Safety and Pharmacokinetics (PK) of a Polyurethane Tenofovir Disoproxil Fumarate (TDF) Vaginal Ring
Condition: HIV
Study type: Interventional
Phase: Phase 1

Summary: 
      This prospective, randomized, single-blinded, placebo controlled trial will examine the
      safety and pharmacokinetics (PK) of a polyurethane tenofovir disoproxil fumarate (TDF)
      vaginal ring when used continuously for 14 consecutive days.

      The primary objective is to assess the safety of TDF vaginal rings when used continuously for
      14 days by healthy, HIV-uninfected, sexually abstinent women, as compared with a placebo
      vaginal ring.
    

Detailed description: 
      Tenofovir disoproxil fumarate (TDF) is a prodrug of TFV (tenofovir), an adenosine nucleoside
      monophosphonate (nucleotide) derivative with potent antiretroviral (ARV) activity. 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 (Human Immunodeficiency Virus-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. TDF is licensed for
      the treatment of HIV-1 infection in the US, the European Union, Middle East, and Africa.

      The study will take place at the Albert Einstein College of Medicine in Bronx, New York, USA.
      Each participant will receive an IVR (intravaginal ring) 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.

      It is hypothesized that both the TDF IVR and placebo IVR will be safe and well tolerated
      among healthy, sexually abstinent women on combined-hormonal contraception. The null
      hypothesis is that there will be no difference in the safety profile between the active
      product and the placebo.

      Careful assessments of safety, including systemic and genital tract, will be undertaken with
      special consideration for issues related to irritation and systemic toxicity. The design of
      the study will allow safety comparisons of TDF ring to a placebo ring. A 14-day safety and PK
      study is proposed for this first-in-human study per FDA (For and Drug Administration)
      guidance. The study duration was carefully selected to control risk to the study
      participants. TFV 1% vaginal gel has been extensively tested in clinical trials at higher
      doses (8-fold dose margin) than the predicted dose delivered by the TDF IVR-001 study, and
      the TFV gel showed no significant adverse events at this higher dose in thousands of women.

      Given the drug release kinetics observed in vitro and in NHP (non-human primate) studies, TDF
      and TFV (formed following hydrolysis of the prodrug TDF) concentrations in cervicovaginal
      fluid (CVF) are expected to reach steady state within a few days and maintain steady state
      concentrations for the duration of the planned 14 days of ring use. Sampling at multiple time
      points and sites (vaginal, cervical, rectal and blood) will provide information on drug
      distribution, kinetics, and, by sampling after ring removal on Day 14, 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. To capture systemic absorption, blood will be sampled
      to determine drug concentrations in blood plasma and PBMCs (peripheral blood mononuclear
      cells). To capture the concentrations of drug within the genital tract, CVF will be sampled
      using Dacron swabs of the introitus, ectocervix, and area adjacent to the ring. Rectal
      sampling with swabs will also be obtained if participants consent to the procedure to
      determine drug concentrations in the rectum. Sampling at different sites (proximal and distal
      to the ring) will provide important information as to how well drug permeates throughout the
      genital tract. Cervical tissue sampling will be highly informative given that it is the
      likely site of drug action. However, biopsies must be taken sparingly for several reasons:
      they are uncomfortable to some and alter the healing process. Accordingly, two baseline
      biopsies will be taken prior to randomization and ring insertion to confirm absence of study
      drug and for PD studies. Subsequent biopsies for PK (pharmacokinetics) and PD
      (pharmacodynamics) studies will be delayed until the ring is removed. Following TDF IVR
      removal a third biopsy will be obtained for PK studies. Two cervical biopsies will be
      obtained following placebo IVR removal for PD studies and to blind safety data. The study
      will not be double-blinded because the TDF and placebo rings are not identical in appearance.
      Therefore, the study clinician will be able to collect two biopsies from participants in the
      placebo group and three biopsies from participants in the TDF ring group after ring removal.
      In order to maintain participant blinding, all participants will be informed that two
      biopsies will be taken before ring insertion and 2-3 biopsies will be taken after ring
      removal. Paired biopsies will provide the best data, as it will avoid inter-individual
      variability; both sets of cervical biopsies (pre- and post-IVR use) will be obtained during
      the second half of the participant's menstrual cycle (cycle days 18-23), which is prior to
      menses. Cervical biopsies will be obtained without local anesthetic. Participants may take
      acetaminophen before and/or after the biopsies are collected if desired.

