Sequencing Mycobacteria and Algorithm-determined Resistant Tuberculosis Treatment (SMARTT): a study protocol for a phase IV pragmatic randomized controlled patient management strategy trial

Abstract

Background Rifampicin-resistant tuberculosis (RR-TB) remains an important global health problem. Ideally, the complete drug-resistance profile guides individualized treatment for all RR-TB patients, but this is only practised in high-income countries. Implementation of whole genome sequencing (WGS) technologies into routine care in low and middle-income countries has not become a reality due to the expected implementation challenges, including translating WGS results into individualized treatment regimen composition. Methods This trial is a pragmatic, single-blinded, randomized controlled medical device trial of a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB. Subjects are 18 years or older and diagnosed with pulmonary RR-TB in four of the five health districts of the Free State province in South Africa. Participants are randomized in a 1:1 ratio to either the intervention (a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB) or control (RR-TB treatment according to the national South African guidelines). The primary effectiveness outcome is the bacteriological response to treatment measured as the rate of change in time to liquid culture positivity during the first 6 months of treatment. Secondary effectiveness outcomes include cure rate, relapse rate (recurrence of RR-TB disease) and TB free survival rate in the first 12 months following RR-TB treatment completion. Additional secondary outcomes of interest include safety, the feasibility of province-wide implementation of the strategy into routine care, and health economic assessment from a patient and health systems perspective. Discussion This trial will provide important real-life evidence regarding the feasibility, safety, cost, and effectiveness of a WGS-guided automated treatment recommendation strategy for individualized treatment of RR-TB. Given the pragmatic nature, the trial will assist policymakers in the decision-making regarding the integration of next-generation sequencing technologies into routine RR-TB care in high TB burden settings. Trial registration ClinicalTrials.gov NCT05017324. Registered on August 23, 2021.

The MAGMA pipeline for comprehensive genomic analyses of clinicalMycobacterium tuberculosissamples

“…To show the functionalities of the MAGMA pipeline, we present the analysis of sequencing data obtained from primary cultures from 79 consecutive participants in the SMARTT trial (Sequencing Mycobacteria and Algorithm-determined Resistant Tuberculosis trial, Clinicaltrials.gov Identifier NCT05017324 ) [3]. For this trial, primary liquid cultures were processed in real time in batches of 4-6 samples on an Illumina MiniSeq for individualized WGS-guided treatment decision-making.…”

“…Sequencing Mtb from sputum or primary liquid culture isolates could greatly contribute to tuberculosis management as results can be used to inform clinical or public health decisions [3]. Analysis DNA extracted directly from sputum samples is also important as it avoids culture bias and thus better reflects in-patient Mtb population diversity.…”