Clinical trial NCT05175794: Triage Test for All Oral DR-TB Regimen (TRiAD Study)
Official title: 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
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Drug Resistant Tuberculosis
MDR-TB
XDR-TB
Tuberculosis
Keywords: GeneXpert
Diagnostic Tool
Lead sponsor: Centre for the AIDS Programme of Research in South Africa
Sponsor class: NETWORK
Collaborators: name: KNCV Tuberculosis Foundation
name: Amsterdam Institute for Global Health and Development
name: Ospedale San Raffaele
name: Foundation for Innovative New Diagnostics, Switzerland
name: National Institute for Medical Research, Tanzania
name: University of St Andrews
name: Global Alliance for TB Drug Development
name: Wits Health Consortium (Pty) Ltd
name: Institute of Human Virology, Nigeria
name: Ethiopian Public Health Institute
First posted: 2022-01-04
Enrollment: 1280
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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)

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to initiation
timeFrame: 4 years
measure: Proportion of patients with favorable treatment outcomes
timeFrame: 4 years
Secondary outcomes:
measure: Adverse Drug Reactions
timeFrame: 4 years
measure: Mortality
timeFrame: 4 years
measure: Time to culture Conversion
timeFrame: 4 years
measure: HR TB Prevalence
timeFrame: 4 years
measure: XDR TB Prevalence
timeFrame: 4 years
measure: Proportion of patients with Bedaquiline and linezolid resistance not eligible for short course treatment
timeFrame: 4 years
measure: Clinical utility of the Tuberculosis Molecular Bacterial Load Assay (TB-MBLA) compared to routine culture to monitor DR-TB treatment response
timeFrame: 4 years
measure: 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
timeFrame: 4 years
measure: Accuracy of Xpert XDR testing compared to WGS
timeFrame: 4 years
measure: Quality of Xpert XDR testing
timeFrame: 4 years
measure: Resistance profile of sputum samples for identification of drug resistance mutations as per pre-existing probes within the Xpert XDR assay
timeFrame: 4 years
measure: Cost effectiveness
timeFrame: 4 years
measure: Operational Feasibility of patient triaging
timeFrame: 4 years
Other outcomes:
Locations:
city: Gulele
country: Ethiopia
facility: Ethiopian Public Health Institute (EPHI)
state: Addis Ababa
city: Yaba
country: Nigeria
facility: Institute of Human Virology Nigeria
state: Lagos State
city: Durban
country: South Africa
facility: CAPRISA Springfield Research Clinic
state: KwaZulu-Natal
city: Bethelsdorp
country: South Africa
facility: Clinical HIV Research Unit (CHRU), WITS Health Consortium
state: Port Elizabeth
Study officials:
affiliation: Deputy Director -CAPRISA
name: Kogieleum Naidoo, MBCHB, PHD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, Mendel CM, Egizi E, Moreira J, Timm J, McHugh TD, Wills GH, Bateson A, Hunt R, Van Niekerk C, Li M, Olugbosi M, Spigelman M; Nix-TB Trial Team. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. N Engl J Med. 2020 Mar 5;382(10):893-902. doi: 10.1056/NEJMoa1901814.
citation: Gillespie SH, Sabiiti W, Oravcova K. Mycobacterial Load Assay. Methods Mol Biol. 2017;1616:89-105. doi: 10.1007/978-1-4939-7037-7_5.