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

Public Health Relevance

In HIV pre-exposure prophylaxis trials such as VOICE, sub-optimal oral and vaginal product adherence has precluded accurate estimation of drug efficacy. We propose to rapidly develop an alternative, breath-based, adherence monitoring tool for clinical investigators studying vaginal and rectal routes of drug (microbicide). Measurement of microbicide adherence using exhaled breath would allow optimal analysis of pre-exposure prophylaxis trials and other clinical trials using vaginal and rectal gels.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1-AARR-E (81))
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Delcarmen-Wiggins, Rebecca
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Xhale, Inc.
United States
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