Clinical trial NCT02431273: Safety and Pharmacokinetic Study of HIV Prophylaxis Using Antiretroviral Intravaginal Rings in Healthy Women
Official title: Open-Label Safety and Pharmacokinetic Study of Single (TDF), Dual (TDF-FTC), and Triple ARV IVR (TDF-FTC-MVC) in Healthy Women
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Human Immunodeficiency Virus (HIV) Prophylaxis
Keywords: TDF
FTC
MVC
TDF-FTC
TDF-FTC-MVC
IVR
ARV
Lead sponsor: Auritec Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: The University of Texas Medical Branch, Galveston
name: Oak Crest Institute of Science
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2015-05-01
Enrollment: 10
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: This study will evaluate the hypothesis that intravaginal rings (IVRs) can safely and in a sustained fashion, deliver the antiretroviral (ARV) drugs - tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and maraviroc (MVC), in healthy women when used in the following drug combinations: 1) TDF ("Single" IVR); 2) TDF-FTC ("Dual" IVR) and; 3) TDF-FTC-MVC ("Triple" IVR).

TDF = tenofovir disoproxil fumarate; FTC = emtrcitabine; MVC = maraviroc

Detailed description: The broad long term goal of this project is to empower women to protect themselves from HIV through woman-controlled sustained local delivery of ARTs via intravaginal rings. The short-term general investigational plan is to evaluate IVRs releasing TDF, TDF-FTC and TDF-FTC-MVC in healthy women for up to 7 days in an open-label study to determine safety and drug concentrations in plasma and cervicovaginal lavage and secretions. Additional exploratory studies will be considered and planned based in part on the results obtained in this study. The long-term investigational plan is to evaluate the safety and efficacy of sustained release TDF, TDF-FTC and TDF-FTC-MVC for their ability to decrease HIV transmission to vulnerable women.

Eligibility criteria: Inclusion Criteria:

* Provides written informed consent
* Healthy female 18-45 years of age
* HIV negative per subject report and results of screening examination
* Negative for sexually transmitted diseases in the past 3 months and at screening exam
* No history of genital herpes simplex I or II per subject report
* Currently using contraception with plans to continue throughout the study duration or having sex with females only
* Pre-menopausal with a regular menstrual cycle with at least 21 days between menses and no history of intermenstrual bleeding or with suppressed menstrual cycle by hormonal contraception such as Depo-Provera or continuous oral contraceptive agents
* Subjects must agree to abstain from vaginal, anal, and oral sex throughout the first week of each dosing period and then use condoms for vaginal/rectal intercourse until after the final visit for use of each IVR
* Subjects must agree to not douche or use any vaginal product other than the Single, Dual and Triple ARV IVRs, including lubricants, feminine hygiene products, and vaginal drying agents throughout the dosing period and until after the final visit
* Subjects must agree to blood draws and vaginal exams throughout the course of the study

Exclusion Criteria:

* HIV positive by subject report or results of screening examination
* Positive history for autoimmune disease
* Abnormal genital exam defined as grade 1 or higher adverse event by DAIDS genital AE grading table
* Abnormal ALT or AST or Hepatitis B infection
* Active vaginal infection as determined by site IoR
* Abnormal renal function (defined as a creatinine clearance of \<50mL/min/1.73 m2)
* Pregnant or less than 6 months post-partum or current lactation
* Current use of an IVR (i.e., Nuvaring, Estring, Femring)
* History of TDF, FTC, and MVC use and/or adverse reaction to any of these drugs
* History of adverse reaction to silicone
* History of toxic shock syndrome
* Currently receiving chemotherapy or immunosuppressive agents
* Use of investigative drugs within 30 days or 5 half-lives
* Currently using or suspected to be using non-therapeutic injection drugs

Primary outcomes:
measure: Number of Participants With Specific Graded Adverse Events in Single, Dual, and Triple Antiretroviral (ARV) Intravaginal Rings (IVRs)
timeFrame: Days 0-21 following insertion of each IVR.
measure: Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Cervicovaginal Fluid (CVF)
timeFrame: Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).
measure: Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Cervicovaginal Lavage (CVL)
timeFrame: Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).
measure: Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Vaginal Tissue
timeFrame: Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).
measure: Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Plasma
timeFrame: Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).
measure: Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Terminal Half-life
timeFrame: Time points at which outcome measure was assessed are Day 7 (day of IVR removal) and daily up to 14 days.
Secondary outcomes:
measure: Acceptability of the IVRs
timeFrame: Days 0-21 following insertion of each IVR.
Other outcomes:
Locations:
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
Study officials:
affiliation: University of Texas Medical Branch (UTMB)
name: Kathleen L Vincent, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Vincent KL, Moss JA, Marzinke MA, Hendrix CW, Anton PA, Pyles RB, Guthrie KM, Dawson L, Olive TJ, Butkyavichene I, Churchman SA, Cortez JM Jr, Fanter R, Gunawardana M, Miller CS, Yang F, Rosen RK, Vargas SE, Baum MM. Safety and pharmacokinetics of single, dual, and triple antiretroviral drug formulations delivered by pod-intravaginal rings designed for HIV-1 prevention: A Phase I trial. PLoS Med. 2018 Sep 28;15(9):e1002655. doi: 10.1371/journal.pmed.1002655. eCollection 2018 Sep.
citation: Moss JA, Butkyavichene I, Churchman SA, Gunawardana M, Fanter R, Miller CS, Yang F, Easley JT, Marzinke MA, Hendrix CW, Smith TJ, Baum MM. Combination Pod-Intravaginal Ring Delivers Antiretroviral Agents for HIV Prophylaxis: Pharmacokinetic Evaluation in an Ovine Model. Antimicrob Agents Chemother. 2016 May 23;60(6):3759-66. doi: 10.1128/AAC.00391-16. Print 2016 Jun.