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

Early Phase 1

Completed

Conditions: Human Immunodeficiency Virus (HIV) Prophylaxis

Interventions: Drug: TDF IVR
Drug: TDF-FTC IVR
Drug: TDF-FTC-MVC IVR

Registration Number: NCT02431273

Lead Sponsor: Auritec Pharmaceuticals

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 10

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
TDF (Single IVR)	TDF IVR	All subjects will be asked to wear "Single" (TDF) IVRs for 7 days.
TDF-FTC (Dual IVR)	TDF-FTC 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.
TDF-FTC-MVC (Triple IVR)	TDF-FTC-MVC 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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Specific Graded Adverse Events in Single, Dual, and Triple Antiretroviral (ARV) Intravaginal Rings (IVRs)	Days 0-21 following insertion of each IVR.	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 Lavage (CVL)	Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).	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	Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).	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	Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).	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	Time points at which outcome measure was assessed are Day 7 (day of IVR removal) and daily up to 14 days.	Drug concentrations \[tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and maraviroc (MVC)\] in terminal half-life were evaluated for each IVR combination.
Pharmacokinetics of the Single, Dual and Triple ARV IVRs: Cervicovaginal Fluid (CVF)	Time points at which outcome measure was assessed are Days 2 (after IVR insertion) and 7 (day of IVR removal).	Drug concentrations \[tenofovir (TFV), tenofovir disoproxil fumarate (TDF), emtricitabine (FTC) and maraviroc (MVC)\] in cervicovaginal fluids (CVF) for each IVR combination.

Secondary Outcome Measures

Name	Time	Method
Acceptability of the IVRs	Days 0-21 following insertion of each IVR.	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.