Safety of Non-Medicated Intravaginal Rings for Microbicide Delivery

DESCRIPTION (provided by applicant): Prevention of sexually transmitted infections (STIs) and unintended pregnancies are urgent health priorities. Intravaginal rings (IVRs) can be developed that deliver more than one drug, thus providing women the option of a product to prevent human immunodeficiency virus (HIV), other STIs and/or pregnancy. The goal of this Planning Grant is to design a Phase I trial to compare the safety and tolerability of non-medicated (placebo) IVRs with the goal of identifying safe backbones to load with drugs for sustained delivery. The success of IVRs in the sustained release of hormones for contraception and the difficulties with adherence to coitally-dependent microbicide gels suggest that IVRs may prove to be a superior option for microbicide delivery. Microbicide trial failures with Nonoxynol-9 (N-9) and cellulose sulfate gels revealed that clinical safety outcomes in early Phase trials were not predictive of safety in Phase III trials. IVRs of differing copolymer composition and diameter are currently in development and include silicone, ethylene vinyl acetate (EVA) and polyurethane (PU). There are no studies that have examined the impact of different ring backbones on the mucosal environment, including inflammatory responses to the device, recruitment of immune cells in response to a ring, or changes in vaginal flora. Moreover, there are currently no studies that have compared the performance and safety of these elastomeric materials. A careful comparative assessment of the biocompatibility of these materials is needed to support the further development of sustained intravaginal dosage forms. Future studies of medicated IVRs will include a placebo arm but will not investigate multiple elastomeric materials side by side in a single trial. Clinical symptoms and gross changes in genital tract epithelium are unlikely to be sufficient to assess the safety of rings designed for microbicide delivery. A randomized clinical trial is proposed to compare the safety and acceptability of four different IVR backbones (hydrophobic and hydrophilic PU, silicone, EVA) or no IVR for 3 weeks among 80 sexually active women. Primary safety objectives will include changes in immune cell populations in the genital tract and at the surface of the ring, inflammatory cytokines and host defense mediators, and vaginal flora following prolonged IVR use. Advanced molecular methods are proposed, including broad range 16S rRNA gene PCR and bacterium-specific quantitative PCR assays to assess the impact of rings on the vaginal microbiota and fluorescence in situ hybridization to determine if rings alter the vaginal epithelium leading to biofilm formation. Changes in prevalent lactobacilli or other bacteria following prolonged ring use may modify genital tract mucosal immunity and enhance susceptibility to HIV. The biological significance of any changes in immune cells, mediators and bacterial flora will be assessed by challenging ectocervical tissue collected before and after ring use with HIV-1 ex vivo. During the R34 planning period, all protocol documents will be developed with guidance from a regulatory consultant and the FDA. The results may significantly impact the future direction of microbicide intravaginal ring design and development. PUBLIC HEALTH RELEVANCE: This study will provide crucial information for advancement of safe intravaginal rings for sustained delivery of drugs to prevent HIV and other sexually transmitted infections. The planning grant will address critical knowledge gaps by proposing a trial that includes both clinical and laboratory assessments of ring safety. Results could significantly impact the future direction of microbicide ring development.