Safety and Pharmacokinetic Study of HIV Prophylaxis Using Antiretroviral Intravaginal Rings in Healthy Women

Open-Label Safety and Pharmacokinetic Study of Single (TDF), Dual (TDF-FTC), and Triple ARV IVR (TDF-FTC-MVC) in Healthy Women

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

Study Overview

• Status: Completed
• Conditions: Human Immunodeficiency Virus (HIV) Prophylaxis
• Intervention / Treatment: Drug: TDF IVR; Drug: TDF-FTC IVR; Drug: TDF-FTC-MVC IVR

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.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Galveston, Texas, United States, 77555-0587
      • University of Texas Medical Branch

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TDF (Single IVR); All subjects will be asked to wear "Single" (TDF) IVRs for 7 days.	Drug: TDF IVR; Other Names: Single IVR
Experimental: TDF-FTC (Dual IVR); If the TDF IVR is determined as safe, study participants will be asked to replace it with "Dual" (TDF-FTC) IVRs for 7 days. There will be follow-up visit between removal of a single IVR and replacing it with a dual IVR.	Drug: TDF-FTC IVR; Other Names: Dual IVR
Experimental: TDF-FTC-MVC (Triple IVR); If the TDF-FTC IVR is determined as safe, study participants will be asked to replace them with "Triple" (TDF-FTC-MVC) IVRs for 7 days. There will be follow-up visit between removal of a dual IVR and replacing it with a triple IVR.	Drug: TDF-FTC-MVC IVR; Other Names: Triple IVR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Specific Graded Adverse Events in Single, Dual, and Triple Antiretroviral (ARV) Intravaginal Rings (IVRs)	Number of Adverse Events (AEs) was recorded. Safety parameters were monitored for each IVR combination and the grading scale for each parameter followed the Female Genital Grading Table for Use in Microbicide Studies. AEs not included in that table were graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 2.0, November 2014 (Grade 1 = mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Potentially Life-Threatening).	Days 0-21 following insertion of each IVR.
Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Cervicovaginal Fluid (CVF)	Drug concentrations [tenofovir (TFV), tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and maraviroc (MVC)] in cervicovaginal fluids (CVF) for each IVR combination.	Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).
Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Cervicovaginal Lavage (CVL)	Drug concentrations [tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and maraviroc (MVC)] in cervicovaginal lavage (CVL) were evaluated for each IVR combination.	Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).
Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Vaginal Tissue	Drug concentrations [tenofovir disoproxil fumarate (TDF), tenofovir (TFV), tenofovir diphosphate (TFV-DP), emtricitabine (FTC) and maraviroc (MVC)] in vaginal tissue (VT) were evaluated for each IVR combination.	Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).
Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Plasma	Drug concentrations [tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and maraviroc (MVC)] in plasma were evaluated for each IVR combination.	Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).
Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Terminal Half-life	Drug concentrations [tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and maraviroc (MVC)] in terminal half-life were evaluated for each IVR combination.	Time points at which outcome measure was assessed are Day 7 (day of IVR removal) and daily up to 14 days.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acceptability of the IVRs	Acceptability of the IVRs was assessed through reported willingness to use the IVR for 28 days in a real-world setting on a likert scale, 1 being "not at all confident" to 5 being "completely confident" for Periods 1 and 2.	Days 0-21 following insertion of each IVR.

Collaborators and Investigators

• Sponsor: Auritec Pharmaceuticals
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); The University of Texas Medical Branch, Galveston; Oak Crest Institute of Science
• Investigators: Principal Investigator: Kathleen L Vincent, MD, University of Texas Medical Branch (UTMB)

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2015
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: August 4, 2014
• First Submitted That Met QC Criteria: April 30, 2015
• First Posted (Estimate): May 1, 2015

Study Record Updates

• Last Update Posted (Actual): July 2, 2019
• Last Update Submitted That Met QC Criteria: June 25, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: MVC; TDF; ARV; FTC; IVR; TDF-FTC; TDF-FTC-MVC
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome
• Other Study ID Numbers: ARV-IVR 01; 2R44HD075636-02 (U.S. NIH Grant/Contract)