Exploratory Human Trials of Combination Rectal Microbicides

直肠间室非常容易感染艾滋病毒，迫切需要开发 专门为直肠隔间使用的杀菌剂。这些产品需要 高效，将艾滋病毒耐药性发展的风险降至最低，并对这两种野生动物进行保护 艾滋病毒的类型和抗药性。因此，项目3的最终目标(探索性人体试验 联合直肠杀菌剂)将开发一种抗逆转录病毒的联合直肠特异性杀菌剂 最有可能拥有这一所需产品配置文件的客户。为此，项目3将开展一系列 Core C开发的三种直肠特异性杀菌剂的创新前期1期临床研究 (配方开发核心)。这些制剂将包括UC781、替诺福韦和联合 含有替诺福韦和UC781的产品。这些研究的设计建立在以下经验的基础上 先前的IP/CP授权(U19 A060614；Anton，PI)，表征了直肠的安全性和药代动力学 (PK)替诺福韦和UC781阴道配方简介。所有三个前期第一阶段研究的设计都是 一模一样。在筛选和收集基线样本后，参与者将获得单剂 特定的直肠杀微生物剂配方。然后，他们将接受详细的粘膜安全性评估， 多室PK、产物分布和直肠组织外植体体外抵抗I的能力 挑战艾滋病病毒。这些数据将提供候选杀微生物剂的独特概况，并有助于 评估产品对进一步临床开发的适用性。然而，所有产品仍将需要 在临床试验网络(如杀菌剂试验网络)内进行正式的第一阶段安全性评估 (MTN)。这项研究将在三个公认在直肠杀菌剂方面表现优异的研究地点进行 (加州大学洛杉矶分校、玛吉妇女研究所(MWRI)和约翰霍普金斯大学(JHU))。 项目3目标1将优化和交叉验证试验地点的研究终点分析。目标 2、3和4将进行UC781、替诺福韦及其组合(UC781和UC781)的第一阶段前试验 替诺福韦)。这些研究将不会有安慰剂组，也不会包含任何剂量递增 组件。选定的剂量是目前用于阴道杀微生物剂(VM)研究的剂量。这三个人 试验将使粘膜毒性和有效性的评估成为可能，允许在以下领域内相互关联 剂量、毒性、有效性和分布，最后允许与已经完成的VM试验进行直接比较 使用相同剂量的抗逆转录病毒产品。

The rectal compartment is highly vulnerable to HIV infection and there is an urgent need to develop microbicides that have been specifically designed for use in the rectal compartment. These products need to be highly effective, minimize the risk of development of HIV resistance, and be protective against both wild type and resistant HIV. As a consequence, the ultimate goal of Project 3 (Exploratory Human Trials of Combination Rectal Microbicides) will be to develop a combination antiretroviral rectal specific microbicide that is most likely to have this desired product profile. Towards this end, Project 3 will undertake a series of innovative pre-Phase 1 clinical studies of the three rectal specific microbicides developed by Core C (Formulation Development Core). These formulations will include UC781, tenofovir and a combination product containing tenofovir and UC781. The design of these studies builds upon experience generated from a previous IP/CP grant (U19 A060614; Anton, PI) that characterized the rectal safety and pharmacokinetic (PK) profile of vaginal formulations of tenofovir and UC781. The design of all three pre-Phase 1 studies is identical. Following screening and collection of baseline samples, participants will receive a single dose of the specific rectal microbicide formulation. They will then undergo detailed assessment of mucosal safety, multicompartmental PK, product distribution, and the ability of rectal tissue explants to resist ex vivo I in vitro challenge with HIV. These data will provide a unique profile of the candidate microbicide and facilitate assessment of product suitability for further clinical development. However, all the products will still require formal Phase 1 safety assessment within a clinical trials network such as the Microbicide Trials Network (MTN). The studies will be conducted at three research sites with recognized excellence in rectal microbicide development (UCLA, Magee Women's Research Institute (MWRI) and Johns Hopkins University (JHU)). Project 3 Aim 1 will be to optimize and cross validate study endpoint assays across the trial sites. Aims 2, 3 and 4 will be to conduct the pre-Phase 1 trials of UC781, tenofovir, and the combination (UC781 and tenofovir) respectively. The studies will not have a placebo group nor contain any dose-escalation component. The selected doses are those currently used in vaginal microbicide (VM) studies. These three trials will enable the assessment of mucosal toxicity and efficacy, permit correlations within the domains of dose, toxicity, efficacy and distribution and, finally, permit direct comparison to already completed VM trials using the same doses of antiretroviral products.