Electronic pillbox-enabled self-administered therapy versus standard directly observed therapy for tuberculosis medication adherence and treatment outcomes in Ethiopia (SELFTB): protocol for a multicenter randomized controlled trial

The World Health Organization (WHO) revealed its commitment to patients with tuberculosis (TB) in its End TB strategy that “everyone with TB should have access to the innovative tools and services they need for rapid diagnosis, treatment, and care; this is a matter of social justice, fundamental to our goal of universal health coverage.” This commitment is a collective responsibility towards human rights, making sure that no family is burdened with avoidable death or catastrophic expenses due to TB by 2030. However, taking pride in the slogan “End TB by 2030” is insufficient for true progress. In order to translate aspirational goals into reality, practical solutions should be sought. The strategy might appear to be a zero-sum if interventions on the disease neglect key socioeconomic burdens that individual patients are incapable of avoiding. The association between TB and poverty is a reality [1‐5], but the disease is a global health security threat that urgently needs collective resources for mutual welfare [6, 7]. In the last three decades, various strategies and intervention packages have been formulated and implemented to halt the disease. However, improvements are not as expected [8, 9]; instead, a drug-resistant form of the disease is spreading [10‐12], with globalization and migration fueling multiple strains worldwide [13‐15]. TB remains the top cause of death worldwide from a single infectious disease and the major cause of death due to antimicrobial resistance. According to the 2019 WHO global TB report, an estimated 10.0 million people fell ill and 1.5 million people died from TB in 2018. Drug-resistant TB (DR-TB) continues to be a public health threat, where there were about half a million new cases of rifampicin-resistant TB, of which 78% had multidrug-resistant TB [16]. Africa accounts for one-quarter of new TB cases and TB-related deaths worldwide, with 2.5 million people falling ill and 417,000 people dying from TB annually. Of the total patients with TB co-infected with HIV globally, 72% of them live in Africa [17]. The true burden of DR-TB in the continent is poorly described, with only 51% of countries having formal data in the WHO global TB database, where DR-TB is largely missed and this requires a major effort to achieve the 2035 targets [16].

The main challenge is how to meet the End TB’s vision of “A world free of TB: zero deaths, disease and suffering due to TB” without bargaining the inherent dignity and economic wellbeing of patients with TB. It remains unclear how resource-limited countries would be able to meet one of the four key indicators of the strategy “Zero TB-affected families facing catastrophic costs due to TB by 2035” in situations where management of TB treatment still relies on directly observed therapy (DOT). Patients with TB from the poorer segments of society may not be benefiting from care delivery innovations: an apparent contradiction between “Global Commitment to End TB” and “reality on the ground.” Management of TB still largely depends on DOT. DOT has been viewed as an efficient strategy for adherence to treatment [18, 19], while evidence has demonstrated that it poses an economic and social burden to patients with TB and healthcare programs from low-income countries [20‐25]. Treatment of TB requires at least 6 months, where patients in the intensive phase of DOT need to collect their medication at healthcare facilities daily and swallow tablets under the direct observation of a healthcare worker throughout the intensive phase [20, 21, 26].

To address the multifaceted problems associated with TB in-person DOT, the WHO recently recommended countries to maximize the use of digital adherence technologies (DATs). Such technologies, in general, have been able to improve TB treatment outcomes [27‐30] and substantially reduce costs [31]. Yet, available data are limited for better conclusions of their effectiveness in various countries and settings [32‐35]. In 2017, the WHO endorsed three DATs: short message service/mobile phone texting (SMS); Medication Event Reminder Monitor System (MERM); and video-supported directly observed therapy (VDOT) [36]. SMS involves sending a standardized and understandable text message to patients with TB regularly to remind and motivate them to take their prescribed medications. MERM is an electronic pillbox that records adherence to treatment, stores medication, emits audible and visual alerts to remind patients to take their medications, and enables healthcare providers to monitor adherence. MERM sleeves (99DOTS prototype) have an additional component that each medication blister is wrapped in 99DOTS envelopes to send to providers a hidden signal unrecognized by the patient. VDOT involves video communication between patients and healthcare providers, where providers watch patients take their medication, live or self-recorded, and provide advice and support. VDOT is mediated primarily through Internet-enabled smartphones, and Internet access is a critical component [36]. In general, there have been limited studies conducted on DATs. For existing studies, effectiveness within various low- and middle-income countries (LMIC) has been the focus of research and has resulted in some controversy. Table 1 summarizes a review of recent studies conducted on the three DATs.

Considering the low-impact of SMS for adherence to TB treatment and the high investment and technology needed for VDOT, the advantage of MERM electronic pillboxes could surpass the other technologies, though more studies from LMIC are needed to inform its effectiveness. There are many electronic pillbox devices available in the global market; several were not endorsed by international health stakeholders (e.g. the WHO) or are not accessible in LMICs. Similar pillboxes have been in use for several decades for various medications. With the use of such an ordinary pillbox, patients can self-manage their medications, identify whether they have taken the dose, and minimize the rate of medication errors [52]. Previous studies found that individuals who used a pillbox had better adherence to treatment [53‐55].

