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

NCT02431273 | Completed Early Phase 1 Results

• 2 other identifiers: ARV-IVR 012R44HD075636-02
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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

Conditions

Human Immunodeficiency Virus (HIV) Prophylaxis

Keywords

TDF; FTC; MVC; TDF-FTC; TDF-FTC-MVC; IVR; ARV

Outcome Measures

Primary Outcomes (6)

• 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 Outcomes (1)

• Acceptability of the IVRs

  Days 0-21 following insertion of each IVR.

Study Arms (3)

TDF (Single IVR)

EXPERIMENTAL

All subjects will be asked to wear "Single" (TDF) IVRs for 7 days.

Drug: TDF IVR

TDF-FTC (Dual IVR)

EXPERIMENTAL

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

TDF-FTC-MVC (Triple IVR)

EXPERIMENTAL

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

Interventions

TDF IVR DRUG

Also known as: Single IVR

TDF (Single IVR)

TDF-FTC IVR DRUG

Also known as: Dual IVR

TDF-FTC (Dual IVR)

TDF-FTC-MVC IVR DRUG

Also known as: Triple IVR

TDF-FTC-MVC (Triple IVR)

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Auritec Pharmaceuticals: lead
• The University of Texas Medical Branch, Galveston: collaborator
• Oak Crest Institute of Science: collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

University of Texas Medical Branch

Galveston, Texas, 77555-0587, United States

Location

Related Publications (2)

• 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.

  PMID: 30265679 DERIVED

• 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.

  PMID: 27067321 DERIVED

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Limitations and Caveats

The study's main limitations include the small sample size, short duration (7 days), and the lack of FTC triphosphate measurements in vaginal tissue biopsies.

Results Point of Contact

• Title: Sarjan Shah
• Organization: Auritec Pharmaceuticals

sshah@auritecpharma.com

909-210-9715

Study Officials

• Kathleen L Vincent, MD

  University of Texas Medical Branch (UTMB)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 4, 2014
• First Posted: May 1, 2015
• Study Start: June 1, 2015
• Primary Completion: December 1, 2016
• Study Completion: December 1, 2016
• Last Updated: July 2, 2019
• Results First Posted: July 2, 2019

Record last verified: 2019-06

Locations

US (1)