Project ADHERE: Clinical Proof-of-Concept of a Tenofovir (TFV) Aptamer-Based Biosensor

Study Overview
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Brief Summary
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Truvada®, an oral pill comprised of two anti-retroviral compounds, emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), is currently the only drug combination approved for pre-exposure prophylaxis (PrEP) in women exposed to high HIV risk through vaginal acquisition. Adherence to the one pill per day regimen is crucial for its effectiveness in reducing the risk of acquiring HIV. Currently, there is no available point of care diagnostic test to quickly measure blood levels of tenofovir in the clinic. This study will determine whether a tenofovir (TFV) aptamer-based biosensor (aptasensor) can detect TFV in biological fluids from women randomized to different dosing regimens representing high and low adherence.

Detailed Description
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Project ADHERE is a pilot, prospective, randomized study which will screen approximately 20 healthy, non-pregnant, HIV negative, premenopausal women (aged 18-50) at Eastern Virginia Medical School (EVMS) who are not at risk of pregnancy and are at low risk for sexually transmitted infections (STIs) in order to have approximately 14 women complete all study visits. The women will be randomized to one of two different dosing regimens of Truvada for up to 14 days. The low adherence cohort will take a total of 3 Truvada pills per week while the high adherence cohort will be assigned to take daily dosing, 7 pills per week. At screening (visit 1), we will screen women for HIV-1 and perform STI tests and serum screening for HepB and creatinine clearance prior to commencing oral PrEP, consistent with oral PrEP initiation guidelines. After screening labs return, they will come to the clinic for visit 2 when baseline blood, urine, and vaginal fluid will be collected, randomize participants to the dosing regimen, watch the participants ingest the first dose, and then direct to them to take subsequent doses in their homes. Reminder text messages will be sent to the participants to facilitate doses being taken at the same time of day upon which they will text message the coordinator after ingesting the pill. Participants will return 24 hours, 7 days, and 14 days after visit 2 for pre-dose collection of blood, urine, and vaginal fluid samples (visits 3, 4, and 5, respectively). For all visits, participants will not to take the next prescribed dose before coming to the clinic. Once samples are collected, participants will ingest the next scheduled pill. However, for the high adherence regimen, the women will take their last dose on day 14 and then come to the clinic 24 hours later on day 15 for collection of samples. Regardless of regimen, sample collection will take place no earlier than 24 hours after last dosing to prevent white coat effects. Samples will be brought to the laboratory for processing and eventual measurement of TFV levels by the TFV aptasensor. Aliquots of plasma and urine will also be analyzed by LC-MS/MS so sensitivity and specificity of the aptasensor can be determined. The ability of the TFV aptasensor to distinguish levels associated with high and low adherence will also be assessed.

Official Title
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Project ADHERE: Clinical Proof-of-Concept of a Tenofovir (TFV) Aptamer-Based Biosensor for Determining Adherence Using Different Dosing Regimens of Disoproxil Fumarate/Emtricitabine (TDF/FTC)

Conditions
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HIV/AIDS, Adherence, Medication, Drug Use

Intervention / Treatment
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* Drug: Tenofovir Disoproxil Fumarate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 to 50 years, inclusive General good health (by volunteer history and per investigator judgment) without any clinically significant systemic disease (including, but not limited to significant liver disease/hepatitis, gastrointestinal disease, kidney disease, thyroid disease, osteoporosis or bone disease, and diabetes) and with an intact gastrointestinal tract, uterus and cervix. Estimated calculated creatinine clearance (eCcr) of at least 80 mL/min Body Mass Index (BMI) of ≥18 and <35kg/m2; and a total body weight >45 kg (99.2 lbs) Willing to give voluntary consent and sign an informed consent form Willing and able to comply with protocol requirements, including swallowing tablets Must be protected from pregnancy by: Condoms Hormonal contraceptives Copper or Levonorgestrel IUD Sterilization of either partner Heterosexual abstinence Same sex relationship If in a relationship, must be in a mutually monogamous relationship with a partner who is not known to be HIV positive and has no known risk of STIs Exclusion Criteria: Currently pregnant Currently breastfeeding or planning to breastfeed during the course of the study In the last three months, diagnosed with or treated for any STI Positive test for HIV, or Hepatitis B surface antigen (HBsAg) Systemic use in the last two weeks or anticipated use during the study of any of the following: antiretrovirals (e.g. Viread®, Atripla®, Emtriva®, or Complera®), or drugs that may interact with TFV (e.g., protease inhibitors, anticonvulsants, antimycobacterials, St. John's Wort). Participation in any other investigational trial with use of a drug/device within the last 30 days or planned participation in any other investigational trial with use of a drug/device during the study Grade 2 or higher laboratory abnormality, per the 2014 update of the Division of AIDS, National Institute of Allergy and Infectious Disease (DAIDS) Table for Grading the Severity of Adverse Events, or clinically significant laboratory abnormality as determined by the clinician Abnormal finding on laboratory or physical examination or a social or medical condition in the volunteer which, in the opinion of the investigator, would make participation in the study unsafe or would complicate interpretation of data

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

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: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Women will be randomized into one of two groups: high adherence (7 pills/week) and how adherence (3 pills/week)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Adherence<br>TDF/FTC (300/200 mg), 7 pills/week. Total of 14 pills | Drug: Tenofovir Disoproxil Fumarate<br>* Women will take 1 pill orally according the dosing regimen of the arm to which they are assigned<br>* Other names: Truvada;|
| Experimental: Low Adherence<br>TDF/FTC (300/2200 mg), 3 pills/week. Total of 6 pills | Drug: Tenofovir Disoproxil Fumarate<br>* Women will take 1 pill orally according the dosing regimen of the arm to which they are assigned<br>* Other names: Truvada;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline TFV levels in plasma | TFV levels will be measured by the TFV aptasensor and compared to LC-MS/MS values | Baseline (pre-dose) | 
| Levels of TFV in plasma after different lengths of time post-first dose | TFV levels will be measured by the TFV aptasensor and compared to LC-MS/MS values | 24 hours | 
| Levels of TFV in plasma after different lengths of time post-first dose | TFV levels will be measured by the TFV aptasensor and compared to LC-MS/MS values | 7 days | 
| Levels of TFV in plasma after different lengths of time post-first dose | TFV levels will be measured by the TFV aptasensor and compared to LC-MS/MS values | 14 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Baseline TFV levels in urine | TFV levels will be measured by the TFV aptasensor and compared to LC-MS/MS values (urine only) | Baseline (pre-dose) | 
| Levels of TFV in urine after different lengths of time post-first dose | TFV levels will be measured by the TFV aptasensor and compared to LC-MS/MS values | 24 hours | 
| Levels of TFV in urine after different lengths of time post-first dose | TFV levels will be measured by the TFV aptasensor and compared to LC-MS/MS values | 7 days | 
| Levels of TFV in urine after different lengths of time post-first dose | TFV levels will be measured by the TFV aptasensor and compared to LC-MS/MS values | 14 days | 
| Baseline TFV levels in vaginal fluid | TFV levels will be measured by the TFV aptasensor | Baseline (pre-dose) | 
| Levels of TFV in vaginal fluid after different lengths of time post-first dose | TFV levels will be measured by the TFV aptasensor | 24 hours | 
| Levels of TFV in vaginal fluid after different lengths of time post-first dose | TFV levels will be measured by the TFV aptasensor | 7 days | 
| Levels of TFV in vaginal fluid after different lengths of time post-first dose | TFV levels will be measured by the TFV aptasensor | 14 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV PrEP, biosensor, tenofovir