- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04302896
Development of a Urine-Based Point-of-Care Test for Adherence to Antiretroviral Drugs (APTAMER)
APT-POCT-01: An Open Label, Pharmacokinetic Study of Plasma/Urine/Salivary Drug Concentrations Over Fourteen Days Following Drug Intake Cessation, In HIV-Uninfected Healthy Volunteers Dosing to Steady-state to Further Development of Point of Care Diagnostic Testing
Study Overview
Status
Conditions
Detailed Description
Poor adherence to antiretroviral (ARV) therapy and HIV pre-exposure prophylaxis (PrEP) incurs costs for patients, health systems, and society. Non-adherence to ARV precedes viral breakthrough and offers opportunities for health-care professionals to intervene. There is a need for accurate, affordable, rapid, and objective monitoring of adherence to be deployed as a companion diagnostic to ARV therapy. Self-reported questionnaires, physician and nurse adherence consistently over-estimate adherence, and pill counts, and pharmacy returns do not yield sufficient precision for individual patients. Therapeutic drug monitoring (TDM) has the advantage tracking medication intake, but sample storage and processing requirements, turnaround times and relatively high cost preclude their widespread deployment. There is a real clinical need for point-of-care adherence testing, which will have high clinical utility by allowing targeting of adherence support and monitoring, better medication review, and integration with community support.
Since the clinical utility of any point-of-care test (POCT) will be its negative predictive value, this trial has been designed as a 'tail' study to track the decline of drug concentrations in plasma, urine and saliva following abrupt drug cessation. Such a study will require dosing to healthy participants who are dosed to steady-state prior to treatment discontinuation.
Serial measurement of drug concentrations in plasma, saliva and urine will be used to develop population-based models which adequately describe the kinetics of elimination and population variability in drug exposure. These models will be used to simulate population drug exposures from which target cut-offs are derived for development of a POCT device.
Approximately thirty healthy, HIV-uninfected participants will be enrolled and equally assigned to one of two ARV dosing arms using a permuted block design randomization scheme.
ARM 1: dolutegravir 50 mg + emtricitabine 200 mg/tenofovir alafenamide 25 mg once daily for 15 days
ARM 2: dolutegravir 50 mg + tenofovir disoproxil fumarate 300 mg + lamivudine 300 mg once daily for 15 days
To assess ARV pharmacokinetics during dosing and over 14 days following ARV cessation, blood, urine, and saliva samples will be collected at Days 1, 2, 8, 15, 16, 17, 18, 19, 22 and 29.
Study Type
Enrollment (Actual)
Phase
- Early Phase 1
Contacts and Locations
Study Locations
-
-
Pennsylvania
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Pittsburgh, Pennsylvania, United States, 15213
- HIV/AIDS Clinical Research Unit / University of Pittsburgh
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- At least 18 years of age at screening, verified per site standard operating procedure (SOP)
- Not pregnant or breastfeeding
- Availability to return for all study visits, barring unforeseen circumstances
Willing and able to
- communicate in English
- provide written informed consent to take part in the study
- provide adequate locator information, as defined in site SOP
- follow the assigned dosing protocol and maintain an accurate dosing log
- Must agree not to participate in other concurrent interventional and/or drug trials
- Understands and agrees to local sexually transmitted infections (STI) reporting requirements
- HIV-1 seronegative at screening
- Must be in general good health in the opinion of the investigator
For female participants of reproductive potential: Using an effective method of contraception and intending to continue use of an effective method for the duration of study participation and for 8 weeks after the last dose of study drug. Acceptable methods include:
- hormonal methods
- IUD (intrauterine device)
- sterilization of participant or partner
Exclusion Criteria:
Participant reports any of the following at Screening:
- Has plans to relocate away from the study site area during the period of study participation
- Pregnant, less than 3 months post-partum, or lactating
- Intends to become pregnant during the period of study participation
- History of adverse reaction to study drugs
- History of osteoporosis or osteopenia
- PrEP (pre-exposure prophylaxis) or (PEP) post-exposure prophylaxis for HIV exposure within 3 months - prior to screening
- Participating in another research study involving drugs or medical devices within 3 months or 5 half-lives (if known) prior to enrollment
- History of gastric bypass
- History of inflammatory bowel disease
- Currently taking or anticipation of taking any medications on list of prohibited medications as specified in section 4.10.
