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

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.

Study Overview

• Status: Completed
• Conditions: HIV/AIDS
• Intervention / Treatment: Drug: Maraviroc Pill; Drug: Dolutegravir Pill; Drug: Truvada Pill

Detailed Description

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:

1. No further doses
2. One dose weekly (Day 0, 7, 14, 21) 4 doses
3. 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.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Clinical and Translational Research Center, UNC Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Maraviroc; 12 Healthy subjects will dose with Maraviroc Pill and we will collect blood and hair over all three phases	Drug: Maraviroc Pill; 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; Other Names: selzentry
Experimental: Dolutegravir; 12 Healthy volunteers will dose with Dolutegravir Pill and we will collect blood and hair over all three phases	Drug: Dolutegravir Pill; 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; Other Names: Tivicay
Experimental: Truvada; 12 healthy volunteers will dose with Truvada Pill and we will collect blood and hair over all three phases	Drug: Truvada Pill; 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; Other Names: Tenofovir/Emtricitabine

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Angela DM Kashuba, BScPhmPharmD, University of North Carolina, Chapel Hill

Publications and helpful links

General Publications

• Hill LM, Golin CE, Pack A, Carda-Auten J, Wallace DD, Cherkur S, Farel CE, Rosen EP, Gandhi M, Asher Prince HM, Kashuba ADM. Using Real-Time Adherence Feedback to Enhance Communication About Adherence to Antiretroviral Therapy: Patient and Clinician Perspectives. J Assoc Nurses AIDS Care. 2020 Jan-Feb;31(1):25-34. doi: 10.1097/JNC.0000000000000089.

Study record dates

Study Major Dates

• Study Start (Actual): June 28, 2017
• Primary Completion (Actual): December 3, 2018
• Study Completion (Actual): December 7, 2018

Study Registration Dates

• First Submitted: July 10, 2017
• First Submitted That Met QC Criteria: July 12, 2017
• First Posted (Actual): July 14, 2017

Study Record Updates

• Last Update Posted (Actual): November 22, 2019
• Last Update Submitted That Met QC Criteria: November 5, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Adherence; Hair
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome; 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; HIV Fusion Inhibitors; Viral Fusion Protein Inhibitors; CCR5 Receptor Antagonists; Tenofovir; Emtricitabine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Maraviroc; Dolutegravir
• Other Study ID Numbers: 17-0546; 1R01AI122319-01 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No