawn for laboratory safety evaluations (AST, and ALT). Following their normal morning daily
      schedule of drug intake, a pre-dose blood sample will be drawn and a single Truvada® tablet
      will be administered on an empty stomach (at least 6 hour fast beforehand). This will be the
      last dose of Truvada® for all subjects. Venous blood (3 mL/time point) will be collected at
      1, 2, 4, 6, 8, 10, 12, and 24 hours post-dose. At each time point, a venous blood DBS (5
      spots) and fingerstick (2 spots) will be collected. Renal and liver function tests will be
      performed.

      Urine samples will be collected pre-dose and over the intervals of 0-4 hours, 4-8 hours, 8-12
      hours, and 12-24 hours. Subjects will have an additional 10 mL blood drawn pre-dose and PBMCs
      will be collected and stored at -70°C to -80°C. After 24 hours, the participant will be
      discharged from the hospital. The subject will be asked to collect all their urine until
      their next study visit in 24 hours.

      Phase 3: Wash-out PK sampling (Weeks 7 to Week 10) Week 7 (Wednesday to Saturday): After the
      intensive PK sampling is complete, participants will return to the clinic once a day for the
      next 4 days (i.e. until the Saturday of Week 7) for a single venous blood draw (5mL),
      fingerprick sample collection for dried blood spot, and a spot urine sample (5-10 mL). The
      subject will be asked to collect all their urine until their next clinic visit.

      Week 8 (Monday and Thursday): A single venous blood draw, fingerprick sample collection for
      dried blood spot, and a spot urine sample (5-10 mL) will be drawn on Monday and Thursday of
      Week 8. A single PBMC sample (10 mL blood) will be collected on Monday morning of week 8
      (i.e. 1 week since last TDF dose).

      Week 9 (Monday): A single venous blood draw, fingerprick sample collection for dried blood
      spot, and a spot urine sample (5-10 mL) will be drawn on Monday. A single PBMC sample (10 mL
      blood) will also be collected on Monday (i.e. 2 weeks since last TDF dose).

      Week 10 (Monday): A single venous blood draw, fingerprick sample collection for dried blood
      spot, and a spot urine sample (5-10 mL) will be drawn on Monday. A single PBMC sample (10 mL
      blood) will also be collected on Monday morning (i.e. 3 weeks since last TDF dose).

      End of Study visit (i.e. end of Week 10):

      A single venous blood draw, fingerprick sample collection for dried blood spot, and a spot
      urine test (5-10 mL) will be drawn on Monday. A single PBMC sample (10 mL blood) will also be
      collected on Monday (i.e. 4 weeks since last TDF dose). A renal and liver function tests will
      be performed.

      At this time the participants will have completed the study and no additional evaluations
      will be performed.

      Tenofovir concentrations will be measured using validated liquid chromatography-triple
      quadrupole mass spectrometry (LC-MS/MS) assays at the Faculty of Associated Medical Sciences
      at Chiang Mai University. Intracellular tenofovir-diphosphate (TFV-DP) concentrations will be
      determined using a validated a LC-MS based assay.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Area under the plasma concentration versus time curve (AUC) of Truvada concentration
time frame: 24, 48, 72 hours post-dose
description: Area under the plasma concentration versus time curve (AUC) of Truvada concentration
measure: Maximum plasma concentration of Truvada
time frame: 24, 48, 72 hours post-dose
description: Maximum plasma concentration of Truvada
measure: Renal clearance of Truvada
time frame: 24, 48, 72 hours post-dose
description: Renal clearance of Truvada
measure: Time to Maximum Plasma Concentration(Cmax) of Truvada
time frame: 24, 48, 72 hours post-dose
description: Time to Maximum Plasma Concentration(Cmax) of Truvada
arm group label: Perfect Adherence
arm group type: Experimental
description: Participants will receive a single tablet of TENOFOVIR DISOPROXIL FUMARATE 300 Mg / EMTRICITABINE 200 Mg ORAL TABLET [TRUVADA] once daily for 6 weeks
arm group label: Moderate Adherence
arm group type: Experimental
description: Participants will receive a single tablet of TENOFOVIR DISOPROXIL FUMARATE 300 Mg / EMTRICITABINE 200 Mg ORAL TABLET [TRUVADA] 4 times per week (Monday, Wednesday, Friday, and Saturday) for 6 weeks
arm group label: Poor Adherence
arm group type: Experimental
description: Participants will receive a single tablet of TENOFOVIR DISOPROXIL FUMARATE 300 Mg / EMTRICITABINE 200 Mg ORAL TABLET [TRUVADA] 2 times per week (Monday, Thursday) for 6 weeks
intervention type: Drug
intervention name: Truvada
description: Participants will be randomized into 1 of 3 groups (10 participants/group) to receive a controlled number of doses of tenofovir disoproxil fumarate (TDF, 300mg) in a combination pill with emtricitabine (FTC, 200mg) (Truvada®)
arm group label: Moderate Adherence
arm group label: Perfect Adherence
arm group label: Poor Adherence
criteria: 
gender: All
minimum age: 18 Years
maximum age: 49 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Paul Drain, MD, MPH
role: Principal Investigator
affiliation: University of Washington
last name: Tim R Cressey, PhD
role: Principal Investigator
affiliation: Chiang Mai University
last name: Oraphan Siriprakaisil, MD
role: Principal Investigator
affiliation: Sanpatong Hospital, Chiang Mai
last name: Virat Klinbuayaem, MD
role: Principal Investigator
affiliation: Sanpatong Hospital, Chiang Mai
facility: 
country: Thailand
responsible party type: Principal Investigator
investigator affiliation: University of Washington
investigator full name: Paul Drain
investigator title: Assistant Professor
mesh term: Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
sharing ipd: Undecided
ipd description: We will make decisions to share IPD on case by case basis