- Unwilling or unable to comply with study procedures, medications and visits
- Allergies to dyes, excipients and components of drugs
- Condomless insertive or receptive anal intercourse with more than one partner in the past six months
- Known HIV-positive sexual partner within the last 6 months
- History of STI in the last 3 months
Has any of the following laboratory abnormalities at Screening:
Note: Grade is per Version 2.1 of the Division of AIDS (DAIDS) Toxicity Table
- Hemoglobin Grade 1 or higher
- Platelet count Grade 1 or higher
- White blood cell count Grade 2 or higher
- Calculated creatinine clearance ≤ 70 mL/minute using the Cockcroft-Gault equation
- Grade 2 or higher ALT and/or AST (i.e., ≥ 2.5x the site laboratory upper limit of normal [ULN])
- Total bilirubin Grade 3 or higher
- Positive for Hepatitis B surface antigen (HBsAg)
- Confirmed positive for Hepatitis C antibody (HCV Ab)
- Has any other condition that, in the opinion of the Principal Investigator or designee, would preclude informed consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Other
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: dolutegravir + emtricitabine/tenofovir alafenamide
Tivicay® (dolutegravir 50 mg tablet) + Descovy® (emtricitabine 200 mg/tenofovir alafenamide 25 mg combination tablet), one tablet of each taken by mouth once daily for 15 days
|
Tivicay® (dolutegravir, DTG), a HIV-1 integrase strand transfer inhibitor (INSTI), is FDA-approved in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients weighing at least 30kg.
Tivicay® 50mg tablets [GlaxoSmithKline] are yellow, round, film-coated, biconvex tablets debossed with "SV 572" on one side and "50" on the other side.
The inactive ingredients in each tablet are D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate.
The tablet film-coating contains the inactive ingredients iron oxide yellow macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.
Other Names:
Descovy® (emtricitabine/tenofovir alafenamide, FTC/TAF) is a combination of two HIV nucleoside analog reverse transcriptase inhibitors (NRTIs) FDA-approved in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35kg.
Descovy® 200 mg/25 mg tablets [Gilead] are blue, rectangular-shaped, and film-coated with "GSI" debossed on one side and "225" on the other side.
The inactive ingredients are croscarmellose sodium, magnesium stearate, and microcrystalline cellulose.
The tablets are film-coated with a coating material containing indigo carmine aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide.
Other Names:
|
Experimental: dolutegravir + tenofovir disoproxil fumarate + lamivudine
Tivicay® (dolutegravir 50 mg tablet) + Viread® (tenofovir disoproxil fumarate 300 mg tablet) + lamivudine 300 mg tablet, one tablet of each taken by mouth once daily for 15 days
|
Tivicay® (dolutegravir, DTG), a HIV-1 integrase strand transfer inhibitor (INSTI), is FDA-approved in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients weighing at least 30kg.
Tivicay® 50mg tablets [GlaxoSmithKline] are yellow, round, film-coated, biconvex tablets debossed with "SV 572" on one side and "50" on the other side.
The inactive ingredients in each tablet are D-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate.
The tablet film-coating contains the inactive ingredients iron oxide yellow macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.
Other Names:
Viread® (tenofovir DF, TDF) is a nucleotide analog HIV-1 reverse transcriptase inhibitor and a hepatitis B reverse transcriptase inhibitor FDA-approved for the treatment of HIV-1 infection in combination with other antiretroviral agents and for the treatment of chronic hepatitis B in adults and pediatric patients 2 years of age and older weighing at least 10kg.
Viread® 300mg tablets [Gilead] are almond-shaped, light blue, film-coated tablets containing 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil, are debossed with "GILEAD" and "4331" on one side and with "300" on the other side.
