Development of a Urine-Based Point-of-Care Test for Adherence to Antiretroviral Drugs

Early Phase 1

Completed

• Conditions: Medication Adherence; HIV
• Interventions: Drug: dolutegravir oral tablet 50mg; Drug: tenofovir disoproxil fumarate oral tablet 300mg; Drug: emtricitabine/tenofovir alafenamide oral tablet 200mg/25mg; Drug: lamivudine oral tablet 300mg

• Registration Number: NCT04302896
• Lead Sponsor: Rhonda Brand

Brief Summary

This is a single-center, open label study to identify adherence levels of commonly prescribed FDA-approved antiretroviral agents by tracking the decline of drug concentrations in plasma, urine and saliva following abrupt drug cessation in HIV-negative adults. Results from this study may provide support for development of a point of care urine testing device to monitor drug adherence.

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 Timeline

• Study First Submitted: 2020-03-06
• Study First Submitted QC: 2020-03-06
• Study First Posted: 2020-03-10
• Study Start: 2020-08-31
• Primary Completion: 2021-09-30
• Study Completion: 2021-09-30
• Status Verified: 2022-03
• Last Update Submitted: 2022-03-02
• Last Update Posted: 2022-03-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

1. At least 18 years of age at screening, verified per site standard operating procedure (SOP)

2. Not pregnant or breastfeeding

3. Availability to return for all study visits, barring unforeseen circumstances

4. 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

5. Must agree not to participate in other concurrent interventional and/or drug trials

6. Understands and agrees to local sexually transmitted infections (STI) reporting requirements

7. HIV-1 seronegative at screening

8. Must be in general good health in the opinion of the investigator

9. 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

1. Participant reports any of the following at Screening:

   1. Has plans to relocate away from the study site area during the period of study participation
   2. Pregnant, less than 3 months post-partum, or lactating
   3. Intends to become pregnant during the period of study participation
   4. History of adverse reaction to study drugs
   5. History of osteoporosis or osteopenia
   6. PrEP (pre-exposure prophylaxis) or (PEP) post-exposure prophylaxis for HIV exposure within 3 months - prior to screening
   7. Participating in another research study involving drugs or medical devices within 3 months or 5 half-lives (if known) prior to enrollment
   8. History of gastric bypass
   9. History of inflammatory bowel disease
   10. Currently taking or anticipation of taking any medications on list of prohibited medications as specified in section 4.10.
   11. Unwilling or unable to comply with study procedures, medications and visits
   12. Allergies to dyes, excipients and components of drugs
   13. Condomless insertive or receptive anal intercourse with more than one partner in the past six months
   14. Known HIV-positive sexual partner within the last 6 months
   15. History of STI in the last 3 months

2. Has any of the following laboratory abnormalities at Screening:

   Note: Grade is per Version 2.1 of the Division of AIDS (DAIDS) Toxicity Table

   1. Hemoglobin Grade 1 or higher
   2. Platelet count Grade 1 or higher
   3. White blood cell count Grade 2 or higher
   4. Calculated creatinine clearance ≤ 70 mL/minute using the Cockcroft-Gault equation
   5. Grade 2 or higher ALT and/or AST (i.e., ≥ 2.5x the site laboratory upper limit of normal [ULN])
   6. Total bilirubin Grade 3 or higher
   7. Positive for Hepatitis B surface antigen (HBsAg)
   8. Confirmed positive for Hepatitis C antibody (HCV Ab)

3. 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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
dolutegravir + emtricitabine/tenofovir alafenamide	dolutegravir oral tablet 50mg	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
dolutegravir + tenofovir disoproxil fumarate + lamivudine	dolutegravir oral tablet 50mg	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
dolutegravir + tenofovir disoproxil fumarate + lamivudine	tenofovir disoproxil fumarate oral tablet 300mg	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
dolutegravir + emtricitabine/tenofovir alafenamide	emtricitabine/tenofovir alafenamide oral tablet 200mg/25mg	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
dolutegravir + tenofovir disoproxil fumarate + lamivudine	lamivudine oral tablet 300mg	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

Primary Outcome Measures

Name	Time	Method
Maximum concentration (Cmax) of dolutegravir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, and metabolites	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)
Minimum concentration (Cmin) of dolutegravir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, and metabolites	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)
Area under the concentration-time curve (AUC) of dolutegravir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, and metabolites	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)
Time to maximum concentration (Tmax) of dolutegravir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, tenofovir alafenamide, and metabolites	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)
Half-life (t½) of dolutegravir, emtricitabine, lamivudine, tenofovir disoproxil fumarate, and tenofovir alafenamide	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

Trial Locations

Locations (1)

HIV/AIDS Clinical Research Unit / University of Pittsburgh; 🇺🇸 Pittsburgh, Pennsylvania, United States