Exploratory Pharmacodynamic Study of Tenofovir-Based Products

Phase I Exploratory Pharmacodynamic Study of Tenofovir-Based Products

This single site study is designed to describe and measure the efficacy of oral versus vaginal dosing of TFV-based products, specifically emtricitabine/tenofovir disoproxil fumarate oral tablets (Truvada) vs tenofovir intravaginal rings (IVR).

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: Tenofovir intravaginal ring; Drug: Truvada

Detailed Description

This study will compare an investigational intravaginal ring containing tenofovir (TFV) with an FDA approved medication in tablet form called Truvada®. It will assess and compare the ability of the tablet and intravaginal ring to prevent HIV transmission (human immunodeficiency virus, the virus that causes AIDS).

The study will enroll healthy, non-pregnant, HIV negative, premenopausal women (aged 18-50, with regular menstrual cycles) who are not at risk of pregnancy.

The enrollment goal is for 20 participants to complete the study.

Participants will be assigned to use one of the study products: oral tablet or intravaginal ring. Participants will take the oral tablet each day for 14 days or wear the intravaginal ring all day and night for 14 days/nights. Blood, genital fluid samples and genital tissue samples (biopsies) will be taken at two visits. These sample collections will take place before and after use of the assigned study product. The samples will be tested to:

1. Determine the levels of drug in the blood and genital tissue samples
2. See if the samples taken from the vagina and cervix after use of study product, provides protection from HIV in the laboratory
3. Ensure that the laboratory test used to measure HIV infection in the samples performs well when used repeatedly.

In addition this study will also evaluate the returned TFV rings to see whether they were used as instructed.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Eastern Virginia Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• 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
• Currently have regular menstrual cycles of 21-35 days by participant record

• Willing to abstain from vaginal intercourse and any other vaginal activity including use of vaginal products (tampons, spermicides, lubricants, and douches) other than study products:

  • 48 hours before Visit 2 until six days after Visit 2
  • 48 hours before Visit 3 until six days after Visit 4
• Vaginal and cervical anatomy that, in the opinion of the investigator, lends itself to easy genital tract sample collection
• Estimated calculated creatinine clearance (eCcr) of at least 60 mL/min
• 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

• Protected from pregnancy by one of the following:

  • sterilization of either partner
  • abstinence
  • same sex relationship
  • condoms
  • combined contraceptives (including oral, patch)
  • copper IUD
• Willing and able to comply with protocol requirements including swallowing tablets
• Willing to give voluntary consent and sign an informed consent form

Exclusion Criteria:

• History of hysterectomy
• Currently pregnant or within two calendar months from the last pregnancy outcome. Note: if recently pregnant must have had at least two spontaneous menses since pregnancy outcome
• Injection of Depo-Provera in the last 10 months or use of other progestin-only based contraceptive (including hormonal IUD)
• 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, by self report
• Positive test for Trichomonas vaginalis, Neisseria gonorrhea, Chlamydia trachomatis, HIV, or Hepatitis B surface antigen (HBsAg) Note: Women with a history of genital herpes who have been asymptomatic for at least three months may be considered for eligibility
• 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 (e.g., acyclovir, valacyclovir, Viread®, Atripla®, Emtriva®, or Complera®)
• Current or anticipated chronic use of NSAIDS, or Tylenol for the duration of 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 either the volunteer or which, in the opinion of the investigator, would make participation in the study unsafe or would complicate interpretation of data
• Known current drug or alcohol abuse which could impact study compliance
• Participation in any other investigational trial within the last 30 days or planned participation in any other investigational trial during the study
• History of gynecological procedures (including genital piercing) on the external genitalia, vagina or cervix within the last 14 days

Study Plan

How is the study designed?

Design Details

• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Tenofovir intravaginal ring; The tenofovir intravaginal ring (TFV IVR) is 55.0 mm in diameter, consisting of a single segment of polyurethane tubing with an outer diameter of 5.5 mm and filled with white TFV-containing paste. The IVR delivers 8-10mg/day of TFV.	Drug: Tenofovir intravaginal ring; The participant will wear the intravaginal ring consecutively for 14 days and nights. Following study product use and at study visit 4, blood and genital tract samples will be taken (to include cervico-vaginal fluid and tissue); Other Names: Tenofovir disoproxil fumarate intravaginal ring; TFV IVR
ACTIVE_COMPARATOR: Truvada oral tablets; The tablets contain 200mg emtricitabine combined with 300mg tenofovir disoproxil fumarate (300mg). The tablets are commercially available as Truvada. The tablets are blue, capsule-shaped, film-coated, debossed with "GILEAD" on one side and with "701" on the other side	Drug: Truvada; The participant will take the tablet for 14 days. taking one tablet each morning. Following study product use and at study visit 4, blood and genital tract samples will be taken (to include cervico-vaginal fluid and tissue); Other Names: Emtricitabine/tenofovir disoproxil fumarate tablets

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
p24 antigen production in cervico-vaginal tissues infected with HIV	• Assess p24 antigen production in cervicovaginal tissues infected ex vivo with HIV-1BaL at baseline and after using Truvada tablets or tenofovir intravaginal ring	Day 14
Analysis of integrated DNA	Integrated viral DNA in cervicovaginal tissues infected ex vivo with HIV-1BaL at baseline and after using Truvada tablets or tenofovir intravaginal ring	Day 14
Anti-HIV activity in cervicovaginal fluid (CVF)	Anti-HIV activity in cervicovaginal fluid at baseline and after using Truvada tablets and tenofovir intravaginal ring	Day 14

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cervicovaginal tissue, fluid and plasma concentrations of tenofovir	Concentrations after use of Truvada tablets and tenofovir intravaginal ring	Day 14
Cervicovaginal tissue concentration of tenofovir diphosphate	Concentrations after use of Truvada tablets and tenofovir intravaginal ring.	Day 14
Cervicovaginal tissue, fluid and plasma concentrations of emtricitabine	Concentrations after use of Truvada tablets and tenofovir intravaginal ring.	Day 14
Cervicovaginal tissue concentration of emtricitabine triphosphate	Concentrations after use of Truvada tablets and tenofovir intravaginal ring.	Day 14
Endogenous nucleotide concentrations in cervicovaginal tissue	Endogenous nucleotides; dATP and dCTP concentrations in cervicovaginal tissue after use of Truvada tablets and tenofovir intravaginal ring	Day 14

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adherence markers in used IVRs	Adherence biomarkers from used IVRs returned to clinic after two weeks of use	Day 14

Collaborators and Investigators

• Sponsor: CONRAD
• Collaborators: Eastern Virginia Medical School; University of North Carolina; Agility Clinical, Inc.
• Investigators: Principal Investigator: Andrea R Thurman, M.D., Eastern Virginia Medical School

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (ACTUAL): August 1, 2016
• Study Completion (ACTUAL): August 1, 2016

Study Registration Dates

• First Submitted: March 9, 2016
• First Submitted That Met QC Criteria: March 23, 2016
• First Posted (ESTIMATE): March 30, 2016

Study Record Updates

• Last Update Posted (ESTIMATE): September 2, 2016
• Last Update Submitted That Met QC Criteria: September 1, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: 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; Tenofovir; Emtricitabine; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
• Other Study ID Numbers: A15-140

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO