Tenofovir disoproxil fumarate (TDF) is a prodrug of TFV, an adenosine nucleoside monophosphonate (nucleotide) derivative with potent antiretroviral (ARV) activity. TDF is licensed for the treatment of HIV-1 infection in the US, the European Union, Middle East, and Africa. TDF permeates cells more rapidly than TFV resulting in increased intracellular accumulation of TFV- diphosphate (TFV-DP), the active metabolite. TDF is more potent than TFV and inhibits HIV-1 and herpes simplex virus type 2 (HSV-2) infection in cell and tissue culture models at approximately 100-fold lower concentrations than TFV, suggesting that it may be an excellent candidate for prevention of HIV.~The study will take place at the Albert Einstein College of Medicine in Bronx, USA and the Thick Partners Study Clinic (Partners in Health Research and Development) in Thika, Kenya. This is the the second clinical study of the polyurethane TDF vaginal ring (TDF IVR-002) following the successful completion of a first-in-human study (TDF IVR-001). It is hypothesized that the TDF IVR will be safe and well tolerated among healthy, sexually active women in the US and Kenya. It is also hypothesized that there will be a favorable PK profile in sexually active women. The null hypothesis is that there will be no difference in the safety profile between the active product and the placebo.~Each participant will receive an IVR containing TDF or a placebo ring. The vaginal ring will be worn continuously for 14 days. It will be inserted into the vagina following cessation of participant's menses, by the study clinician at Visit 3 and removed by the study clinician at Visit 7. Each participant will be followed for 7 days following ring removal.~Building on the results of the first TDF IVR study in sexually abstinent women, a longer Phase 1 study was designed in order to assess the safety and PK of TDF IVR in sexually active women. Vaginal rings have been tested in several clinical trials in women 18 years of age and older and have been found to be safe. Given the drug release kinetics observed in vitro, in preclinical studies, and in the first Phase 1 study, TDF and TFV (formed following hydrolysis of the prodrug TDF) concentrations in CVF are expected to reach steady state within one day and within one month for tissue and maintain steady state concentrations for the duration of the planned 84 days of ring use. Sampling at multiple time points will provide information on drug kinetics, and, by sampling after ring removal how long drug persists. The latter may be important as behavior studies suggest that some women may remove a ring at time of menses or around sex. Tissue sampling in US women in the hours and days immediately following ring insertion will provide valuable information about early tissue levels and the time required to achieve drug concentrations needed for protection. To capture systemic absorption, blood will be sampled to determine drug concentrations in plasma and DBS. To capture the concentrations of drug within the genital tract, CVF will be collected from the posterior fornix using Dacron swabs. Cervical tissue sampling will be highly informative given that it is the likely site of drug action. However, biopsies must be taken sparingly as they are uncomfortable to some and alter the healing process. Accordingly, 2 biopsies for PK studies will be obtained in US women at Days 28 and 56 when the ring is changed, and at Day 84 when the final ring is removed. US women will also have an additional 2 biopsies collected at only 1 of 7 time-points (5 or 6 women per time-point at either 1 hour, 4 hours, 1, 7, 14, or 21 days after ring insertion, or 5-7 days after ring removal). Participants in Kenya will have 2 cervical biopsies collected at each of 2 study visits (Days 28 and 84). The study will be single-blinded because the TDF and placebo rings are not identical in appearance. All participants will be informed that 2 biopsies will be taken during study visits in which biopsies will be collected. Cervical biopsies will be obtained without local anesthetic. Participants may take acetaminophen before and/or after the biopsies are collected, if desired. Participants will be instructed to abstain from sex for 7 days after biopsy collection to allow adequate time to heal.~Primary Objective:~• Assess the safety of TDF IVR when used continuously for 84 days by healthy, HIV-uninfected, sexually active women, as compared with the placebo IVR~Secondary Objectives:~Examine systemic and genital tract PK of TDF release during and after 84 days of continuous IVR use in sexually active women~Evaluate the acceptability of the study IVR in HIV-uninfected, sexually active women over 84 days of use~This is a two-site, two-arm, randomized single blind placebo-controlled trial. The study population will include approximately 80 healthy, 18-45 year old females who are HIV-uninfected, non-pregnant, non-breastfeeding, sexually active and using contraception. Forty US women and 40 Kenyan women will be stratified by site and will be randomized 3:1 (30 TDF:10 placebo at each site).~The Kenya site will not initiate enrollment until an interim analysis is performed on the first 20 US women who have completed 30 days of ring use. Enrollment at both sites will include women using a copper intrauterine device (IUD) or a hormonal contraceptive method other than an IVR. To ensure participants are protected from pregnancy and sexually transmitted infections (STI) during study participation, condoms will be distributed at each study visit. As this is a Phase 1 trial of a TDF IVR, only healthy women with a low risk profile for HIV will be recruited and will be asked to wear a TDF or placebo IVR for 84 days. Participants will be strongly encouraged to include their male partner in the study. If participants are willing, education and counseling will be provided to male partners at all study visits and up to 20 males at the Thika site will be invited to participate in qualitative interviews if able and willing to provide written informed consent.~The approximate time to complete study enrollment is expected to be 12 months. Given the need to carefully screen and exclude women who are not able to comply to study procedures, we anticipate that the Thika site will not enroll more than 1 participant per week. Two study groups are planned at each site. All groups will be assigned to complete a total of 9 study visits (Screening [visit 1], Enrollment [visit 2], Day 14 [visit 3], 28 [visit 4], 42 [visit 5], 56 [visit 6], 70 [visit 7], 84 [visit 8], 89 [visit 9]). Each US participant will be asked to undergo additional PK sampling at one of the following time-points: either 1 hour (visit 2a), 4 hours (visit 2b), 1 (visit 2c), 7 (visit 2d), 14 (visit 3a), or 21 days (visit 3b) after ring insertion, or 5-7 (visit 9a) and 10-12 days (visit 10) after ring removal.~The two study groups are:~Reservoir-type polyurethane TDF IVR group;~Reservoir-type polyurethane Placebo IVR group;~The expected duration for participants is approximately 120 days (including a screening visit, an enrollment visit, 84 days of continuous IVR use, and 5-7 days following IVR removal). Participants will undergo Visit 2 within 28 days of screening. No study data will be collected after the Final Study/Early Termination Visit unless the participant is pregnant at the Final Study/Early Termination Visit. Participants who have AEs at the Final Study/Early Termination Visit that have not resolved or stabilized will be followed beyond the Final Study/Early Termination Visit until a clinically acceptable resolution of the AE(s) is confirmed and documented. Clinical acceptability of resolution will be determined by the Project Leader (PL) in consultation with the Protocol Safety Review Team (PSRT). Participants identified as infected with HIV during the study will be managed in accordance with the study protocol. Participants who are pregnant at the Final Study/Early Termination Visit may be followed in accordance with procedures described in the study protocol.
This prospective, two-site, two-arm, randomized, single-blind, placebo-controlled trial will examine the safety and pharmacokinetics (PK) of a polyurethane tenofovir disoproxil fumarate (TDF) vaginal ring when used continuously for 84 consecutive days by sexually active women.~The primary objective is to assess the safety of TDF vaginal rings when used continuously for 84 days by healthy, HIV-uninfected, sexually active women, as compared with a placebo vaginal ring.