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

Tuberculosis Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05175794
• Other study ID #: CAPRISA 094
• Secondary ID: TRIAD
• Status: Recruiting
• Start date: May 26, 2022
• Est. completion date: June 1, 2025

Study information

• Verified date: February 2024
• Source: Centre for the AIDS Programme of Research in South Africa
• Contact: Kogieleum Naidoo, MBCHB, PHD
• Phone: +27 31 655 0707
• Email: kogie.naidoo[@]caprisa.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 1280
• Est. completion date: June 1, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• MDR-TB
• Tuberculosis
• Tuberculosis, Multidrug-Resistant

Intervention

Diagnostic Test:
• Xpert® MTB/XDR
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.

Locations

Country	Name	City	State
Ethiopia	Ethiopian Public Health Institute (EPHI)	Gulele	Addis Ababa
Nigeria	Institute of Human Virology Nigeria	Yaba	Lagos State
South Africa	Clinical HIV Research Unit (CHRU), WITS Health Consortium	Bethelsdorp	Port Elizabeth
South Africa	CAPRISA Springfield Research Clinic	Durban	KwaZulu-Natal

Sponsors (11)

Lead Sponsor	Collaborator
Centre for the AIDS Programme of Research in South Africa	Amsterdam Institute for Global Health and Development, Ethiopian Public Health Institute, Foundation for Innovative New Diagnostics, Switzerland, Global Alliance for TB Drug Development, Institute of Human Virology, Nigeria, KNCV Tuberculosis Foundation, National Institute for Medical Research, Tanzania, Ospedale San Raffaele, University of St Andrews, Wits Health Consortium (Pty) Ltd

Countries where clinical trial is conducted

Ethiopia,  Nigeria,  South Africa, 

References & Publications (2)

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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to initiation	Time to initiation of an appropriate all oral treatment regimen from date of first sputum collected	4 years
Primary	Proportion of patients with favorable treatment outcomes	Proportion of patients with favorable treatment outcomes at month 12 from diagnosis	4 years
Secondary	Adverse Drug Reactions	Incidence of adverse drug reactions documented during all oral treatment	4 years
Secondary	Mortality	All cause mortality documented during treatment and follow up	4 years
Secondary	Time to culture Conversion	Time specific rates of culture conversion	4 years
Secondary	HR TB Prevalence	Prevalence of HR TB (cohort 2)	4 years
Secondary	XDR TB Prevalence	Prevalence of XDR TB (cohort 2)	4 years
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Operational Feasibility of patient triaging	The Operational Cost including Infrastructure and Human resource requirements for the study approach.	4 years

External Links

•   WHO consolidated guidelines on tuberculosis