Triage Test for All Oral DR-TB Regimen (TRiAD Study)

February 16, 2024 updated by: Dr Kogieleum Naidoo, Centre for the AIDS Programme of Research in South Africa

Phase 4 Operational Study to Assess the Effectiveness, Feasibility, Acceptability, and Cost-effectiveness of the GeneXpert MTB/XDR (Xpert XDR; Cepheid) Assay for Rapid Triage-and-treatment of DR-TB

A Phase 4 operational study to assess the effectiveness, feasibility, acceptability, and cost effectiveness of the GeneXpert MTB/XDR (Xpert XDR; Cepheid) assay for rapid triage-and-treatment of DR-TB-A multi-centre, multi-country prospective cohort study

Study Overview

Status

Recruiting

Intervention / Treatment

Detailed Description

The TriAD study is a multi-center, multi-country Prospective Pragmatic Cohort study assessing the effectiveness, feasibility, acceptability, and cost-effectiveness of implementing the Xpert MTB/XDR (Xpert XDR; Cepheid) assay for rapid triage-and-treatment with short, all- oral drug resistant tuberculosis (DR-TB) treatment. The proposed study aims to screen approximately 4800 GeneXpert MTB/RIF or Ultra MTB-positive (irrespective of rifampicin resistance status) patients from 9 study sites in South Africa, Nigeria and Ethiopia to enrol 880 rifampicin resistant (RR) and 400 isoniazid mono-resistant (HR) patients over a period of 12-18 months. The Xpert XDR assay, a rapid genotypic test, will be implemented as a reflex test to detect resistance to isoniazid, fluoroquinolones and second-line injectable agents to provide rapid genotypic susceptibility testing for DR-TB detection. Patients that test positive for Mycobacterium tuberculosis with rifampicin resistance will be enrolled in Cohort 1 (n=880). Patients that test positive for Mycobacterium tuberculosis that are rifampicin susceptible with isoniazid mono-resistance will be enrolled in Cohort 2 (n=400). Results from the Xpert XDR assay will be used to guide selection of appropriate, evidence-based, all-oral DR-TB treatment regimens of shortest possible duration. The tuberculosis molecular bacterial load assay (TB-MBLA) will be used as an adjunct to provide bacillary load monitoring over the course of treatment to assess real-time treatment response. Operational research will provide information about the feasibility, acceptability and cost-effectiveness to inform policies and guidelines for programmatic implementation of the triage-and-treat model.

Study Type

Observational

Enrollment (Estimated)

1280

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

    • Addis Ababa
      • Gulele, Addis Ababa, Ethiopia
    • Lagos State
      • Yaba, Lagos State, Nigeria
        • Recruiting
        • Institute of Human Virology Nigeria
        • Contact:
        • Contact:
    • KwaZulu-Natal
      • Durban, KwaZulu-Natal, South Africa, 4091
    • Port Elizabeth
      • Bethelsdorp, Port Elizabeth, South Africa, 6200
        • Recruiting
        • Clinical HIV Research Unit (CHRU), WITS Health Consortium
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Two screening strategies will be adopted:

  1. Patients with suspected pulmonary TB or confirmed M.tb positive (< 5 days since treatment initiation) will be screened and consented to provide an additional sputum sample for Xpert MTB/XDR testing. This will be in addition to the routine sample collected for GeneXpert MTB/RIF or Ultra testing
  2. We will concurrently contact all patients with newly identified RR-TB during the study enrolment period directly for participation in this study (laboratory records)

Description

Inclusion Criteria:

  1. Ambulant adults ≥ 18 years of age
  2. Newly diagnosed PTB patients receiving less than 5 days of treatment since new diagnosis:

    1. Cohort 1: < 5 days of DR-TB treatment
    2. Cohort 2: < 5 days of INH mono-resistant TB treatment preceding study entry for the current TB episode, or
  3. Sputum positive (smear and or culture) TB patients classified as failing first line treatment
  4. Any currently available Nucleic Acid Amplification Tests for drug-resistance detection changes/assay positive for M.tb infection with:

    Cohort 1: at least Rifampicin resistance Cohort 2: Rifampicin susceptible co-occurring with INH, fluoroquinolone, ethionamide or aminoglycoside resistance (detected by Xpert XDR) occurring alone or in combination

  5. Capacity to provide informed consent
  6. HIV infected and uninfected participants are allowed in the study. Participants already on ART will be allowed in the study provided the ART regimen in use has no contraindications to the proposed TB drug regimen
  7. Willing to have samples collected, stored indefinitely, and used for research purposes
  8. Able to provide reasonable proof of identity (to satisfaction of study team member) at or prior to enrolment

Exclusion criteria:

  1. Has a known severe allergy to any of the BPaL component drugs
  2. Has DST showing infection with a strain resistant to any of the component drugs
  3. Has TB meningitis, other central nervous system TB, or TB osteomyelitis; or
  4. Is pregnant or breastfeeding
  5. Is unable to take oral medications
  6. Persons with any other medical condition, precluding study participation based on investigator judgement
  7. Any co-existing condition that in the opinion of the attending clinician renders the participant unsuitable for participation in the study
  8. Co-enrolment in other interventional research studies

