Background Drug-sensitive tuberculosis treatment is for six months; adherence problems are common. Digital adherence technologies may improve outcomes.

Methods In a cluster-randomised trial, 24 counties/districts in China were randomised (1:1) to two groups. Patients received: a medication monitor for daily drug-dosing reminders and health care worker monthly adherence monitoring with management of patients with poor adherence (intervention); or routine care (control; silent-mode monitor measured adherence). Adults with GeneXpert-positive drug-sensitive tuberculosis were enrolled and followed-up with sputum (solid culture) at 12 and 18 months. The objective was to assess whether digital adherence technologies combined with health care worker support for patients struggling with adherence improves treatment outcomes and reduces recurrence. The primary composite unfavourable outcome was death/lost-to-follow-up/failure on treatment or recurrence by 18 months from treatment start. Secondary outcomes included adherence. 12 clusters/group (125 patients/cluster), unfavourable outcome of 18% in control, coefficient of variation 0.3, gave 85% power for a 40% reduction in outcome. Analysis accounted for study design with multiple imputation for the primary outcome. Only the independent endpoints review committee who assessed endpoint data for some participants were masked to study group. The trial was registered at Current Controlled Trials (ISRCTN35812455).

Findings From Jan2017-Mar2019, 3075 patients were enrolled and 2686 (87%) contributed to the primary outcome. Post-randomisation two intervention clusters were merged. Overall 71% were male, median age 44 years. Of 433 unfavourable outcomes, 289(67%) were treatment lost-to-follow-up, 42(10%) recurrence. The intervention had no impact on unfavourable outcome (adjusted risk ratio 1.01, 95% confidence interval 0.73-1.4) and other treatment outcomes. Treatment non-adherence was reduced by 60-65%.

Interpretation Our medication monitor intervention did reduce non-adherence but had no impact on the unfavourable outcome which included lost-to-follow-up and recurrence. There was a failure to change management following identification of non-adherence at monthly reviews. Recurrence was rare and measurement may have been limited due to programmatic conditions and using solid culture.

Funding Bill & Melinda Gates Foundation

Evidence before this study Prior to the start of the study we searched Medline and Embase (December 2015) using search terms (digital pill box* OR smart pill box* OR SMS OR text messag*) AND TB or tuberculosis. We found one systematic review assessing the effect of mobile phone text messaging on treatment adherence used as a proxy for treatment outcomes and development of drug resistance. Four studies (three observational and one randomised trial) were included, meta-analysis was not conducted, and authors concluded mixed findings for the effectiveness of text messaging to promote adherence. Our previous study in China, published in 2015, reported improved adherence to TB treatment with text messaging and/or smart pill box reminders. The study was not powered for treatment outcomes.

Since then two studies have reported improved TB outcomes. A study conducted in Kenya assessed weekly motivational messages, daily text reminders, a USSD platform for patients to confirm daily adherence followed by SMS and calls from the research team for patients who had not confirmed adherence and clinic notification of patients with no confirmation for more than 2 days. The intervention reduced unsuccessful outcome by 68%, entirely through reducing loss to follow-up. The second study was a stepped-wedge trial from Uganda assessing a text messaging based intervention, where patients received daily text dosing reminders and were asked to confirm a dose taken using a toll-free number. Adherence data were reviewed at clinics visits every two weeks or monthly resulted in differentiated management. The authors showed improved successful treatment outcomes, though among a per-protocol population (97% and 52% of the populations in the control and intervention phases) who enrolled onto the intervention within the first two months of treatment. A recent systematic review in 2022 reported variable effects of digital adherence technologies on treatment outcomes.

Added value of this study This is the first trial to report the impact of a digital adherence technology intervention (smart pill box reminder, monthly review of adherence data and differentiated care for those where lack of pill box opening, as a proxy for adherence, was a problem) on a composite unfavourable endpoint of poor treatment outcome or subsequent retreatment including culture-confirmed recurrence, among drug-sensitive patients. The study found that monthly review of adherence data was not adequate to influence poor treatment outcomes, in particular losses to follow-up, or recurrence. There was a failure to change management following identification of non-adherence at the monthly reviews. We did demonstrate, however, a reduction in non-adherence in the intervention versus standard of care, similar to our previous study, indicating improved quality of treatment with the smart pill box intervention.

Implications of all the available evidence Currently there is no strong evidence that digital adherence technology interventions improve health outcomes, including treatment recurrence. More frequent review of adherence data with a streamlined approach for identifying patients with adherence issues and escalating supportive management of these patients, may be key for improving outcomes.

Shitong Huan, an author on the manuscript, is an employee of the Bill & Melinda Gates Foundation China office.

ISRCTN 35812455

This study was funded by the Bill & Melinda Gates Foundation

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Institutional Review Board of the Chinese Center for Disease Control and Prevention, Beijing, China gave ethical approval for this work. The London School of Hygiene & Tropical Medicine Ethics Committee of the London School of Hygiene & Tropical Medicine, London, UK gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

Yes

All data in the present study will be available online at DataCompass (https://datacompass.lshtm.ac.uk/) on publication of the article in a peer-reviewed journal.