ENLIGHTEN: Establishing Novel Antiretroviral (ARV) Imaging for Hair to Elucidate Non-Adherence

Study Overview
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Brief Summary
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Purpose: Perform a 3-phase (single dose, multi dose, dose proportionality) study in healthy volunteers using daily tenofovir+emtricitabine, dolutegravir, and maraviroc dosing to quantify intra- and inter-subject variability and dose proportionality. The influence of covariates on ARV hair distribution (e.g., hair growth rate, race, hair color, hair treatment) will also be measured. Using both population PK modeling and physiologic based PK (PBPK) approaches, a statistical model to quantify ARV adherence patterns based on signal intensity/pattern will be developed. Participants: Healthy volunteers, aged 18 to 70 years of age, inclusive on the date of screening, with an intact gastrointestinal system and at least 1cm caput hair. Procedures (methods): Participants will be sequentially assigned to enroll in a dosing arm, beginning with maraviroc (MVC), then dolutegravir (DTG), and ending with tenofovir/emtricitabine (TFV/FTC). All participants will take a single observed dose of study product in Phase 1, with blood and hair samples obtained on Days 3, 7, 14, 21 and 28 days post-dose. In Phase 2, all participants take 28 days straight of daily dosing, observed, of the same study product. Blood and hair samples obtained on the same days post-dose. In Phase 3, participants will be randomized to stop their drug, or decrease dosing to one or three doses weekly. Hair and blood samples will again be obtained on the same days post-dose. All participants will complete a follow-up safety visit with 14 days of completing study sampling.

Detailed Description
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Details: Participants will be sequentially assigned to enroll in dosing arm, beginning with Maraviroc, then Dolutegravir and ending with Tenofovir/Emtricitabine, Participation will last approximately 3 months and will include a screening visit, three 28-day phases, and a follow-up safety visit. Phase 1 consists of a 28-day study period with a single dose of study product on Day 0. Phase 2 consists of a 28-day study period with each subject receiving a single daily observed dose of study product beginning on Day 0. Phase 3 consists of a 28-day study period, with three randomized drug-dosing schemas beginning on Day 0. Participants will either: stop taking their study product, dose once per week, or dose three times per week. Participants will return to the clinic for hair and blood sampling on days 3/7/14/21/28 post-dose for all three phases. Adverse events will be assessed at every visit. Safety labs will be drawn at the midpoint and at the end of each study phase, and at any time indicated due to suspected adverse events. Description of Study Phases Screening: Participants will be recruited from a variety of advertisements, and pre-screened using a telephone Institutional Review Board (IRB)-approved questionnaire. If participants are interested and pass the initial screening, a screening study visit in the research center will be scheduled. This visit should take approximately 90 minutes, during which full physical examination and medical history will be obtained, as well as physical diagnostics to assess for eligibility. This visit must be completed within the 28 days prior to enrollment. Phase 1: Consists of a 28-day study period, with a single dose of study product on Day 0 (Maraviroc, Dolutegravir, or tenofovir/emtricitabine). Day 0 can be scheduled on either Mondays or Tuesdays, and once eligibility is confirmed on the day of enrollment, a witnessed dose of study product will be administered. Participants will return to the clinic for hair and blood sampling on Days 3/7/14/21/28 days post-dose. Adverse events will be assessed at every visit. Safety labs will be drawn at the midpoint and at the end of the study phase, and at any time indicated due to suspected adverse events. These visits should last less than 30 minutes. Phase 2: Consists of a 28-day study period, with each subject receiving a single daily observed dose of study product beginning on Day 0. Day 0 can be scheduled on either Mondays or Tuesdays, once continued eligibility is confirmed. Target scheduling will have Phase 2 begin within 2 weeks of completing Phase 1, but could be extended up to 28 days as clinic availability dictates. Participants will return to the clinic daily for dosing, and for hair and blood sampling on Days 3/7/14/21/28 days post-dose. Adverse events will be assessed at every visit. Safety labs will be drawn at the midpoint, and at the end of the study phase, and at any time indicated due to adverse events. These visits should last less than 30 minutes. Dosing only visits should last less than 5 minutes. Phase 3: Consists of a 28-day study period, with three randomized drug-dosing schemas. Day 0 can be scheduled on Mondays, Tuesdays or Fridays, once continued eligibility is confirmed. Target scheduling will have Phase 3 begin as soon as possible after completing Phase 2, on a Monday/Tuesday/Or Friday within the week. On Day 0, participants will be randomized to one of 3 potential dosing schemes: No further doses One dose weekly (Day 0, 7, 14, 21) 4 doses Three Doses weekly (Mondays, Wednesdays, Fridays) (Days 0, 2, 4, 7, 9, 11, 14, 16, 18, 21, 23, 25) 12 doses Participants will return to clinic for observed dosing as scheduled, and for hair and blood sampling on days 3/7/14/21/28). Safety labs will be drawn at the midpoint, at the end, and at any time indicated due to adverse events. These visits should last less than 30 minutes. Dosing only visits should last less than five minutes.

