Ignite Creation Date:
2024-05-06 @ 2:10 PM
Last Modification Date:
2024-10-26 @ 1:26 PM
Study NCT ID:
NCT04239326
Status:
COMPLETED
Last Update Posted:
2023-10-04
First Post:
2020-01-20
Brief Title:
Clinical Evaluation of tNGS for Diagnosis of DR-TB
Sponsor:
Foundation for Innovative New Diagnostics Switzerland
Organization:
Foundation for Innovative New Diagnostics Switzerland
Study Overview
Official Title:
Multicentre Clinical Trial to Assess the Performance of Culture-free End-to-end Targeted NGS tNGS Solutions for Diagnosis of Drug Resistant TB DR-TB
Status:
COMPLETED
Status Verified Date:
2023-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
SeqTreat
Brief Summary:
Current rapid molecular assays for detection of drug-resistant TB from direct clinical samples have important limitations They are not suited for high-throughput settings can only be used to detect a limited number of target gene regions and are not ideal for detection of phenotypic resistance conferred by mutations across large gene regions eg pyrazinamide
Culture-free end-to-end targeted NGS tNGS Solutions for Diagnosis of Drug Resistant TB can offer higher throughput and greater accuracy across more TB drugs than current WHO endorsed molecular assays and a significantly faster time to result than phenotypic drug susceptibility testing DST
Evidence regarding the clinical diagnostic accuracy and operational characteristics of tNGS solutions is needed to comprehensively evaluate tNGS for diagnosis of drug-resistant TB among patients who have been diagnosed with TB and will be critical to inform global and national policy
Culture-free end-to-end targeted NGS tNGS Solutions for Diagnosis of Drug Resistant TB can offer higher throughput and greater accuracy across more TB drugs than current WHO endorsed molecular assays and a significantly faster time to result than phenotypic drug susceptibility testing DST
Evidence regarding the clinical diagnostic accuracy and operational characteristics of tNGS solutions is needed to comprehensively evaluate tNGS for diagnosis of drug-resistant TB among patients who have been diagnosed with TB and will be critical to inform global and national policy
Detailed Description:
In recent years tuberculosis TB control efforts have been complicated by the rise and spread of MDR-TB or TB that is resistant to the first-line drugs isoniazid INH and rifampicin RIF and XDR-TB or MDR-TB that has developed additional resistance to a fluoroquinolone FQ and any of the second-line injectable compounds SLI amikacin AMK kanamycin KAN andor capreomycin CAP The rapid diagnosis and appropriate treatment of MXDR-TB is essential to prevent significant morbidity mortality and further transmission of disease For treatment of uncomplicated MDR-TB the World Health Organization WHO recently endorsed a 6-9 month treatment regimen replacing conventional 18-24 month regimens The FQs and SLIs are key components of the 6-9 month regimen and so it is necessary to rule-out resistance to these compounds prior to treating patients with the shorter regimen For longer MDR-TB treatment regimens WHO no longer endorses the use of CAP or KAN but the regimens still rely heavily on FQs with AMK and PZA listed as recommended Group C drugs thus ensuring that the rapid diagnosis of all of these drugs is still relevant and critical to the timely treatment of DR-TB4
The current standard for comprehensive DR-TB diagnosis is culture-based DST liquid culture eg MGIT or solid culture eg LJ which can only be implemented in custom-built Biosafety Level 3 BSL3 laboratories The global response to the need for comprehensive DST in the last two decades has therefore been focused on the scale-up of BSL3 facilities and MGIT liquid culture systems to expand global capacity While this enabled some standardization of DST workflows and resulted in a foundation for a global network of reference TB laboratories it has come at considerable cost and effort in terms of infrastructure needs significant hands-on time and expertise for routine use Moreover the slow growth of Mycobacterium tuberculosis Mtb in culture means it takes 6-8 weeks to get results from conventional culture-based DST and data has shown that often culture comes too late to have an impact on the patient outcomes More recently the global response to the public health need for universal DST has been a wide rollout and broad adoption of rapid molecular TB tests with limited DST capabilities to support early treatment decisions and complement traditional phenotypic DST eg Cepheid Xpert MTBRIF or Ultra Hain GenoType MTBDRplus However