Test to Treat TB: Impact of Sputum Sequencing-guided Individualised Therapy on Outcomes in Drug-resistant Tuberculosis

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Conditions studied: Tuberculosis, Multidrug-Resistant

In brief

Resistance to anti-tuberculosis drugs is a continually growing problem. Multidrug-resistant tuberculosis (MDRTB) is resistance to at least rifampicin and isoniazid, and extensively drug-resistant TB is additional resistance to a fluoroquinolone and a second injectable line drug. Methods currently employed in testing for resistance are inadequate and a contributing factor to the 40-50% MDR-TB treatment success rate. Current drug susceptibility testing methods are slow for most drugs, taking weeks. Rapid molecular methods such as the line probe assays, e.g. Hain GenoType MDRTBplus and sl, provide resistant calls to only a limited number of drugs, and are often less useful in smear negative patients. Molecular technologies such as sequencing can provide a comprehensive readout of drug resistance and are able to detect resistant populations at very low levels (≤1%), thus enabling individualized therapy. This can be done directly from sputum. Targeted sequencing amplifies regions of genomic DNA associated with resistance prior to sequencing. Rapid analytic software is used to process the raw sequence data, identify resistance causing mutations and provide a readout of clinically relevant information. However, the feasibility, and more importantly the impact, of this approach has not been evaluated in a clinical trial to establish proof of concept. Aim 1: To conduct a randomised controlled trial to determine the impact of sputum-based targeted sequencing in detecting resistance to second-line TB drugs compared to the current programmatic standard of care (Hain MDRTBplus/sl and adjunct phenotypic drug susceptibility testing) when used to inform of treatment for MDR-TB. Aim 2: To compare currently available drug resistant sequencing pipelines for diagnostic accuracy, sensitivity, specificity and predictive value as compared to culture based phenotypic drug susceptibility testing. Aim 3: To compare the feasibility, accuracy, turn-aroundtime, and cost implications of the above-mentioned diagnostic approaches.

Key facts

Study ID: NCT05007795
Run by: University of Cape Town
People needed: 280
Starts: 2026-06-01
Expected to finish: 2028-10-30
Last updated by the study team: 2026-05-06

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

You may qualify if…

Subjects are required to meet ALL of the following inclusion criteria to participate:
Newly diagnosed culture and/or Xpert/MTB Ultra positive pulmonary TB
Rifampicin resistance detected using GeneXpert
Provide written informed consent prior to all trial-related procedures
Male or female aged 18 years and older.
Patients on TB treatment for less than or equal to 7 days.
Patients receiving both the shorter and longer MDR-TB regimen will be eligible.

You may not qualify if…

Subjects will be excluded from participation if they meet ANY of the following criteria:
A subject who in the opinion of the investigator is unlikely to cope with regular visits to the trial site either because of travel constraints, or drug or alcohol abuse, or other reason.
Currently on MDR-TB treatment and completed 7 days of treatment.
Any participant with a clinically significant pre-existing medical condition that, in the opinion of the investigator, may be significantly worsened by the patient's participation in the study
Any subject with a Karnofsky score < 50.
Having participated in other clinical studies within 8 weeks prior to trial start where investigational agents were used that may potentially impact current trial outcome.
Participant who is pregnant, breast-feeding (and not willing to stop), or planning to conceive a child within 6 months of cessation of treatment.
Any pre-existing laboratory abnormality, which in the opinion of the investigator will place the participant at risk (see detailed protocol for grade of abnormality).

Where it is running

University of Cape Town — Cape Town, Western Cape, South Africa

Full record on ClinicalTrials.gov

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