Exploratory Human Trials of Combination Rectal Microbicides

直肠隔室非常容易受到艾滋病毒感染，迫切需要开发 特别设计用于直肠隔室的杀微生物剂。这些产品需要 高度有效，最大限度地减少艾滋病毒耐药性的发展风险，并对野生 类型和耐药的艾滋病毒。因此，项目3的最终目标（探索性人体试验） 联合直肠杀微生物剂）将开发一种联合抗逆转录病毒直肠特异性杀微生物剂 最有可能具有这种期望的产品轮廓。为此，项目3将开展一系列 Core C开发的三种直肠特异性杀微生物剂的创新性1期前临床研究 （制剂开发核心）。这些制剂将包括UC 781、替诺福韦和一种组合。 含有替诺福韦和UC 781的产品。这些研究的设计建立在以下方面的经验基础上： 之前的IP/CP授权（U19 A060614; Anton，PI），描述了直肠安全性和药代动力学 (PK)替诺福韦和UC 781的阴道制剂的特征。所有三项1期前研究的设计均为 一模一样在筛选和收集基线样本后，受试者将接受单次剂量的 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， 多房室PK、产物分布和直肠组织外植体在体外抵抗离体I的能力 艾滋病毒的挑战。这些数据将提供候选杀微生物剂的独特概况，并促进 进一步临床开发的产品适用性评估。然而，所有产品仍将需要 在临床试验网络（如杀微生物剂试验网络）内进行正式的1期安全性评估 （MTN）。这些研究将在三个研究中心进行，这些研究中心在直肠杀微生物剂方面具有公认的优势 （加州大学洛杉矶分校、马吉妇女研究所和约翰霍普金斯大学）。 项目3的目标1是优化和交叉验证试验中心的研究终点测定。旨在 2、3和4将进行UC 781、替诺福韦和联合用药（UC 781和 替诺福韦）。这些研究将不设安慰剂组，也不包含任何剂量递增 成分所选剂量是目前用于阴道杀微生物剂（VM）研究的剂量。这三 试验将能够评估粘膜毒性和疗效，允许在以下领域内的相关性： 剂量、毒性、疗效和分布，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药物。

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.