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Test to Treat TB: Impact of Sputum Sequencing-guided Individualised Therapy on Outcomes in Drug-resistant Tuberculosis (T3-RCT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05007795
Recruitment Status : Not yet recruiting
First Posted : August 16, 2021
Last Update Posted : September 29, 2021
Sponsor:
Collaborators:
University of Stellenbosch
Ospedale San Raffaele
Stichting Katholieke Universiteit
University of Cape Town Lung Institute
Information provided by (Responsible Party):
Keertan Dheda, University of Cape Town

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.


Condition or disease Intervention/treatment Phase
Tuberculosis, Multidrug-Resistant Diagnostic Test: Targeted sequencing using the GenoScreen Deeplex assay Not Applicable

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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 : March 2022
Estimated Primary Completion Date : August 2023
Estimated Study Completion Date : June 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
Experimental: Sequence based resistance testing and individualized treatment
Sputum extracted for targeted sequencing and drug resistance profile provided to clinician for individualized treatment.
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.




Primary Outcome Measures :
  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). [ 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.


Secondary Outcome Measures :
  1. 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.


Other Outcome Measures:
  1. 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

  2. Rate of treatment failure [ Time Frame: 6, 12, 18, 24 month post treatment initiation ]
    Rate of treatment failures in conventional and interventional arm

  3. Culture conversion rates [ Time Frame: 6, 12, 18, 24 month post treatment initiation ]
    Culture conversion rates in conventional and interventional arm

  4. Relapse rate [ Time Frame: 6 and 12 months of follow-up ]
    Rate of relapse in conventional and interventional arm

  5. Rates of resistance amplification [ Time Frame: 12 and 24 months post treatment initiation ]
    Rates of resistance amplification in conventional and interventional arm

  6. Adverse event rates [ Time Frame: 6, 12, 18, 24 month post treatment initiation ]
    Adverse event rates in conventional and interventional arm

  7. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).

Information from the National Library of Medicine

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


Contacts
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Contact: Keertan Dheda, MD/PhD +27214066509 keertan.dheda@uct.ac.za
Contact: Ali Esmail, MD ali.esmail@uct.ac.za

Locations
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South Africa
University of Cape Town
Cape Town, Western Cape, South Africa
Sponsors and Collaborators
University of Cape Town
University of Stellenbosch
Ospedale San Raffaele
Stichting Katholieke Universiteit
University of Cape Town Lung Institute
Investigators
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Principal Investigator: Keertan Dheda, MD/PhD University of Cape Town
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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: September 29, 2021
Last Verified: September 2021
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.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Multidrug-Resistant
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Infections