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.

Author summary

Why was this study done?

• TB is the infectious disease that kills the most people annually and is spread by droplets released into the air from persons with TB in their lungs.

• Multiple antibiotics taken over many months are necessary to cure this infection, and if doses are missed or full treatment is not completed, infected people can continue spreading the disease, and antibiotic resistance may occur.

• New methods to confirm that all the correct medication doses are taken and support patients over the long treatment course are crucial to saving lives and combatting disease spread.

What did the researchers do and find?

• We tested a new FDA-approved technology that uses a sensor made of minerals that is swallowed with TB medication and subsequently records the ingestion on a cellphone.

• We tested the sensor system accuracy to identify ingestions and we also randomly assigned persons with TB to receive the new system or the standard of care currently available, directly observed therapy, for supporting and confirming medication taking during TB treatment for periods up to 29 weeks.

• We found the system was highly accurate and that persons using this system were confirmed as taking 93% of their daily prescribed doses as opposed to 63% using directly observed therapy. In this study, the difference observed was mainly driven by the ability of the system to confirm doses 7 days a week compared to only on working days for directly observed therapy.

What do these findings mean?

• These findings indicate that novel sensor-based systems that use cell phones to remotely record digital data are as accurate as actually watching a person swallow their medications and can be used to confirm and support TB treatment 7 days a week, compared to 5 days a week for the current standard of care available. However, this technology still needs to be tested over the full course of TB treatment.

• WOT should be tested in high-burden TB settings, where it may substantially support LMIC TB programs.