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

HIV Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02904369
• Other study ID #: A15-137
• Status: Completed
• Phase: Phase 1
• First received: September 1, 2016
• Last updated: February 16, 2018
• Start date: October 6, 2016
• Est. completion date: November 21, 2017

Study information

• Verified date: January 2018
• Source: CONRAD
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 73
• Est. completion date: November 21, 2017
• Est. primary completion date: November 21, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• HIV

Intervention

Drug:
• Emtricitabine

• Tenofovir alafenamide

• Tenofovir disoproxil

Locations

Country	Name	City	State
Dominican Republic	Profamilia	Santo Domingo
United States	Eastern Virginia Medical School Clinical Research Center	Norfolk	Virginia
United States	Magee-Womens Research Institute and Foundation	Pittsburgh	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
CONRAD	Agility Clinical, Inc., United States Agency for International Development (USAID)

Countries where clinical trial is conducted

United States,  Dominican Republic, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Anti-HSV activity in cervicovaginal and rectal fluid (mean percentage inhibition of plaque forming units (pfu) in Vero cells infected with HSV-2)	Anti-HSV activity in CV and rectal fluid after a single dose, and after two weeks of daily dosing compared to baseline	Baseline, Day 17
Other	Number of participants with gastrointestinal adverse events	Changes from baseline in adverse events	Baseline, Day 17
Other	Number of participants with systemic safety laboratory abnormalities	Changes from baseline in safety laboratory abnormalities	Baseline, Day 17
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	Number of participants with Grade 2 or higher adverse events	Changes from baseline in adverse events	Baseline, Day 17