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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Human Immunodeficiency Virus (HIV) Prophylaxis

Intervention / Treatment
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* Drug: TDF IVR
* Drug: TDF-FTC IVR
* Drug: TDF-FTC-MVC IVR


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TDF (Single IVR)<br>All subjects will be asked to wear Single (TDF) IVRs for 7 days. | Drug: TDF IVR<br> <br> * Other names: Single IVR;|
| Experimental: TDF-FTC (Dual IVR)<br>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<br> <br> * Other names: Dual IVR;|
| Experimental: TDF-FTC-MVC (Triple IVR)<br>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<br> <br> * Other names: Triple IVR;|

What is the study measuring?
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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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TDF, FTC, MVC, TDF-FTC, TDF-FTC-MVC, IVR, ARV