Wirelessly observed therapy compared to directly observed therapy to confirm and support tuberculosis treatment adherence: A randomized controlled trial

Abstract

Background: Excellent adherence to tuberculosis (TB) treatment is critical to cure TB and avoid the emergence of resistance. Wirelessly observed therapy (WOT) is a novel patient self-management system consisting of an edible ingestion sensor (IS), external wearable patch, and paired mobile device that can detect and digitally record medication ingestions. Our study determined the accuracy of ingestion detection in clinical and home settings using WOT and subsequently compared, in a randomized control trial (RCT), confirmed daily adherence to medication in persons using WOT or directly observed therapy (DOT) during TB treatment.

Methods and findings: We evaluated WOT in persons with active Mycobacterium tuberculosis complex disease using IS-enabled combination isoniazid 150 mg/rifampin 300 mg (IS-Rifamate). Seventy-seven participants with drug-susceptible TB in the continuation phase of treatment, prescribed daily isoniazid 300 mg and rifampin 600 mg, used IS-Rifamate. The primary endpoints of the trial were determination of the positive detection accuracy (PDA) of WOT, defined as the percentage of ingestions detected by WOT administered under direct observation, and subsequently the proportion of prescribed doses confirmed by WOT compared to DOT. Initially participants received DOT and WOT simultaneously for 2-3 weeks to allow calculation of WOT PDA, and the 95% confidence interval (CI) was estimated using the bootstrap method with 10,000 samples. Sixty-one participants subsequently participated in an RCT to compare the proportion of prescribed doses confirmed by WOT and DOT. Participants were randomized 2:1 to receive WOT or maximal in-person DOT. In the WOT arm, if ingestions were not remotely confirmed, the participant was contacted within 24 hours by text or cell phone to provide support. The number of doses confirmed was collected, and nonparametric methods were used for group and individual comparisons to estimate the proportions of confirmed doses in each randomized arm with 95% CIs. Sensitivity analyses, not prespecified in the trial registration, were also performed, removing all nonworking (weekend and public holiday) and held-dose days. Participants, recruited from San Diego (SD) and Orange County (OC) Divisions of TB Control and Refugee Health, were 43.1 (range 18-80) years old, 57% male, 42% Asian, and 39% white with 49% Hispanic ethnicity. The PDA of WOT was 99.3% (CI 98.1; 100). Intent-to-treat (ITT) analysis within the RCT showed WOT confirmed 93% versus 63% DOT (p < 0.001) of daily doses prescribed. Secondary analysis removing all nonworking days (weekends and public holidays) and held doses from each arm showed WOT confirmed 95.6% versus 92.7% (p = 0.31); WOT was non-inferior to DOT (difference 2.8% CI [-1.8%, 9.1%]). One hundred percent of participants preferred using WOT. WOT associated adverse events were <10%, consisting of minor skin rash and pruritus associated with the patch. WOT provided longitudinal digital reporting in near real time, supporting patient self-management and allowing rapid remote identification of those who needed more support to maintain adherence. This study was conducted during the continuation phase of TB treatment, limiting its generalizability to the entire TB treatment course.

Conclusions: In terms of accuracy, WOT was equivalent to DOT. WOT was superior to DOT in supporting confirmed daily adherence to TB medications during the continuation phase of TB treatment and was overwhelmingly preferred by participants. WOT should be tested in high-burden TB settings, where it may substantially support low- and middle-income country (LMIC) TB programs.

Trial registration: ClinicalTrials.gov NCT01960257.

Conflict of interest statement

CAB serves as the Chair of an Independent Study Monitoring Committee for ViiV-GlaxoSmithKline and on a scientific advisory panel for ViiV. CAB also serves as an expert consultant for NDA Partners, Inc. CAB is the Director of the UCSD Anti-viral Research Center (AVRC) and receives grant/contract support from Gilead for the conduct of a clinical trial and grant support on CAB’s behalf from the National Institutes of Health/National Institute of Allergy and Infectious Diseases and the National Institute on Mental Health. TFB serves as a member of the Board of Directors of Durect Corporation (Cupertino, California), as a scientific advisor to the Guthy Jackson Charitable Foundation (Beverly Hills, California), and as an education advisor to UCSF-Stanford Center of Excellence in Regulatory Science and Innovation (CERSI). TFB also serves as an expert consultant for NDA Partners, LLC., Merck, and for the Bill and Melinda Gates Foundation. CAP, through the University of Florida, has research funding from the NIH, GlaxoSmithKline, and LegoChem. Previously, CAP had funding from the Critical Path for TB Drug Development. AJT serves as an expert consultant for RAND bioPartners, Inc. All the above authors state that none of these activities represent any conflicts or competing interests relevant to this research effort. All other authors declare no competing interests.

Figures

Fig 1. Study flow sheet.

AE, adverse event; DOT, directly observed therapy; INH, isoniazid; IS, ingestion sensor; IS-Rifamate, IS-enabled combination isoniazid 150 mg/rifampin 300 mg; PK, pharmacokinetic; SOC, standard of care; TB, tuberculosis; WOT, wirelessly observed therapy.

Fig 2. Visualization of confirmed versus unconfirmed doses.

Each row represents one patient. Each dot represents one day. Confirmed (black) and not confirmed (gray) doses are shown for each patient on study through the course of the follow-up based on the ITT analysis. Patients are ordered according to their length of follow-up after randomization. DOT, directly observed therapy; ITT, intent to treat; WOT, wirelessly observed therapy.

Fig 3. Longitudinal patterns of taking and timing adherence data of IS-Rifamate using WOT in two participants.

The first participant has highly regular taking and timing adherence, in this case achieved by setting an alarm reminder. The second participant displays variable timing adherence, but taking adherence is maintained with WOT adherence support. INH, isoniazid; IS, ingestion sensor; IS-Rifamate, IS-enabled combination isoniazid 150 mg/rifampin 300 mg; RIF, rifampin; WOT, wirelessly observed therapy.