AbstractBackgroundWHO’s directly observed therapy (DOT) strategy for tuberculosis (TB) treatment depends upon a well–organized healthcare system. This study sought to evaluate the effectiveness of self-administered drug intake supported by a family member versus in-clinic DOT.MethodsThis open–label, nationally-representative stratified cluster randomized controlled non–inferiority trial with two parallel equal arms involved drug–susceptible pulmonary TB patients in the continuation treatment phase. We randomly assigned outpatient–TB–centres (52 clusters) to intervention and control arms. The intervention included an educational/counseling session to enhance treatment adherence; weekly visits to outpatient–TB–centres to receive medication, and daily SMS medication reminders and phone calls to track adherence and record side effects. Controls followed clinical DOT at Outpatient–TB–centres. Both groups participated in baseline and 4–5 months follow–up surveys. The trial’s non–inferiority comparisons include: treatment success as the clinical (primary) outcome and medication adherence (self–reported), knowledge, depressive symptoms, stigma, quality of life, and social support as non–clinical (secondary) outcomes.ResultsPer–protocol analysis showed that the intervention (n = 187) and control (n = 198) arms achieved successful treatment outcome of 92.0 and 92.9%, respectively, indicating that the treatment success in the intervention group was non–inferior to DOT. Knowledge, depression, stigma, quality of life, and social support also showed non–inferiority, demonstrating substantial improvement over time for knowledge (change in the intervention = 1.05: 95%CL (0.49, 1.60); change in the control = 1.09: 95%CL (0.56, 1.64)), depression score (change in the intervention = − 3.56: 95%CL (− 4.99, − 2.13); change in the control = − 1.88: 95% CL (− 3.26, − 0.49)) and quality of life (change in the intervention = 5.01: 95%CL (− 0.64, 10.66); change in the control = 7.29: 95%CL (1.77, 12.81)). The intervention resulted in improved treatment adherence.ConclusionsThis socially empowering alternative strategy might be a preferable alternative to DOT available to patients in Armenia and in other countries. Further research evaluating cost effectiveness of the intervention and generalizability of the results is warranted.Trial registrationClinicaltrials.gov:NCT02082340, March 10, 2014.