Official Title
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ENLIGHTEN: Establishing Novel Antiretroviral (ARV) Imaging for Hair to Elucidate Non-Adherence

Conditions
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HIV/AIDS

Intervention / Treatment
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* Drug: Maraviroc Pill
* Drug: Dolutegravir Pill
* Drug: Truvada Pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Healthy volunteer between the ages of 18 and 70, inclusive on the date of screening, with an intact gastrointestinal tract. Healthy is defined as no clinically relevant abnormalities identified by a detailed medical history, full physical examination, including blood pressure and pulse rate measurement, and clinical laboratory tests Recent medical history in good medical standing, without evidence of fever five days prior to enrollment HIV-negative Able to swallow pills Has minimum hair required to provide study samples Not allergic to any component of the study drug Signed and dated informed consent indicating that they have been informed of all pertinent details of the trial and are willing to participate Willing and able to comply with scheduled visits, laboratory tests and trial procedures Willing to use at least one form of acceptable birth control throughout the duration of the study Negative, or receiving treatment, for syphilis at screening Hemoglobin Grade 2 or lower, with no clinically significant medical issues that would preclude blood sampling Exclusion Criteria Age outside of desired range Confirmed positive results for HIV, Hepatitis B or C at screening Subjects of all genders actively involved in the conception process, in addition to cisgender female subjects who are in the immediate post-partum period or breastfeeding Insufficient amount of hair or unwilling to keep hair length at least 1 centimeter throughout duration of study Unable or unwilling to comply with all lifestyle measures and/or visits Impaired renal function, as documented by a creatinine clearance <80 mL/min with the Cockcroft-Gault equation Has donated blood within the past 56 days in the amount greater than 500 mL Has taken an investigational drug in the past 4 months Clinical, laboratory, or surgical abnormalities that would preclude sample collection Has a condition, which, in the opinion of the investigator, is likely to interfere with follow-up or ability to take the study medication appropriately Any clinically significant laboratory result Grade 2 or greater according to the Division of AIDS (DAIDS) Laboratory Grading Tables History of regular alcohol consumption exceeding 14 drinks (1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of spirits) per week

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Prospective. Single-center, open-label, 3-arm, triple stage study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Maraviroc<br>12 Healthy subjects will dose with Maraviroc Pill and we will collect blood and hair over all three phases | Drug: Maraviroc Pill<br>* Subjects will take a single dose in Phase 1, Daily Doses in Phase 2 for 28 days, and then be randomized in Phase 3 to zero doses, one dose a week or three doses weekly<br>* Other names: selzentry;|
| Experimental: Dolutegravir<br>12 Healthy volunteers will dose with Dolutegravir Pill and we will collect blood and hair over all three phases | Drug: Dolutegravir Pill<br>* Subjects will take a single dose in Phase 1, Daily Doses in Phase 2 for 28 days, and then be randomized in Phase 3 to zero doses, one dose a week or three doses weekly<br>* Other names: Tivicay;|
| Experimental: Truvada<br>12 healthy volunteers will dose with Truvada Pill and we will collect blood and hair over all three phases | Drug: Truvada Pill<br>* Subjects will take a single dose in Phase 1, Daily Doses in Phase 2 for 28 days, and then be randomized in Phase 3 to zero doses, one dose a week or three doses weeklySubjects will take a single dose in Phase 1, Daily Doses in Phase 2 for 28 days, and then be randomized in Phase 3 to zero doses, one dose a week or three doses weekly<br>* Other names: Tenofovir/Emtricitabine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hair Antiretroviral Imaging | Signal Strength concentrations will be measured in hair for all study drugs, inclusive of FTC (emtricitabine), tenofovir (TFV), maraviroc (MRV), and dolutegravir (DTG) using Matrix-assisted Laser Desorption Electrospray Ionization (IR-MALDESI) to be reported by signal abundance (au). Signal abundance is the industry standard unit, and higher values represent greater signal with capability to relate to comparative concentrations. | Up to 28 days post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peripheral Blood Mononuclear Cells (PBMC) Antiretroviral Concentrations | Concentrations of emtricitabine-triphosphate, tenofovir-diphosphate will be measured in peripheral blood mononuclear cells in the Truvada arm only. Truvada is a combination pill, so results for both FTC and TFV are reported in separate columns. | Up to 28 days post-dose | 
| Plasma Antiretroviral Concentrations | Concentrations will be measured in hair of all study drugs, inclusive of FTC (emtricitabine), TFV (tenofovir), MRV (Maraviroc), and DTG (dolutegravir) | Up to 28 days post-dose | 
| Whole Blood Antiretroviral Concentrations | Concentrations will be measured in dried blood spots of all study drugs, inclusive of FTC (emtricitabine), TFV (tenofovir), MRV (Maraviroc), and DTG (dolutegravir). Truvada is a combination pill, so results for both FTC and TFV are reported in separate columns. | Up to 28 days post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adherence, Hair