Wirelessly Observed Therapy to Monitor Treatment of Mycobacterium Tuberculosis

DESCRIPTION (provided by applicant): Eradication of Mycobacterium Tuberculosis (MTB) has been a major goal of the CDC, the Global Alliance on TB, and the WHO for decades. Poor adherence to therapy has long been a recognized barrier to effective treatment of MTB infection. Inconsistent and interrupted treatment has led to rising numbers of MTB cases and the emergence of drug resistant MTB. One third of the world's population (~2 billion people,) are infected with MTB, over 9 million people a year develop active tuberculosis, and mortality approaches 2 million deaths annually. Short course Directly Observed Treatment (DOTS) is the gold standard for ensuring MTB treatment adherence and is used by public health authorities; however, DOTS is resource intensive, time consuming, difficult to scale, and represents the largest single cost to MTB treatment. At the same time that standard of care with DOTS for TB treatment is not consistently utilized due to cost and resource constraints, available alternatives for adherence assessment, such as patient questionnaires, pill-counts, MEMS caps, and prescription refill rates have been shown to be inaccurate. There remains an unmet need for a tool that can reliably, efficiently, and cost-effectively confirm medication ingestion events and provides verification of MTB treatment adherence and completion as an alternative to DOTS. INNOVATION: Proteus Biomedical, Inc. is developing Wirelessly Observed Therapy (WOT) as a reliable, real- time, and cost-effective alternative to DOTSfor electronically and remotely confirming adherence to MTB therapy. WOT utilizes the Raisin System and its proprietary, Ingestible Event Marker (IEM)-enabled medication to confirm directly the type, dose, date, and time of actual medication ingestion event. The system also provides dosing reminders, refill reminders, medication supply status, and appointment reminders for patients to promote self-management. It also offers a tool for the health providers to help to differentiate adherent patients from those with low adherence, such that care can be tailored in a highly targeted manner. WOT supported by the Raisin system could provide the US public health departments with a reliable alternative to physically and economically burdensome DOTS, and a means ofreducing the economic burden of MTB management. RESEARCH OBJECTIVES: This Phase I proposal focuses on (1) the development and testing of a combination of the Raisin IEM with isoniazid-rifampin therapy (Isonorif ); (2) researching and designing user interfaces specifically for MTB patients and healthcare workers for the deployment of WOT; and (3) designing and obtaining IRB approval to conduct SBIR Phase II clinical studies using WOT. In Phase 1, Specific Goals [and Benchmarks for Success] include: (1) Develop a combination of the Raisin IEM with a fixed-dose combination of isoniazid-rifampin (IsonaRif ) by over-encapsulation to yield Raisin-enabled IsonaRif : [Benchmark for Success: Raisin- enabled Isonorif remains intact during friability testing]; (2) Demonstrate that the dissolution properties of IsonaRif in combination with the Raisin IEM are substantially equivalent to those of standard IsonaRif pharmaceutical formulation. [Benchmark for Success: Demonstration that the dissolution properties of Isonarifin combination with the Raisin IEM are not significantly affected, when compared to standard IsonaRif pharmaceutical formulation]; (3) Demonstrate that the activations metrics of the Raisin IEM in combination with IsonaRif are substantially equivalent to those of other validated IEM form factors. [Benchmarks for Success: Substantial equivalence in time-to-activation, activation count, transmitted ID, number of ID counts, and IEM activity lifetim between the Raisin-enabled Isonorif and other IEM form factors]; (4) Develop MTB-specific WOT User Interfaces for MTB Patients and Healthcare Workers by incorporating feedback from US PHD clinicians, workers, and patients undergoing continuation phase therapy for active tuberculosis. [Benchmarks for Success: (A) Health Care Worker User Interfaces: Interfaces that are developed to include: (i) the ability to see confirmation of ingestion of MTB medication ingestion, which will include documentation compatible with US PHD requirements; (ii) system generated warnings when any patient has gone for more than a user-defined number of hours without medication ingestion; (iii) side effects inventory; and (iv) capability for patients to communicate and ask questions of their health care providers. Additional features requestedby public health workers may be incorporated as feasible. (B) Patient User Interfaces: user interface designs that incorporate (i) medication reminders, (ii) reminders for and confirmation of medication-taking, (iii) reminders for a change of adhesive monitor, (iv) medication supply status, and (v) medical appointment reminder]; and (5) Design and prepare for execution of SBIR Phase 2 studies. [Benchmarks for Success: (1) IRB approval, (2) identification of study sites, and (3) establishment of operationalinfrastructure to initiate a SBIR Phase II studies] PU