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

NCT02904369 | Completed Phase 1

• 1 other identifier: A15-137
• Study Type: interventional
• Target: 73
• Locations: 2 countries
• Sites: 3

Brief Summary

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.

Conditions

HIV

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (1)

• Number of participants with Grade 2 or higher adverse events

  Baseline, Day 17

Other Outcomes (3)

• Anti-HSV activity in cervicovaginal and rectal fluid (mean percentage inhibition of plaque forming units (pfu) in Vero cells infected with HSV-2)

  Baseline, Day 17

• Number of participants with gastrointestinal adverse events

  Baseline, Day 17

• Number of participants with systemic safety laboratory abnormalities

  Baseline, Day 17

Study Arms (3)

F/TAF 200/10

EXPERIMENTAL

Emtricitabine (FTC) + Tenofovir Alafenamide (TAF) (200/10 mg)

Drug: Emtricitabine; Drug: Tenofovir alafenamide

F/TAF 200/25

EXPERIMENTAL

Emtricitabine (FTC) + Tenofovir Alafenamide (TAF) (200/25 mg)

Drug: Emtricitabine; Drug: Tenofovir alafenamide

F/TDF 200/300

ACTIVE COMPARATOR

Emtricitabine (FTC) + Tenofovir Disoproxil Fumarate (TDF) (200/300 mg)

Drug: Emtricitabine; Drug: Tenofovir disoproxil

Interventions

Emtricitabine DRUG

F/TAF 200/10; F/TAF 200/25; F/TDF 200/300

Tenofovir alafenamide DRUG

F/TAF 200/10; F/TAF 200/25

Tenofovir disoproxil DRUG

F/TDF 200/300

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• CONRAD: lead
• United States Agency for International Development (USAID): collaborator
• Agility Clinical, Inc.: collaborator

Study Sites (3)

Magee-Womens Research Institute and Foundation

Pittsburgh, Pennsylvania, 15213, United States

Location

Eastern Virginia Medical School Clinical Research Center

Norfolk, Virginia, 23507, United States

Location

Profamilia

Santo Domingo, Dominican Republic

Location

Related Publications (2)

• Ouattara LA, Thurman AR, Jacot TA, Cottrell M, Sykes C, Blake K, Fang X, Ju S, Vann NC, Schwartz J, Doncel GF. Genital Mucosal Drug Concentrations and anti-HIV Activity in Tenofovir-Based PrEP Products: Intravaginal Ring vs. Oral Administration. J Acquir Immune Defic Syndr. 2022 Jan 1;89(1):87-97. doi: 10.1097/QAI.0000000000002820.

  PMID: 34878438 DERIVED

• Thurman AR, Schwartz JL, Cottrell ML, Brache V, Chen BA, Cochon L, Ju S, McGowan I, Rooney JF, McCallister S, Doncel GF. Safety and Pharmacokinetics of a Tenofovir Alafenamide Fumarate-Emtricitabine based Oral Antiretroviral Regimen for Prevention of HIV Acquisition in Women: A Randomized Controlled Trial. EClinicalMedicine. 2021 May 23;36:100893. doi: 10.1016/j.eclinm.2021.100893. eCollection 2021 Jun.

  PMID: 34041459 DERIVED

MeSH Terms

Interventions

Emtricitabine; tenofovir alafenamide; Tenofovir

Intervention Hierarchy (Ancestors)

Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 1, 2016
• First Posted: September 19, 2016
• Study Start: October 6, 2016
• Primary Completion: November 21, 2017
• Study Completion: November 21, 2017
• Last Updated: February 19, 2018

Record last verified: 2018-01

Data Sharing

• IPD Sharing: Will not share

Locations

DO (1); US (2)