The evriMed500, manufactured by Wisepill Technologies, South Africa, is among the MERMs available on the market. The device is TB-appropriate technology allowing customization of the container for patients with drug-susceptible TB, MDR-TB, and TB-HIV [56]. It is currently being tested in several clinical trials and is being used clinically in India and China for patients with TB [57]. It costs less than US$10 per patient based on conservative reuse assumptions [58]. The evriMED500 dispenser consists of an electronic module and a medication container with three indicator lights/LEDs (green, yellow, and red). The green LED will flash once when the container is opened and again once when the container is closed, will quickly flash three times when the container is opened and closed quickly, will flash in sequence during the (daily) Medication Alarm, and will be on solid while connected via USB to a computer. The yellow LED indicated a need to refill medications and will flash with the green LED at the time of the Medication Alarm. If the Medication Alarm is not enabled, only the yellow LED will flash. The yellow LED will be on solid when the container is opened. The red LED flash indicates low battery power and will flash with the green LED at the time of the Medication Alarm. The red LED will be on solid when the container is opened. The device requires two AA batteries, which should last for more than 12 months. It can store more than 12,000 records/events.

In-person DOT is highly challenging for most patients with TB in sub-Saharan Africa. In these settings, DOT did not provide a significant solution for suboptimal treatment adherence. Instead, home-based and community-based therapies were shown to be possible alternative strategies to health-facility DOT according to studies conducted in Tanzania [59‐61], Kenya [62, 63], Zambia [64], South Africa [65, 66], and Eritrea [67].

Ethiopia is among several countries highly encumbered by the TB epidemic and one of the least resourced in the world. According to the 2019 global TB report of the WHO, there were 113,613 TB cases reported in the country; and of the annual $94 million needed for TB care and control, the country’s domestic contribution was only 11% of this [17]. Despite TB care and treatment services being delivered free of charge, patients with TB face out-of-pocket payments [68, 69] and income losses [70] due to transportation, accommodation, and food to get treatment at a healthcare facility. This can be a major obstacle to adherence and has forced patients to stop working, sell their property, borrow money, and reduce their overall income [71]. These, in turn, have increased rates of loss to follow-up, disease relapse, and drug resistance [72]. Patients who travel daily to healthcare facilities for medication have also increased the transmission potential of the disease, especially in the capital city Addis Ababa, a highly congested city with overcrowded housing and public transportation [73]. Several studies conducted in Addis Ababa reported that patients with TB consider their daily DOT visits as worthless [74‐78], and providers see DOT as a very challenging strategy for patients with TB [76]. As a result, daily DOT survives in principle, while implementation is irregular as both patients with TB and providers have uncertainties concerning the program. Providers report that patients with TB prefer taking the tablets at home once they have the necessary advice and counseling [74, 76]. Patients complain that they travel for daily DOT on foot under harsh road conditions for up to 2 h and 2.5 km, taking several rests on their way because of their sickness [74, 77, 79]. They spend substantial money on transportation [76, 80] and some lose their job due to work absences related to daily DOT [74, 78, 79]. Providers also report that patients appear exhausted and dissatisfied during DOT visits [74, 78]. Some patients claim that once they are initially informed of the disease, no-one talks with them on the subsequent DOT days; they just swallow the drug and return home [76]. Additionally, patients face stigma on their route to daily DOT and change their name in the TB clinic to disguise their identity [80]. The challenge is similar in other parts of Ethiopia [70, 81‐83]. Such evidence discloses the difficulty of Ethiopia to meeting the overall End TB strategy targets by 2035 [84] unless significant investment is made to shape the current DOT strategy to a more advanced, technology-led, patient-centered strategy that could be responsive to individual patient preferences, needs, and values.

The main aim of this trial is to evaluate the effectiveness of pillbox-enabled SAT over standard DOT on adherence to TB medication and treatment outcomes in Ethiopia—a high TB burden country in sub-Saharan African. The secondary objectives are to assess the cost-effectiveness, thus individual and societal costs of treatment and quality-adjusted life years (QALY), when management of adherence followed pillbox-enabled SAT versus the standard DOT, and to assess the usability and acceptability by patients and their healthcare providers of the pillbox-enabled SAT.

This study will be the first in Ethiopia, and of the three in sub-Saharan Africa, to evaluate the effectiveness of pillbox-enabled SAT as a multicenter randomized controlled trial. The study will provide evidence of whether pillbox-enabled SAT is superior to the standard DOT for medication adherence and treatment outcomes. The study will assess whether digital adherence intervention is cost-effective, usable, and acceptable. The study targets patients with TB living in Ethiopia, a high TB burden LMIC in sub-Saharan Africa where alternative TB treatment strategies to in-person DOT do not exist.

If effective, this approach could substantially improve adherence to treatment, increase sputum conversion, reduce patient-side costs due to daily DOT, and improve quality of life. It could also have a strong public health impact by reducing transmission of the disease to healthcare providers and the community at large as the approach can reduce patients’ daily travels to healthcare facilities for in-person DOT. This approach will provide patients with TB the freedom and ownership of their treatment, which ultimately reduces mortality and morbidity thereby contributing significantly to the End TB Strategy. The findings will enable patients, healthcare providers, and policymakers to make informed decisions about the value of the intervention.

The study intends to use several clinical, biomedical, behavioral, and economic measurement tools to learn extensively about the desired outcomes of interest. The assessment of adherence using electronic, self-report, and biological specimens will provide credible and reliable justification of results. The diagnostic tools we plan to use are WHO-approved, and the questionnaires are valid and psychometrically sound for use in a local context. The study will collect original data from both patients and their TB care providers in local facilities, providing substantial evidence on the usability and acceptability of the intervention in real-world settings.