Clinical trial NCT02722343: Exploratory Pharmacodynamic Study of Tenofovir-Based Products
Official title: Phase I Exploratory Pharmacodynamic Study of Tenofovir-Based Products
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV
Lead sponsor: CONRAD
Sponsor class: OTHER
Collaborators: name: Eastern Virginia Medical School
name: University of North Carolina
name: Agility Clinical, Inc.
First posted: 2016-03-30
Enrollment: 25
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL

Brief summary: 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).

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.

Eligibility criteria: 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

Primary outcomes:
measure: p24 antigen production in cervico-vaginal tissues infected with HIV
timeFrame: Day 14
measure: Analysis of integrated DNA
timeFrame: Day 14
measure: Anti-HIV activity in cervicovaginal fluid (CVF)
timeFrame: Day 14
Secondary outcomes:
measure: Cervicovaginal tissue, fluid and plasma concentrations of tenofovir
timeFrame: Day 14
measure: Cervicovaginal tissue concentration of tenofovir diphosphate
timeFrame: Day 14
measure: Cervicovaginal tissue, fluid and plasma concentrations of emtricitabine
timeFrame: Day 14
measure: Cervicovaginal tissue concentration of emtricitabine triphosphate
timeFrame: Day 14
measure: Endogenous nucleotide concentrations in cervicovaginal tissue
timeFrame: Day 14
Other outcomes:
measure: Adherence markers in used IVRs
timeFrame: Day 14
Locations:
city: Norfolk
country: United States
facility: Eastern Virginia Medical School
state: Virginia
Study officials:
affiliation: Eastern Virginia Medical School
name: Andrea R Thurman, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.