Whole genome sequencing precision medicine strategy to shorten treatment for rifampicin-resistant tuberculosis (SMARTT): a pragmatic, randomised, single-blind phase 4 trial
Abstract
Background: All patients with rifampicin-resistant tuberculosis should receive a short course of effective treatment. We aimed to evaluate the effectiveness of whole genome sequencing (WGS)-guided treatment in shortening duration of treatment for rifampicin-resistant tuberculosis.
Methods: We did a pragmatic, randomised, single-blind phase 4 trial in 13 hospitals and 35 clinics in South Africa. Adults with pulmonary rifampicin-resistant tuberculosis were randomly assigned (1:1, using adaptive randomisation) to standard of care (WHO all-oral 9-month, seven-drug regimen or 18-month individualised regimen) or a four-drug, 6-month WGS-guided regimen generated by a feature-based artificial intelligence (AI) model. Bacteriological effectiveness, defined as difference in time to culture conversion measured as change in mycobacterial load using a non-linear mixed-effects model, was the primary outcome. Due to operational constraints and the inability to perform culture-free WGS, we performed an analysis of clinical effectiveness in a modified intention-to-treat (mITT) population (risk difference for unfavourable treatment outcomes, 10% non-inferiority margin) and safety (serious adverse events). This trial is registered with ClinicalTrials.gov, NCT05017324.
Findings: 204 participants were randomly assigned between Sept 23, 2021, and Feb 9, 2023 (101 to the standard of care group, 103 to the WGS group), of which 162 culture-positive individuals were included in the mITT analysis (78…
How strong is the evidence?
Evidence Hub reads this as a randomized trial, done in people. Its evidence level is 2 of 5 (High · randomized trial). Randomized trials of a reasonable size are the strongest single-study design. Reported size: 204 participants or records.
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