Safety of Non-Medicated Intravaginal Rings for Microbicide Delivery

描述（由申请人提供）： 预防性传播感染和意外怀孕是紧迫的卫生优先事项。 阴道环（IVRs）可以提供一种以上的药物，从而为妇女提供了一种产品的选择，以防止人类免疫缺陷病毒（HIV），其他性传播感染和/或怀孕。该计划补助金的目标是设计一项I期试验，以比较非药物（安慰剂）IVRs的安全性和耐受性，目的是确定安全的骨干，以装载持续输送的药物。IVRs在持续释放用于避孕的激素方面的成功以及在粘附性交依赖性杀微生物剂凝胶方面的困难表明IVRs可能被证明是用于杀微生物剂递送的上级选择。使用壬苯醇醚-9（N-9）和硫酸纤维素凝胶的杀微生物剂试验失败表明， 在III期临床试验中，这些试验不能预测安全性。目前正在开发不同共聚物组成和直径的IVR，包括硅酮、乙烯醋酸乙烯酯（伊娃）和聚氨酯（PU）。尚无研究检查不同环骨架对粘膜环境的影响，包括对器械的炎症反应、环引起的免疫细胞募集或阴道植物群的变化。此外，目前还没有研究比较这些弹性材料的性能和安全性。需要对这些材料的生物相容性进行仔细的比较评估，以支持持续阴道内剂型的进一步开发。未来的药物IVR研究将包括安慰剂组，但不会在单一试验中同时研究多种弹性材料。 临床症状和生殖道上皮细胞的大体变化不太可能足以评估设计用于杀菌剂递送的环的安全性。拟在80名性活跃女性中进行一项随机临床试验，以比较4种不同IVR骨干（疏水性和亲水性PU、硅胶、伊娃）或无IVR 3周的安全性和可接受性。主要安全性目的将包括生殖道和环表面的免疫细胞群、炎性细胞因子和宿主防御介质以及长期使用IVR后阴道植物群的变化。提出了先进的分子方法，包括广泛的16 S rRNA基因PCR和细菌特异性定量PCR测定，以评估环对阴道微生物群的影响，以及荧光原位杂交，以确定环是否改变阴道上皮细胞，导致生物膜形成。长期使用戒指后，流行的乳酸杆菌或其他细菌的变化可能会改变生殖道粘膜免疫力，并增加对艾滋病毒的易感性。将通过用HIV-1离体挑战在环使用前后采集的宫颈外组织，评估免疫细胞、介质和细菌植物群的任何变化的生物学意义。在R34计划期间，将在监管顾问和FDA的指导下制定所有方案文件。这些结果可能会对未来杀微生物剂阴道环的设计和开发产生重大影响。 公共卫生相关性： 这项研究将为促进安全的阴道环持续输送药物以预防艾滋病毒和其他性传播感染提供重要信息。规划补助金将通过提出一项包括对戒指安全性的临床和实验室评估的试验来解决关键的知识差距。 这些结果可能会对杀微生物剂环的未来发展方向产生重大影响。

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.