Tenofovir Adherence to Rapidly Guide and Evaluate PrEP and HIV Therapy (TARGET)

February 5, 2020 updated by: Paul Drain, University of Washington

Pharmacokinetics of Tenofovir in Blood, Plasma and Urine of Healthy Adults With Perfect, Median and Low Drug Adherence

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
30

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Thailand
      • Chiang Mai, Thailand
        • Sanpatong Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 49 years (ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age ≥18 and <50 years old
  • HIV and Hepatitis B surface Ag negative
  • Normal renal function (estimated GFR >60 mL/min by the Cockcroft-Gault equation)
  • Willing/able to provided written informed consent

Exclusion Criteria:

  • Pregnant female
  • Any significant lab abnormality of neutrophil count, hemoglobin, platelets, AST, or ALT (Defined as Grade ≥3 by DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0, Nov. 2014)
  • History of using PrEP or thought to be eligible to receive PrEP.
  • Any clinically significant diseases or clinically significant findings during the screening medical history or physical examination that, in the investigator's opinion, might compromise participation in this study
  • Any concurrent participation in another clinical trial

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: PREVENTION
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
EXPERIMENTAL: Perfect Adherence
Participants will receive a single tablet of TENOFOVIR DISOPROXIL FUMARATE 300 Mg / EMTRICITABINE 200 Mg ORAL TABLET [TRUVADA] once daily for 6 weeks
Drug: Truvada
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®)
EXPERIMENTAL: Moderate Adherence
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
Drug: Truvada
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®)
EXPERIMENTAL: Poor Adherence
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
Drug: Truvada
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®)

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Area under the plasma concentration versus time curve (AUC) of Truvada concentration
Time Frame: 24, 48, 72 hours post-dose
Area under the plasma concentration versus time curve (AUC) of Truvada concentration
24, 48, 72 hours post-dose

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Maximum plasma concentration of Truvada
Time Frame: 24, 48, 72 hours post-dose
Maximum plasma concentration of Truvada
24, 48, 72 hours post-dose
Renal clearance of Truvada
Time Frame: 24, 48, 72 hours post-dose
Renal clearance of Truvada
24, 48, 72 hours post-dose
Time to Maximum Plasma Concentration(Cmax) of Truvada
Time Frame: 24, 48, 72 hours post-dose
Time to Maximum Plasma Concentration(Cmax) of Truvada
24, 48, 72 hours post-dose

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Washington

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Institute of Allergy and Infectious Diseases (NIAID)
Chiang Mai University

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Tim R Cressey, PhD, Chiang Mai University
  • Principal Investigator: Oraphan Siriprakaisil, MD, Sanpatong Hospital, Chiang Mai
  • Principal Investigator: Virat Klinbuayaem, MD, Sanpatong Hospital, Chiang Mai

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2017

Primary Completion (ACTUAL)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 1, 2018

Study Completion (ACTUAL)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 1, 2018

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
January 4, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
January 5, 2017

First Posted (ESTIMATE)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
January 6, 2017

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
February 7, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 5, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • STUDY00000058
  • R21AI127200-01 (NIH)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

We will make decisions to share IPD on case by case basis

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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