Test to Treat TB: Impact of Sputum Sequencing-guided Individualised Therapy on Outcomes in Drug-resistant Tuberculosis (T3-RCT)
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ClinicalTrials.gov Identifier: NCT05007795 |
Recruitment Status :
Not yet recruiting
First Posted : August 16, 2021
Last Update Posted : July 27, 2023
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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.
Condition or disease | Intervention/treatment | Phase |
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Tuberculosis, Multidrug-Resistant | Diagnostic Test: Targeted sequencing using the GenoScreen Deeplex assay | Not Applicable |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 280 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Diagnostic |
Official Title: | Test to Treat TB: Impact of Sputum Sequencing-guided Individualised Therapy on Outcomes in Drug-resistant Tuberculosis (TB): a Proof of Concept Randomized Controlled Trial |
Estimated Study Start Date : | July 2023 |
Estimated Primary Completion Date : | August 2026 |
Estimated Study Completion Date : | July 2027 |
Arm | Intervention/treatment |
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No Intervention: Programmatic MDR TB treatment regimen
Conventional 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.
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Experimental: Sequence based resistance testing and individualized treatment
Sputum extracted for targeted sequencing and drug resistance profile provided to clinician for individualized treatment.
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Diagnostic Test: Targeted sequencing using the GenoScreen Deeplex assay
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. |
- 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). [ Time Frame: 14 days ]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.
- Feasibility of targeted sequencing to initiate more than or equal to five effective TB drugs within 14 days of diagnosis. [ Time Frame: 14 days ]To determine the proportion of patients in the interventional group with a drug-resistant profile and placed on ≥ 5 likely effective drugs within 14 days of rifampicin resistant tuberculosis diagnosis.
- Favourable outcome rate [ Time Frame: 6, 12, 18, 24 month post treatment initiation ]Rate of favourable outcome (cure or treatment complete) in conventional and interventional arms
- Rate of treatment failure [ Time Frame: 6, 12, 18, 24 month post treatment initiation ]Rate of treatment failures in conventional and interventional arm
- Culture conversion rates [ Time Frame: 6, 12, 18, 24 month post treatment initiation ]Culture conversion rates in conventional and interventional arm
- Relapse rate [ Time Frame: 6 and 12 months of follow-up ]Rate of relapse in conventional and interventional arm
- Rates of resistance amplification [ Time Frame: 12 and 24 months post treatment initiation ]Rates of resistance amplification in conventional and interventional arm
- Adverse event rates [ Time Frame: 6, 12, 18, 24 month post treatment initiation ]Adverse event rates in conventional and interventional arm
- Cost effectiveness [ Time Frame: 24 month post treatment initiation ]Cost implications of the targeted sequencing diagnostic approach compared to the current programmatic standard of care.
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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | All |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
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.
Exclusion Criteria:
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).
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05007795
Contact: Keertan Dheda, MD/PhD | +27214066509 | keertan.dheda@uct.ac.za | |
Contact: Ali Esmail, MD | ali.esmail@uct.ac.za |
South Africa | |
University of Cape Town | |
Cape Town, Western Cape, South Africa |
Principal Investigator: | Keertan Dheda, MD/PhD | University of Cape Town |
Responsible Party: | Keertan Dheda, Professor, University of Cape Town |
ClinicalTrials.gov Identifier: | NCT05007795 |
Other Study ID Numbers: |
T3-RCT 743-2018 ( Other Identifier: University of Cape Town Human Research Ethics Committee ) |
First Posted: | August 16, 2021 Key Record Dates |
Last Update Posted: | July 27, 2023 |
Last Verified: | July 2023 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Yes |
Plan Description: | De-identified individual participant data will be made available to researchers who provide methodologically sound proposals to the principal investigator. |
Supporting Materials: |
Study Protocol Informed Consent Form (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. |
Studies a U.S. FDA-regulated Drug Product: | No |
Studies a U.S. FDA-regulated Device Product: | No |
Tuberculosis Tuberculosis, Multidrug-Resistant Mycobacterium Infections Actinomycetales Infections |
Gram-Positive Bacterial Infections Bacterial Infections Bacterial Infections and Mycoses Infections |