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

Study Overview
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Brief Summary
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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

Detailed Description
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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.

Official Title
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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

Conditions
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Drug Resistant Tuberculosis, MDR-TB, XDR-TB, Tuberculosis

Intervention / Treatment
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* Diagnostic Test: Xpert® MTB/XDR


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ambulant adults ≥ 18 years of age up to 70 years of age Newly diagnosed PTB patients receiving less than 5 days of treatment preceding study entry for the current TB episode, or Sputum positive TB patients classified as failed after or relapse RHZE treatment Xpert MTB/RIF or Ultra assay positive for M.tb infection with at least Rifampicin resistance for cohort 1 and INH-mono resistance (detected by Xpert XDR) for cohort 2 Capacity to provide informed consent 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 Willing to have samples collected, stored indefinitely, and used for research purposes Able to provide reasonable proof of identity (to satisfaction of study team member) at or prior to enrolment Exclusion Criteria: Study participants will be excluded if one or more of the following conditions apply: Has a known severe allergy to any of the BPaL component drugs Has DST showing infection with a strain resistant to any of the component drugs Has TB meningitis, other central nervous system TB, or TB osteomyelitis; or Is pregnant or breastfeeding Is unable to take oral medications Persons with any other medical condition, precluding study participation based on investigator judgement Any co-existing condition that in the opinion of the attending clinician renders the participant unsuitable for participation in the study Co-enrolment in other interventional research studies

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cohort 1<br>Participants that test positive for Mycobacterium tuberculosis (M.tb) with rifampicin resistance will be enrolled in Cohort 1 (n=880). | Diagnostic Test: Xpert® MTB/XDR<br>* 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.<br>* Other names: Xpert XDR;|
| Cohort 2<br>Participants that test positive for M.tb that are rifampicin susceptible with isoniazid mono-resistance will be enrolled in Cohort 2 (n=400). | Diagnostic Test: Xpert® MTB/XDR<br>* 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.<br>* Other names: Xpert XDR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to initiation | 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 | 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 | Incidence of adverse drug reactions documented during all oral treatment | 4 years | 
| Mortality | All cause mortality documented during treatment and follow up | 4 years | 
| Time to culture Conversion | Time specific rates of culture conversion | 4 years | 
| HR TB Prevalence | Prevalence of HR TB (cohort 2) | 4 years | 
| XDR TB Prevalence | Prevalence of XDR TB (cohort 2) | 4 years | 
| Proportion of patients with Bedaquiline and linezolid resistance not eligible for short course treatment | 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 | 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 | 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 | The performance of Xpert XDR will be compared to Culture DST, LPA and Next Generation Sequencing. | 4 years | 
| Quality of Xpert XDR testing | Quality of Xpert XDR testing will be assessed using: indeterminate rates measured by the number of Xpert XDR tests regarded as invalid divided by the total number of Xpert XDR tests performed 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 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 | 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: Frequency of detection of additional resistance conferring mutations by WGS not detected by Xpert XDR Impact of these previously undetected mutation on conferring resistance to the new drugs in the bedaquiline, pretomanid and linezolid regimen | 4 years | 
| Cost effectiveness | 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 | The Operational Cost including Infrastructure and Human resource requirements for the study approach. | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GeneXpert, Diagnostic Tool