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

Primary Purpose

Human Immunodeficiency Virus (HIV) Prophylaxis

Status

Completed

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

TDF IVR

TDF-FTC IVR

TDF-FTC-MVC IVR

About this trial

This is an interventional prevention trial for Human Immunodeficiency Virus (HIV) Prophylaxis focused on measuring TDF, FTC, MVC, TDF-FTC, TDF-FTC-MVC, IVR, ARV

Eligibility Criteria

18 Years - 45 Years (Adult)FemaleAccepts Healthy Volunteers

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

Sites / Locations

University of Texas Medical Branch

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

TDF (Single IVR)

TDF-FTC (Dual IVR)

TDF-FTC-MVC (Triple IVR)

Arm Description

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

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.

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.

Outcomes

Primary Outcome Measures

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).

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.

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.

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.

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.

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.

Secondary Outcome Measures

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.

Full Information

NCT ID

NCT02431273

First Posted

August 4, 2014

Last Updated

June 25, 2019

Sponsor

Auritec Pharmaceuticals

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT02431273

Brief Title

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

2. Study Status

Record Verification Date

June 2019

Overall Recruitment Status

Completed

Study Start Date

June 2015 (Actual)

Primary Completion Date

December 2016 (Actual)

Study Completion Date

December 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Auritec Pharmaceuticals

Collaborators

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

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Human Immunodeficiency Virus (HIV) Prophylaxis

Keywords

TDF, FTC, MVC, TDF-FTC, TDF-FTC-MVC, IVR, ARV

7. Study Design

Primary Purpose

Prevention

Study Phase

Early Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

10 (Actual)

8. Arms, Groups, and Interventions

Arm Title

TDF (Single IVR)

Arm Type

Experimental

Arm Description

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

Arm Title

TDF-FTC (Dual IVR)

Arm Type

Experimental

Arm Description

Arm Title

TDF-FTC-MVC (Triple IVR)

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

TDF IVR

Other Intervention Name(s)

Single IVR

Intervention Type

Drug

Intervention Name(s)

TDF-FTC IVR

Other Intervention Name(s)

Dual IVR

Intervention Type

Drug

Intervention Name(s)

TDF-FTC-MVC IVR

Other Intervention Name(s)

Triple IVR

Primary Outcome Measure Information:

Title

Number of Participants With Specific Graded Adverse Events in Single, Dual, and Triple Antiretroviral (ARV) Intravaginal Rings (IVRs)

Description

Time Frame

Days 0-21 following insertion of each IVR.

Title

Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Cervicovaginal Fluid (CVF)

Description

Drug concentrations [tenofovir (TFV), tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and maraviroc (MVC)] in cervicovaginal fluids (CVF) for each IVR combination.

Time Frame

Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).

Title

Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Cervicovaginal Lavage (CVL)

Description

Drug concentrations [tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and maraviroc (MVC)] in cervicovaginal lavage (CVL) were evaluated for each IVR combination.

Time Frame

Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).

Title

Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Vaginal Tissue

Description

Time Frame

Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).

Title

Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Plasma

Description

Drug concentrations [tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and maraviroc (MVC)] in plasma were evaluated for each IVR combination.

Time Frame

Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).

Title

Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Terminal Half-life

Description

Drug concentrations [tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and maraviroc (MVC)] in terminal half-life were evaluated for each IVR combination.

Time Frame

Time points at which outcome measure was assessed are Day 7 (day of IVR removal) and daily up to 14 days.

Secondary Outcome Measure Information:

Title

Acceptability of the IVRs

Description

Time Frame

Days 0-21 following insertion of each IVR.

10. Eligibility

Sex

Female

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

45 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kathleen L Vincent, MD

Organizational Affiliation

University of Texas Medical Branch (UTMB)

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Texas Medical Branch

City

Galveston

State/Province

Texas

ZIP/Postal Code

77555-0587

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

30265679

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.

Results Reference

derived

PubMed Identifier

27067321

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.

Results Reference

derived

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

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