The inactive ingredients in each tablet are croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.
Viread® 300mg tablets are coated with Opadry II Y-30-10671-A, which contains FD&C blue #2 aluminum lake, hypromellose 2910, lactose monohydrate, titanium dioxide, and triacetin.
Other Names:
Lamivudine (Epivir®, 3TC) is a nucleoside analogue reverse transcriptase inhibitor FDA-approved in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients at least 3 months of age.
Lamivudine 300mg tablets [Apotex Inc.] are gray, modified diamond-shaped, film-coated, and engraved with "LMV 300" on one side and APO on the reverse side.
Inactive ingredients are black iron oxide, colloidal silicon dioxide, crospovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose anhydrous, magnesium stearate, polyethylene glycol, and titanium dioxide.
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Maximum concentration (Cmax) of dolutegravir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, and metabolites
Time Frame: Pre-dose; 24, 168, and 336 after the first dose; then 24, 48, 72, 98, 168, and 336 hours after the final dose
|
Cmax of dolutegravir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, and metabolites in plasma, whole blood (dried spot), saliva, and urine as measured by liquid chromatography tandem mass spectrometry (LC-MS/MS)
|
Pre-dose; 24, 168, and 336 after the first dose; then 24, 48, 72, 98, 168, and 336 hours after the final dose
|
Time to maximum concentration (Tmax) of dolutegravir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, and metabolites
Time Frame: Pre-dose; 24, 168, and 336 after the first dose; then 24, 48, 72, 98, 168, and 336 hours after the final dose
|
Tmax of dolutegravir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, and metabolites in plasma, whole blood (dried spot), saliva, and urine as measured by liquid chromatography tandem mass spectrometry (LC-MS/MS)
|
Pre-dose; 24, 168, and 336 after the first dose; then 24, 48, 72, 98, 168, and 336 hours after the final dose
|
Minimum concentration (Cmin) of dolutegravir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, and metabolites
Time Frame: Pre-dose; 24, 168, and 336 after the first dose; then 24, 48, 72, 98, 168, and 336 hours after the final dose
|
Cmin of dolutegravir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, and metabolites in plasma, whole blood (dried spot), saliva, and urine as measured by liquid chromatography tandem mass spectrometry (LC-MS/MS)
|
Pre-dose; 24, 168, and 336 after the first dose; then 24, 48, 72, 98, 168, and 336 hours after the final dose
|
Area under the concentration-time curve (AUC) of dolutegravir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, and metabolites
Time Frame: Pre-dose; 24, 168, and 336 after the first dose; then 24, 48, 72, 98, 168, and 336 hours after the final dose
|
AUC of dolutegravir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, and metabolites in plasma, whole blood (dried spot), saliva, and urine as measured by liquid chromatography tandem mass spectrometry (LC-MS/MS)
|
Pre-dose; 24, 168, and 336 after the first dose; then 24, 48, 72, 98, 168, and 336 hours after the final dose
|
Half-life (t½) of dolutegravir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, and tenofovir alafenamide
Time Frame: Pre-dose; 24, 168, and 336 after the first dose; then 24, 48, 72, 98, 168, and 336 hours after the final dose
|
Estimated t½ of dolutegravir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, and tenofovir alafenamide as measured in plasma, whole blood (dried spot), saliva, and urine
|
Pre-dose; 24, 168, and 336 after the first dose; then 24, 48, 72, 98, 168, and 336 hours after the final dose
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Ken Ho, MD, University of Pittsburgh
- Study Chair: Rhonda Brand, PhD, University of Pittsburgh
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Antiviral Agents
- Reverse Transcriptase Inhibitors
- Nucleic Acid Synthesis Inhibitors
- Enzyme Inhibitors
- Anti-HIV Agents
- Anti-Retroviral Agents
- HIV Integrase Inhibitors
- Integrase Inhibitors
- Tenofovir
- Emtricitabine
- Emtricitabine tenofovir alafenamide
- Lamivudine
- Dolutegravir
Other Study ID Numbers
- STUDY19100009
- R01AI122301 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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