Test to Treat TB: Impact of Sputum Sequencing-guided Individualised Therapy on Outcomes in Drug-resistant Tuberculosis
T3-RCT
2 other identifiers
interventional
280
1 country
1
Brief Summary
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for not_applicable
Started Jun 2026
Typical duration for not_applicable
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 13, 2021
CompletedFirst Posted
Study publicly available on registry
August 16, 2021
CompletedStudy Start
First participant enrolled
June 1, 2026
ExpectedPrimary Completion
Last participant's last visit for primary outcome
May 31, 2028
Study Completion
Last participant's last visit for all outcomes
October 30, 2028
May 6, 2026
May 1, 2026
2 years
August 13, 2021
May 5, 2026
Conditions
Outcome Measures
Primary Outcomes (1)
Impact of targeted genome sequencing to initiate more than or equal to five effective TB drugs within 14 days of diagnosis (reference standard phenotypic DST).
Impact of sputum-based targeted sequencing in detecting resistance to second-line TB drugs using the GenoScreen Deeplex assay 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.
14 days
Secondary Outcomes (1)
Feasibility of targeted sequencing to initiate more than or equal to five effective TB drugs within 14 days of diagnosis.
14 days
Other Outcomes (7)
Favourable outcome rate
6, 12, 18, 24 month post treatment initiation
Rate of treatment failure
6, 12, 18, 24 month post treatment initiation
Culture conversion rates
6, 12, 18, 24 month post treatment initiation
- +4 more other outcomes
Study Arms (2)
Programmatic MDR TB treatment regimen
NO INTERVENTIONConventional MDR-TB laboratory tests. Sputum culture (and smear microscopy) will be evaluated monthly during the treatment period (and 6 monthly during the follow-up period) for the conventional arm.
Sequence based resistance testing and individualized treatment
EXPERIMENTALSputum extracted for targeted sequencing and drug resistance profile provided to clinician for individualized treatment.
Interventions
Targeted sequencing to be performed on DNA extracted directly from clinical sputum samples using an on-demand strategy to generate a drug resistant profile. Clinicians treating the patients will have access to this and prescribe 5 or more effective drugs to the patients within 14 days of diagnosis.
Eligibility Criteria
You may qualify if:
- 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).
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- University of Cape Townlead
- University of Stellenboschcollaborator
- Ospedale San Raffaelecollaborator
- Stichting Katholieke Universiteitcollaborator
- University of Cape Town Lung Institutecollaborator
Study Sites (1)
University of Cape Town
Cape Town, Western Cape, South Africa
MeSH Terms
Conditions
Condition Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Keertan Dheda, MD/PhD
University of Cape Town
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- not applicable
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- DIAGNOSTIC
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Professor
Study Record Dates
First Submitted
August 13, 2021
First Posted
August 16, 2021
Study Start (Estimated)
June 1, 2026
Primary Completion (Estimated)
May 31, 2028
Study Completion (Estimated)
October 30, 2028
Last Updated
May 6, 2026
Record last verified: 2026-05
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, ICF
- Time Frame
- Beginning 3 months to 5 years following publication.
- Access Criteria
- Individual participant data will be made available to researchers who provide methodologically sound proposals beginning 3 months and ending 5 years following publication. Data sharing requests should be directed to keertan.dheda@uct.ac.za. A data access agreement will need to be concluded.
De-identified individual participant data will be made available to researchers who provide methodologically sound proposals to the principal investigator.