Effectiveness of a Comprehensive Package Based on Electronic Medication Monitors at Improving Treatment Outcomes Among Tuberculosis Patients in Tibet: A Multi-Centre Randomised Controlled Trial

Background: World Health Organisation recommends that electronic medication monitors (EMMs), a form of digital adherence technology, complement directly observed treatment (DOT) for tuberculosis (TB), as DOT is inconvenient and costly. However, existing evidence about their effectiveness is inconclusive. We evaluated the effectiveness of a comprehensive package based on EMMs among TB patients in Tibet.Methods: We conducted this pragmatic, unblinded, multi-centre, individually-randomised, controlled, superiority trial in six counties in rural Shigatse, Tibet. Eligible participants were drug-susceptible TB patients aged ≥15 years starting standard TB treatment. TB doctors recruited patients from the public TB dispensary in each county and randomised them to intervention or control (near 1:1 ratio), based on the predetermined allocation sequence (permuted block design with variable block sizes of two/four/six, stratified by county). Intervention patients received an EMM box. This included audio medication-adherence reminders and recorded box-opening data, which were transmitted to a cloud-based server accessible to healthcare providers to allow remote adherence monitoring. A linked smartphone app enabled text/audio/video communication between patients and healthcare providers. We provided a free data plan to patients. We also trained family members to support patients with using the EMM and app. Control patients received usual care plus a deactivated EMM (this only recorded and transmitted box-opening data that was not accessible to healthcare providers), no access to the app, and we did not train family treatment supporters. Our primary outcome was a binary indicator of poor monthly adherence, defined as missing ≥20% of planned doses in the treatment month, measured using EMM opening data and verified by counting used medication blister packages during consultations. We recorded other secondary treatment outcomes based on national tuberculosis reporting data. We analysed the primary outcome based on the intention-to-treat population. Registered at ISRCTN: 52132803.Findings: Between 17 November 2018 and 5 April 2021 we randomised 278 patients: 143 to the intervention and 135 to the control. The final patient ended treatment on 4 October 2021. In the intervention arm 9.8% (84/854) of patient treatment months showed poor adherence compared to 36% (287/798) in the control arm. The corresponding intervention versus control adjusted risk difference was -28.7 percentage points (95% CI: -35.5, -22.2; p≤0.001). Five out of six secondary treatment outcomes also demonstrated clear improvements including treatment success, which was 93% (132/142) in the intervention arm and 70.9% in the control arm (95/134), with an adjusted risk difference of 39.8 percentage points (95% CI: 18.5, 52.1); p≤0.001.Interpretation: Our interventions were considerably effective at improving TB treatment adherence and outcomes, and our trial suggests that EMMs adapted to local context may positively impact TB programmes in high-burden and low-resource settings.Trial Registration: Registered at ISRCTN: 52132803.Funding: The study was funded by TB REACH, administrated from the STOP TB Partnership at the United Nations.Declaration of Interest: We declare no competing interests.Ethical Approval: We obtained ethics approval from the Office of Research Ethics at the University of Toronto (Ref: 36569) and the Ethics Review Committee of the Tibet Centre for Disease Control and Prevention (Ref: 006).