Mobile Tuberculosis Treatment Support Tools to Increase Treatment Success in Patients with Tuberculosis in Argentina: Protocol for a Randomized Controlled Trial

Background Tuberculosis (TB) is an urgent global health threat and the world’s deadliest infectious disease despite being largely curable. A critical challenge is to ensure that patients adhere to the full course of treatment to prevent the continued spread of the disease and development of drug-resistant disease. Mobile health interventions hold promise to provide the required adherence support to improve TB treatment outcomes. Objective This study aims to evaluate the effectiveness of the TB treatment support tools (TB-TSTs) intervention on treatment outcomes (success and default) and to assess patient and provider perceptions of the facilitators and barriers to TB-TSTs implementation. Methods The TB-TSTs study is an open-label, randomized controlled trial with 2 parallel groups in which 400 adult patients newly diagnosed with TB will be randomly assigned to receive usual care or usual care plus TB-TSTs. Participants will be recruited on a rolling basis from 4 clinical sites in Argentina. The intervention consists of a smartphone progressive web app, a treatment supporter (eg, TB nurse, physician, or social worker), and a direct adherence test strip engineered for home use. Intervention group participants will report treatment progress and interact with a treatment supporter using the app and metabolite urine test strip. The primary outcome will be treatment success. Secondary outcomes will include treatment default rates, self-reported adherence, technology use, and usability. We will assess patients’ and providers’ perceptions of barriers to implementation and synthesize lessons learned. We hypothesize that the TB-TSTs intervention will be more effective because it allows patients and TB supporters to monitor and address issues in real time and provide tailored support. We will share the results with stakeholders and policy makers. Results Enrollment began in November 2020, with a delayed start due to the COVID-19 pandemic, and complete enrollment is expected by approximately July 2022. Data collection and follow-up are expected to be completed 6 months after the last patient is enrolled. Results from the analyses based on the primary end points are expected to be submitted for publication within a year of data collection completion. Conclusions To our knowledge, this randomized controlled trial will be the first study to evaluate a patient-centered remote treatment support strategy using a mobile tool and a home-based direct drug metabolite test. The results will provide robust scientific evidence on the effectiveness, implementation, and adoption of mobile health tools. The findings have broader implications not only for TB adherence but also more generally for chronic disease management and will improve our understanding of how to support patients facing challenging treatment regimens. Trial Registration ClinicalTrials.gov NCT04221789; https://clinicaltrials.gov/ct2/show/NCT04221789. International Registered Report Identifier (IRRID) DERR1-10.2196/28094

1 R01 AI147129-01 3 BCHI RUBINSTEIN, F Secondary outcomes will include: treatment default rates, self-reported adherence, technology use and usability. Findings have broader implications not only for TB adherence but disease management more generally and will improve our understanding of how to support patients facing challenging treatment regimens.
PUBLIC HEALTH RELEVANCE: Tuberculosis remains one of the top ten causes of death globally despite it being largely curable. Patients face many challenges to adhere to treatment and mobile health (mHealth) interventions may address these challenges and support patients to complete their treatment. We will improve an interactive intervention based on the combined input from patients and TB experts and evaluate the intervention's impact on treatment outcomes in a randomized clinical trial. Findings have broader implications not only for TB adherence but disease management more generally and will improve our understanding of how to support patients in challenging treatment regimens.

CRITIQUE 1
Overall Impact: The goal is to provide more effective treatment strategies for TB (especially with respect to improving adherence). The work is in Argentina and Univ. of Washington. A major value is their redesign and implementation of test strips for home use with short reaction time (3-5 min.). This will help alleviate the problem of shortage of healthcare experts in this area. Another good outcome will be a database of test strip images suitable for developing classifiers by them and others. An app that goes along with the test strips will be developed and evaluated. But, there were too few details on the interventions to be developed.

CRITIQUE 2
Overall Impact: This application is responsive to PA-18-722 aiming to enhance patient adherence to patient treatment or prevention regimen. The current application seeks to implement and test a mHealth solution to enhance compliance to tuberculosis treatment in Argentina. Although direct observation treatment (DOT) has been shown to be very effective, it is resource consuming. In regions where cell phone technology has high penetrance, a phone app with bidirectional communication between caretakers and patients, couple with an effective way to verify compliance may be an effective solution to low compliance and failure to meet WHO objective with respect to TB control. The application is clear, easy to follow and proposes to expand on the development of an app that has already been developed, and partially field tested. Compliance is tested using a calorimetric assay on a strip testing the presence of isoniazid with automatic readout by the cell phone app. A randomized trial of 360 subjects will examine whether the intervention impact the rate of cure at six months. A third Aim will determine usability of the app. Significant preliminary work support feasibility of the project, including existence of preliminary app, filed data as to produce a better version of the app, and demonstration of the ability to enroll subjects with a new diagnosis of tuberculosis. Improved compliance to TB treatment is definitely a high priority goal. The investigators are well-qualified, operate in a supportive environment, and are fluent in Spanish. The project introduces several innovations, from the ability of the application to communicate to communicate with electronic health records to the development of a more usable drug assay. The approach has several strengths including end-user and care providers' input in app design, the provision of alternative strategies to the most common pitfalls encountered in the design of mHealth interventions, a formal usability intervention, and local authorities buy-in. There also a few weaknesses to the application including representativity of the study sample as a cell phone with camera is required, the use of a yet unproven and unstandardized test strip for compliance detection, and probable underpowering of the clinical study. Overall, the strengths and impact significantly outweigh the weaknesses thus generating significant enthusiasm for the application.

CRITIQUE 3
Overall Impact: The overall goal of this proposal is to develop tuberculosis treatment support tools named TB-TST which include an app and a paper-based drug metabolite to monitor adherence and improve treatment outcomes. They plan to refine the existing TBST with a patient centered design, perform an RCT to evaluate in impact on users vs non-users and assess patient provider satisfaction. Overall it is a well written and structured grant involving a significant health problem in both developing and under developed countries. The challenge to monitor the adherence regime is high to due to several reasons including the stigma associated with this disease. The scientific premise is based on the evidence that mHealth based system supported by education, drug usage monitoring by biochemical means along with health care provider support can improve outcomes. This proposal has several innovative aspects that result in an integrated system built on patient centered design. The investigative team is strong and is collaborative although implementation can be challenging over adherence issues which reduces the enthusiasm in a minor fashion for a strong grant proposal.