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Cohort 1
Participants that test positive for Mycobacterium tuberculosis (M.tb) with rifampicin resistance will be enrolled in Cohort 1 (n=880).
The Xpert MTB/XDR Assay, performed on the GeneXpert Instrument Systems, is a nested real-time polymerase chain reaction(PCR) in vitro diagnostic test for the detection of extensively drug resistant (XDR) Mycobacterium tuberculosis (MTB) complex DNA in unprocessed sputum samples or concentrated sediments prepared from sputum. In specimens where MTB is detected, the Xpert MTB/XDR Assay can also detect isoniazid (INH) resistance associated mutations in the katG and fabG1 genes, oxyRahpC intergenic region and inhA promoter; ethionamide (ETH) resistance associated with inhA promoter mutations only; fluoroquinolone (FLQ) resistance associated mutations in the gyrA and gyrB quinolone resistance determining regions (QRDR); and second line injectable drug (SLID) associated mutations in the rrs gene and the eis promoter region.
Other Names:
  • Xpert MTB/XDR Assay
  • Xpert XDR
Cohort 2
Participants that test positive for M.tb that are rifampicin susceptible with isoniazid mono-resistance will be enrolled in Cohort 2 (n=400).
The Xpert MTB/XDR Assay, performed on the GeneXpert Instrument Systems, is a nested real-time polymerase chain reaction(PCR) in vitro diagnostic test for the detection of extensively drug resistant (XDR) Mycobacterium tuberculosis (MTB) complex DNA in unprocessed sputum samples or concentrated sediments prepared from sputum. In specimens where MTB is detected, the Xpert MTB/XDR Assay can also detect isoniazid (INH) resistance associated mutations in the katG and fabG1 genes, oxyRahpC intergenic region and inhA promoter; ethionamide (ETH) resistance associated with inhA promoter mutations only; fluoroquinolone (FLQ) resistance associated mutations in the gyrA and gyrB quinolone resistance determining regions (QRDR); and second line injectable drug (SLID) associated mutations in the rrs gene and the eis promoter region.
Other Names:
  • Xpert MTB/XDR Assay
  • Xpert XDR

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Time to initiation
Time Frame: 4 years
Time to initiation of an appropriate all oral treatment regimen from date of first sputum collected
4 years
Proportion of patients with favorable treatment outcomes
Time Frame: 4 years
Proportion of patients with favorable treatment outcomes at month 12 from diagnosis
4 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Adverse Drug Reactions
Time Frame: 4 years
Incidence of adverse drug reactions documented during all oral treatment
4 years
Mortality
Time Frame: 4 years
All cause mortality documented during treatment and follow up
4 years
Time to culture Conversion
Time Frame: 4 years
Time specific rates of culture conversion
4 years
HR TB Prevalence
Time Frame: 4 years
Prevalence of HR TB (cohort 2)
4 years
XDR TB Prevalence
Time Frame: 4 years
Prevalence of XDR TB (cohort 2)
4 years
Proportion of patients with Bedaquiline and linezolid resistance not eligible for short course treatment
Time Frame: 4 years
Proportion of patients with Bedaquiline and linezolid resistance not eligible for short course treatment
4 years
Clinical utility of the Tuberculosis Molecular Bacterial Load Assay (TB-MBLA) compared to routine culture to monitor DR-TB treatment response
Time Frame: 4 years
Quantitative results from the TB-MBLA, a real-time quantitative PCR (RT-qPCR) assay, that detects and quantifies killing of 16S rRNA from both viable replicating and dormant M. tuberculosis in patient sputum during treatment, will be compared to routine culture in monitoring treatment response
4 years
Feasibility of Tuberculosis Molecular Bacterial Load Assay (TB-MBLA) will be compared to routine culture in bacteriological follow-up for people on DR-TB treatment
Time Frame: 4 years
Feasibility of TB-MBLA Assessed by comparison to liquid culture with respect to accuracy, result turn-around time, failure rates.
4 years
Accuracy of Xpert XDR testing compared to WGS
Time Frame: 4 years
The performance of Xpert XDR will be compared to Culture DST, LPA and Next Generation Sequencing.
4 years
Quality of Xpert XDR testing
Time Frame: 4 years

Quality of Xpert XDR testing will be assessed using:

  1. indeterminate rates measured by the number of Xpert XDR tests regarded as invalid divided by the total number of Xpert XDR tests performed
  2. Contamination rates or frequency of DNA contamination: number of Xpert XDR tests flagging contamination divided by the total number of Xpert XDR tests performed or events
  3. performance variation will be measured by performance in discrimination of (i) INH resistance compared to culture across study sites, (ii) aminoglycoside resistance compared to culture across study sites and (iii) fluroquinolone resistance compared to culture across study sites
4 years
Resistance profile of sputum samples for identification of drug resistance mutations as per pre-existing probes within the Xpert XDR assay
Time Frame: 4 years

Cultured isolates from the same sputum sample will undergo WGS sequencing to identify additional resistance mutations to new and re-purposed drugs. The endpoints measured for this objective includes:

  1. Frequency of detection of additional resistance conferring mutations by WGS not detected by Xpert XDR
  2. Impact of these previously undetected mutation on conferring resistance to the new drugs in the bedaquiline, pretomanid and linezolid regimen
4 years
Cost effectiveness
Time Frame: 4 years

Data for Costing studies will be collected through semi-structured interviews of key informants and document review. Methods will include a construction of incremental cost effectiveness ratios (ICER) and CE-model to estimate the costs and benefits from a societal perspective, generalizable to other settings.

timely initiated on treatment

4 years
Operational Feasibility of patient triaging
Time Frame: 4 years
The Operational Cost including Infrastructure and Human resource requirements for the study approach.
4 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 26, 2022

Primary Completion (Estimated)

December 31, 2024

Study Completion (Estimated)

June 1, 2025

Study Registration Dates

First Submitted

September 22, 2021

First Submitted That Met QC Criteria

December 14, 2021

First Posted (Actual)

January 4, 2022

Study Record Updates

Last Update Posted (Actual)

February 20, 2024

Last Update Submitted That Met QC Criteria

February 16, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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