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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Drug-resistant Tuberculosis; Cost-Benefit Analysis; HIV Coinfection
• Intervention / Treatment: Diagnostic test: Targeted next-generation sequencing

• Study Type: Interventional
• Enrollment (Estimated): 2500
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: John Z Metcalfe, MD, PhD; Phone Number: +14152068314; Email: john.metcalfe@ucsf.edu
• Study Contact Backup: Name: Rob Warren, PhD

Study Locations

• South Africa
  • Cape Town, South Africa
    • Recruiting
    • South African National Health Laboratory Service
    • Contact: Robin M Warren, PhD
    • Contact: Nabila Ismail, PhD; Email: nabilai@sun.ac.za

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Active RR-TB diagnosed at a study facility during the study period
2. Positive Mtb culture, smear, or specimen derivative (e.g., GenoLyse remnant, Xpert cartridge extract)

Exclusion Criteria:

1. Patient expects to relocate/move residence outside of the study region
2. 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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sequencing Intervention in addition to standard of care; 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; 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.
No Intervention: Standard of Care; 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?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with clinical uptake of sequencing intervention results	The number of sequencing intervention results with treatment regimen adjustment where appropriate treatment change is indicated	At the anticipated completion of prescribed treatment, up to 18 months
Cost-effectiveness of the sequencing intervention	Costs of necessary personnel, consumables, facility, logistics, and per unit tests	At the anticipated completion of prescribed treatment, up to 18 months

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); University Hospital Heidelberg; University of Stellenbosch; Translational Genomics Research Institute; National Institute for Communicable Diseases, South Africa; Find; National Health Laboratory Service (NHLS), South Africa
• Investigators: Principal Investigator: John Z Metcalfe, MD, PhD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2024
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: September 12, 2022
• First Submitted That Met QC Criteria: September 20, 2022
• First Posted (Actual): September 23, 2022

Study Record Updates

• Last Update Posted (Actual): January 26, 2026
• Last Update Submitted That Met QC Criteria: January 22, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Blood-Borne Infections; Urogenital Diseases; Genital Diseases; Immune System Diseases; Infections; RNA Virus Infections; Virus Diseases; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; HIV Infections; Tuberculosis, Multidrug-Resistant
• Other Study ID Numbers: AI153213; R01AI153213 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No