SMART: A Breath-based Adherence Technology to Monitor HIV Microbicide Gel Use

描述（由申请人提供）：在HIV暴露前预防（PrEP）试验中，次优口服和杀微生物剂依从性妨碍了药物疗效的准确估计。衡量遵守情况是一项重大的、尚未解决的挑战。在杀微生物剂试验中，已经测试了其他客观的坚持措施，但没有一个措施可以衡量产品的实际使用。我们建议迅速开发一种替代的，基于呼吸的，遵守监测工具的研究人员研究杀微生物剂管理利用技术已经开发的口服给药。 Xhale已经开发了一种基于呼吸的技术，称为SMART（R）（自我监测和报告治疗）依从性系统，以使用FDA批准的GRAS调味剂作为依从性使能标记（AEM）来实时监测个体受试者的逐剂量口服药物依从性。AEM（例如，2-丁醇）在胃和小肠中被快速吸收，并代谢成挥发性代谢物（例如，2-丁酮），迅速出现在呼吸中。当受试者通过直接向SMART（R）设备（微型气相色谱仪，mGC）“吹气”来提供呼吸样本时，拍摄面部照片。通过mGC测量这种代谢物明确记录了特定个体口服药物的摄入。详细的试验数据本地存储在mGC设备中，并使用无线或蜂窝路由器技术实时传输到中央数据存储库进行分析。后者是一个基于互联网的数据库，供地球仪上任何地方有互联网连接的授权个人审查。SMART（R）是便携式的，旨在由受试者自我管理。尽管SMART（R）最初是为口服药物设计的，但它可以很容易地用于记录杀微生物剂的放置。使用替诺福韦（TFV）凝胶作为模型剂，该资助的目的是构建一个SMART（R）系统，优化用于杀微生物剂应用：目的1。在男性（直肠途径）和女性（直肠和阴道途径）中使用交叉设计，确定杀微生物剂应用的最佳AEM（类型和剂量）。(Time：0-12个月）目标2.制定战略（即，多筒注射器施用器）以有效地将最佳AEM结合到直肠和阴道TFV凝胶的放置中，其不需要改变其制造工艺，并且保持呼吸标记物的有利浓度-时间曲线。(Time：12-24个月）目标3.优化SMART（R）器件的杀菌剂应用。(Time：0-24个月）使用SMART（R）测量杀微生物剂依从性将通过提供实时可操作的依从性数据来实现对PrEP试验的最佳分析。通过提供一个“金标准”工具来监测杀微生物剂的依从性，SMART（R）不仅可以提供一个上级试验数据集，而且还可以用于识别与依从性差相关的行为，并制定减轻这些行为的策略。1

DESCRIPTION (provided by applicant): In HIV pre-exposure prophylaxis (PrEP) trials sub-optimal oral and microbicide adherence has precluded accurate estimation of drug efficacy. Measurement of adherence is a major, unmet challenge. Other objective measures of adherence in microbicide trials have been tested, but none measure the actual use of the product. We propose to rapidly develop an alternative, breath-based, adherence monitoring tool for investigators studying microbicide administration by leveraging technology already developed for oral dosing. Xhale has developed a breath-based technology, termed the SMART(R) (Self Monitoring and Reporting Therapeutics) Adherence System, to monitor individual subject, dose-by-dose, oral medication adherence in real-time using FDA-approved GRAS flavorants as the adherence enabling marker (AEM). The AEM (e.g., 2- butanol), which is easily and safely incorporated into drug product without altering its manufacturing processes or bioavailability, is rapidly absorbed in the stomach and small intestine, and metabolized to a volatile metabolite (e.g., 2-butanone) that quickly appears in breath. As the subject provides a breath sample by "blowing" directly into the SMART(R) device (miniature gas chromatograph, mGC), a facial picture is taken. Measurement of this metabolite(s) by the mGC unambiguously documents ingestion of oral drugs by a specific individual. Detailed trial data is stored locally i the mGC device and transmitted real-time using wireless or cellular router technology to a central data repository for analysis. The latter is an internet-based database for review by authorized individuals anywhere on the globe with an internet connection. SMART(R) is portable and designed to be self-administered by subjects. Although originally designed for oral drugs, SMART(R) can be easily adapted to document placement of microbicides. Using tenofovir (TFV) gel as a model agent, the aims of this grant are to construct a SMART(R) system optimized for microbicide applications: Aim 1. Using a crossover design in men (rectal route) and women (rectal and vaginal routes), identify an optimal AEM (type and dose) for microbicide applications. (Time: 0-12 months) Aim 2. Develop strategies (i.e., multiple-barrel syringe applicators) to effectively incorporate the optimal AEM into the placement of rectal and vaginal TFV gels that requires no change in their manufacturing processes, and preserves a favorable concentration-time profile of the breath marker. (Time: 12-24 months) Aim 3. Optimize the SMART(R) device for microbicide applications. (Time: 0-24 months) Measurement of microbicide adherence using SMART(R) would allow optimal analysis of PrEP trials by providing real-time actionable adherence data. By providing a "gold standard" tool to monitor microbicide adherence, SMART(R) could not only provide a superior trial dataset, but could also be used to identify behaviors associated with poor adherence and enable strategies to mitigate them. 1