Safety of Non-Medicated Intravaginal Rings for Microbicide Delivery

描述(由申请人提供)： 防止性传播感染和意外怀孕是当务之急。可以开发出提供一种以上药物的阴道内环(IVR)，从而为妇女提供预防人类免疫缺陷病毒(HIV)、其他性传播感染和/或怀孕的产品选择。这项计划拨款的目标是设计一项第一阶段试验，比较非药物(安慰剂)静脉注射受体的安全性和耐受性，目的是确定安全的脊椎，以便为持续给药加载药物。IVRs在持续释放用于避孕的激素方面的成功，以及在坚持性交依赖的杀微生物剂凝胶方面的困难，表明IVRs可能被证明是提供杀微生物剂的更好选择。用壬醇-9(N-9)和硫酸纤维素凝胶进行的杀微生物剂试验失败表明早期的临床安全性结果 在第三阶段试验中，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，包括有机硅、乙烯-乙酸乙烯酯(EVA)和聚氨酯(PU)。目前还没有研究考察不同的环骨架对粘膜环境的影响，包括对设备的炎症反应，对环的免疫细胞的招募，或阴道菌群的变化。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，以支持阴道内持续剂型的进一步开发。未来对药物IVR的研究将包括安慰剂手臂，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的大体变化不太可能足以评估为杀菌剂输送而设计的环的安全性。为比较4种不同IVR骨架(疏水和亲水性PU、硅胶、EVA)和不使用IVR的安全性和可接受性，对80例性活跃女性进行了随机临床试验。主要的安全目标将包括生殖道和环表面免疫细胞群的变化，炎性细胞因子和宿主防御介质，以及长期使用IVR后的阴道菌群。提出了先进的分子方法，包括广泛的16S rRNA基因聚合酶链式反应和细菌特异性定量聚合酶链式反应，以评估环对阴道微生物区系的影响，以及荧光原位杂交，以确定环是否改变阴道上皮导致生物被膜的形成。长期使用环后，流行的乳酸菌或其他细菌的变化可能会改变生殖道粘膜免疫，并增强对艾滋病毒的易感性。免疫细胞、介质和细菌菌群的任何变化的生物学意义将通过挑战在使用HIV-1体外环状病毒之前和之后收集的宫颈外组织来评估。在R34计划期间，所有方案文件将在监管顾问和FDA的指导下制定。这一结果可能会对未来杀微生物剂阴道环的设计和开发方向产生重大影响。 公共卫生相关性： 这项研究将为安全的阴道内环的发展提供重要的信息，以持续地给药以预防艾滋病毒和其他性传播感染。计划拨款将通过提议一项包括环安全性的临床和实验室评估的试验来解决关键的知识缺口。结果可能会对杀菌剂环未来的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.