PK and PD Study of Oral F/TAF for HIV Prevention

Study Overview
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Brief Summary
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This multi-center Phase I study is designed to characterize the PK and PD of F/TAF oral tablets to assess systemic and genital tract bioavailability in healthy women. The oral tablets to be used in the study are F/TAF (200/10 mg), F/TAF (200/25 mg) and F/TDF (200/300 mg, Truvada). Samples will be obtained before, during and after dosing in two study phases.

Detailed Description
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The purpose of this multi-center Phase I protocol, titled Exploratory Pharmacokinetic and Pharmacodynamic Study of Oral F/TAF for the Prevention of HIV Acquisition is to assess local and systemic pharmacokinetics (PK), pharmacodynamics (PD), and safety characteristics of three oral tablets: F/TAF (200/10 mg), F/TAF (200/25 mg) and F/TDF (200/300 mg). The study will enroll healthy, non-pregnant, HIV negative, premenopausal women (aged 18-50) who are not at risk of pregnancy and will have two phases: a Single Dose phase (one site only) and a Multiple Dose phase (all three sites). The enrollment goal is for approximately 72 participants to complete the study. All 72 women are expected to undergo the Multiple Dose phase and the 24 women expected to complete the study at the EVMS site are also expected to undergo the Single Dose phase. In the Single Dose phase, approximately 24 women will be randomized to one of two products: F/TAF (200/25 mg) or F/TDF (200/300 mg), and will undergo blood, cervicovaginal (CV), and rectal sample collections before and after a single dose for PK and PD assessments. In the Multiple Dose phase, approximately 72 women will be randomized to one of three products: F/TAF (200/10 mg), F/TAF (200/25 mg) or F/TDF (200/300 mg), and will undergo blood, CV, and rectal sample collections for PK and PD assessments before, during and after two weeks of daily dosing.

Official Title
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Exploratory Pharmacokinetic and Pharmacodynamic Study of Oral F/TAF for the Prevention of HIV Acquisition

Conditions
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HIV

Intervention / Treatment
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* Drug: Emtricitabine
* Drug: Tenofovir alafenamide
* Drug: Tenofovir disoproxil


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. History of regular menstrual cycles (for cycling women), by volunteer report 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) History of Pap smears and follow-up consistent with standard clinical practice as outlined in the Study Manual or willing to undergo a Pap smear at Visit 1 Willing to give voluntary consent and sign an informed consent form Willing and able to comply with protocol requirements, including swallowing tablets May not be using progestin-only hormonal contraception and must be protected from pregnancy by: Condoms Combined hormonal contraceptive (acceptable, but recruitment efforts should be made to limit as much as possible the number of women using them in the study, such that they do not represent the majority of participants.) Copper 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 sexually transmitted infections (STIs) Exclusion Criteria: Currently pregnant Currently breastfeeding or planning to breastfeed during the course of the study History of sensitivity/allergy to any component of the study products, topical anesthetic, or to both silver nitrate and Monsel's solution In the last three months, diagnosed with or treated for any STI Positive test for Trichomonas vaginalis, Neisseria gonorrhea, Chlamydia trachomatis, HIV, or Hepatitis B surface antigen (HBsAg) Symptomatic bacterial vaginosis (BV) Current, active Hepatitis C infection Chronic or acute vulvar or vaginal symptoms (pain, irritation, spotting/bleeding, discharge, etc.) Known bleeding disorder that could lead to prolonged or continuous bleeding with biopsy Systemic use in the last two weeks or anticipated use during the study of any of the following: corticosteroids, antibiotics, anticoagulants or other drugs known to prolong bleeding and/or clotting, antifungals, or antivirals or antiretrovirals (e.g. acyclovir, valacyclovir, Viread®, Atripla®, Emtriva®, or Complera®), or drugs that may interact with TAF (e.g., protease inhibitors, anticonvulsants, antimycobacterials, St. John's Wort). See Table 1 from the Patient Information brochure below: Current or anticipated chronic use of NSAIDs or Tylenol for the duration of the study Positive urine drug screen, or known current drug or alcohol abuse which could impact study compliance. Note: therapeutic use of benzodiazepines is acceptable; investigator may discuss with CONRAD participants that may be eligible for enrollment despite a positive drug screen (e.g., false positives, use of cold medications). Participation in any other investigational trial with use of a drug/device within the last 30 days or planned participation in any other investigational with use of a drug/device trial 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: F/TAF 200/10<br>Emtricitabine (FTC) + Tenofovir Alafenamide (TAF) (200/10 mg) | Drug: Emtricitabine<br> <br> Drug: Tenofovir alafenamide<br> <br> |
| Experimental: F/TAF 200/25<br>Emtricitabine (FTC) + Tenofovir Alafenamide (TAF) (200/25 mg) | Drug: Emtricitabine<br> <br> Drug: Tenofovir alafenamide<br> <br> |
| Active Comparator: F/TDF 200/300<br>Emtricitabine (FTC) + Tenofovir Disoproxil Fumarate (TDF) (200/300 mg) | Drug: Emtricitabine<br> <br> Drug: Tenofovir disoproxil<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma, cervicovaginal and rectal fluid concentrations of tenofovir alafenamide (TAF), tenofovir (TFV), and emtricitabine (FTC) | Concentrations after use of study tablets after single dose, and during (plasma) and after two weeks of daily dosing | Day 17 | 
| PBMC concentrations of tenofovir-diphosphate (TFV-DP), emtricitabine-triphosphate (FTC-TP), deoxyadenosine triphosphate (dATP) and deoxycytidine triphosphate (dCTP) | Concentrations after use of study tablets after single dose, and during and after two weeks of daily dosing | Day 17 | 
| Cervicovaginal tissue concentrations of TAF, TFV, FTC, TFV-DP, FTC-TP, dATP and dCTP | Concentrations after use of study tablets after single dose, and after two weeks of daily dosing | Day 17 | 
| Pharmacokinetic parameter (Cmax) of F/TAF in the systemic compartment | Concentrations after use of study tablets after single dose, and during and after two weeks of daily dosing | Day 17 | 
| p24 antigen production in cervicovaginal and rectal tissue infected with HIV | p24 antigen production in CV tissue infected with HIV ex vivo after a single dose, and in CV and rectal tissue infected with HIV ex vivo after two weeks of daily dosing compared to baseline | Day 17 | 
| Anti-HIV activity in cervicovaginal and rectal fluid (TZM-bl inhibition measured as mean percent reduction compared to control) | Anti-HIV activity in CV and rectal fluid after a single dose, and after two weeks of daily dosing compared to baseline | Day 17 | 
| Pharmacokinetic parameter (Tmax) of F/TAF in the systemic compartment | Concentrations after use of study tablets after single dose, and during and after two weeks of daily dosing | Day 17 | 
| Pharmacokinetic parameter (AUC) of F/TAF in the systemic compartment | Concentrations after use of study tablets after single dose, and during and after two weeks of daily dosing | Day 17 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Grade 2 or higher adverse events | Changes from baseline in adverse events | Baseline, Day 17 |