Pragmatic Use of Next-generation Sequencing for Management of Drug-resistant Tuberculosis

Study Overview
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Brief Summary
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TS ELiOT is a stepped-wedge, cluster randomized trial assessing the effect of a next-generation sequencing-based strategy on rifampin-resistant tuberculosis management and patient outcomes.

Official Title
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Targeted Sequencing to Enhance, Liberate, and Optimize Treatment of Drug-resistant Tuberculosis

Conditions
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Drug-resistant Tuberculosis, HIV Coinfection, Cost-Benefit Analysis

Intervention / Treatment
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* Diagnostic Test: Targeted next-generation sequencing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Active RR-TB diagnosed at a study facility during the study period Positive Mtb culture, smear, or specimen derivative (e.g., GenoLyse remnant, Xpert cartridge extract) Exclusion Criteria: Patient expects to relocate/move residence outside of the study region Patient does not agree to participate in the study In addition, participants later found to have isolates with rifamycin susceptibility on at least two additional tests (e.g., phenotypic DST, LPA, or sequencing) will be considered late exclusions.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequencing Intervention in addition to standard of care<br>Batched targeted deep sequencing in addition to the locally accepted standard of care drug susceptibility determination of multidrug/extensively drug-resistant tuberculosis (M/XDR-TB) | Diagnostic Test: Targeted next-generation sequencing<br>* During intervention periods, an additional patient sample derived from routinely collected specimens will be processed by a local technician. Extracted DNA extracted from these samples will be batched on a regular basis for targeted deep sequencing. Sequencing results will be regularly transmitted to a clinical advisory committee.<br>|
| No Intervention: Standard of Care<br>Locally accepted standard of care which is consistent with the WHO recommendations for the drug susceptibility determination of M/XDR-TB | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with prespecified end of treatment outcomes | The number of participants with each of the following prespecified end of treatment outcomes will be reported: cure, treatment completed, loss to follow up, treatment failure, death, transfer, and still on treatment. | At the anticipated completion of prescribed treatment, up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 12-month relapse-free survival | Length of time after treatment ends that the patient survives without TB recurrence | From completion of prescribed treatment to death or TB recurrence, up to 12 months | 
| Exposure time to ineffective drugs | Cumulative length of time on individual drugs to which Mtb is found to be resistant, per participant | At the anticipated completion of prescribed treatment, up to 18 months | 
| Number of participants with acquired drug resistance | Number of participants with M.tuberculosis acquiring additional drug resistance during treatment | At the anticipated completion of prescribed treatment, up to 18 months | 
| Time to effective treatment initiation with three drugs | Length of time from diagnosis to treatment initiation with at least three effective drugs to which M.tuberculosis is susceptible | From diagnosis to treatment initiation with at least three effective drugs, up to 18 months | 
| Time to effective treatment initiation with four drugs | Length of time from diagnosis to treatment initiation with at least four effective drugs to which M.tuberculosis is susceptible | From diagnosis to treatment initiation with at least four effective drugs, up to 18 months | 
| Time to culture conversion | Length of time from diagnosis to stable culture conversion, defined as the first of two (consecutive or non-consecutive) negative sputum cultures without an intervening positive culture, and/or visits wherein the participant is unable to produce sputum and has no signs of active TB, up to 9 months | From diagnosis to stable culture conversion, up to 9 months |