      Primary Objective:

      • Assess the safety of TDF IVR when used continuously for 14 days by healthy, HIV-uninfected,
      sexually abstinent women, as compared with the placebo IVR

      Secondary Objective:

      • Examine systemic and genital tract PK of TDF release during and after 14 days of continuous
      use of a reservoir-type IVR containing TDF

      Exploratory Objectives:

        -  Evaluate the acceptability of and adherence to the study IVR

        -  Evaluate the PD during and after 14 days of continuous use of a reservoir-type IVR
           containing TDF by measuring the antiviral activity of genital tract secretions ex vivo
           and challenging biopsy tissue with virus

        -  Examine the impact of the study IVR on genital tract mucosal immunity and the vaginal
           microbiota

        -  Examine the PK of TDF and TFV in rectal fluid during and after 14 days of continuous use
           of a reservoir-type TDF IVR

        -  Evaluate mechanical properties and drug content following 14 days of continuous use of
           reservoir-type IVRs

      This is a single-site, two-arm, randomized single-blind, placebo-controlled trial. The study
      population will include approximately 30 healthy, 18-45 year old women who are
      HIV-uninfected, non-pregnant, sexually abstinent and using adequate contraception, as
      described in the protocol. This sample size was chosen with the goal of having 12 women per
      group complete the study and includes additional women to account for participants who may
      not complete the study or are lost to follow-up. Only female volunteers will be recruited
      since an IVR can only be used by women and the endpoints require genital sampling. To ensure
      participants are protected from pregnancy during study participation, to minimize variability
      among contraceptive methods, and to ensure adequate time between menses for ring use and
      sample collection, all volunteers must be using low-dose combined hormonal contraceptive
      pills. As this is a first-in-human trial of an intravaginal TDF ring, only healthy women will
      be recruited and will be asked to wear a TDF or placebo IVR for 14 days.

      The approximate time to complete study enrollment is expected to be 9 months. Two study
      groups are planned. Both groups will be assigned to complete a total of 9 study visits:
      (Screening [Visit 1], Enrollment [Visit 2], Days 0 [Visit 3], 1 [Visit 4], 3-5 [Visit 5], 7
      [Visit 6], 14 [Visit 7], 16-18 [Visit 8], 21 [visit 9]). A Safety Call will also be conducted
      on Day 10 of the study.

      The two study groups are:

        1. Reservoir-type TDF IVR group;

        2. Reservoir-type polyurethane IVR group;

      The expected duration for participants is approximately 5 - 10 weeks (including a screening
      visit, an enrollment visit, two weeks of continuous IVR use, and one week following IVR
      removal). Participants will undergo Visit 2 within 45 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 (adverse events) 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 PL (Program Leader) in consultation with the Protocol Safety Review Team
      (PSRT). Participants who are pregnant at the Final Study/Early Termination Visit may be
      followed in accordance with procedures described in the study protocol.
    

Intervention name(s): TDF Intravaginal Ring; Placebo Intravaginal Ring
Intervention type(s): Drug; Drug
Intervention description(s): The TDF IVR intravaginal ring is formulated using flexible outer tubing, comprised of hydrophilic, aliphatic polyether urethane, and an inner core compartment comprised of 86% w/w TDF and 14% w/w sodium chloride (NaCl). The TDF intravaginal ring will be worn continuously for 14 days. It will be inserted into the vagina following cessation of participant's menses at Visit 3 and removed at Visit 7.; The placebo ring is formulated using flexible outer tubing, comprised of hydrophilic, aliphatic polyether urethane, and an inner core comprised of sodium chloride (NaCl). The Placebo intravaginal ring will be worn continuously for 14 days. It will be inserted into the vagina following cessation of participant's menses at Visit 3 and removed at Visit 7.
Other intervention name(s): TDF IVR; Placebo
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Prevention