the inherent design of probe- or array-based molecular diagnostics limits their coverage to a limited number of specific mutations included in the initial design-locked assay and prevents them from integrating new mutations and new drug resistance prediction without going back to complete product development and validation Next generation sequencing NGS technology has the potential to revolutionize global comprehensive DST Targeted NGS tNGS can be used to interrogate more than numerous genome-wide targets in the Mycobacterium tuberculosis MTB that contain mutations associated with resistance and differentiate them from mutations that do not confer resistance providing better performance than probe or array-based molecular diagnostics
For DR-TB diagnosis tNGS offers huge potential gains over culture-based methods and other molecular diagnostics in terms of speed ease of use and comprehensive coverage However the uptake of sequencing for DR-TB patient care in LMICs has been limited due to i the absence of a standardized and complete solution directly from clinical samples to data analysis and interpretation ie an end-to-end solution ii lack of verification and validation of such commercial end-to-end sequencing solutions to drive policy and guidelines for use of sequencing as an in vitro diagnostic and iii perceived technical and cost barriers The WHO and FIND developed a technical guide on requirements and utilization of sequencing for clinical diagnosis of DR-TB and a consensus-based Target Product Profile TPP for sequencing The standard components of an End-to-end solution include DNA extraction from sputum sample library preparation sequencing and data analysisinterpretation for clinical result reporting Based on the published TPP guidelines a number of manufacturers have developed end-to-end solutions for DR-TB diagnosis These sequencing solutions require rigorous analytical testing laboratory validation and clinical evaluation in order to ensure that they meet technical as well as operational target product profile criteria
The current study is part of a two-phase project to assess performance of culture-free tNGS end-to-end solutions for drug resistant TB diagnosis and to recommend their use in diverse clinical settings
Phase 1 is an analytical study performed at the manufacturer site It is a blinded laboratory analytical validation of tNGS end-to-end solutions using a well-characterized panel of MTB strains
Phase 2 the current study is a multi-centre clinical trial to evaluate the diagnostic accuracy and performance of up to 3 tNGS end-to-end sequencing solutions in settings of intended use
The two study phases will provide complementary bodies of evidence to address the study objectives and determine whether tNGS solutions meet the diagnostic performance criteria outlined in the NGS Target Product Profile TPP for clinical diagnosis of drug resistant TB The purpose of this clinical trial is to confirm accuracy estimates observed in the laboratory validation study and ensure that tNGS diagnostic performance characteristics are consistent at sites of intended use
The focus of this protocol is the multi-centre clinical evaluation of the diagnostic accuracy and technical performance of End-to-end tNGS solutions for DR-TB diagnosis
The current standard for comprehensive DR-TB diagnosis is culture-based DST liquid culture eg MGIT or solid culture eg LJ which can only be implemented in custom-built Biosafety Level 3 BSL3 laboratories The global response to the need for comprehensive DST in the last two decades has therefore been focused on the scale-up of BSL3 facilities and MGIT liquid culture systems to expand global capacity While this enabled some standardization of DST workflows and resulted in a foundation for a global network of reference TB laboratories it has come at considerable cost and effort in terms of infrastructure needs significant hands-on time and expertise for routine use Moreover the slow growth of Mycobacterium tuberculosis Mtb in culture means it takes 6-8 weeks to get results from conventional culture-based DST and data has shown that often culture comes too late to have an impact on the patient outcomes More recently the global response to the public health need for universal DST has been a wide rollout and broad adoption of rapid molecular TB tests with limited DST capabilities to support early treatment decisions and complement traditional phenotypic DST eg Cepheid Xpert MTBRIF or Ultra Hain GenoType MTBDRplus However the inherent design of probe- or array-based molecular diagnostics limits their coverage to a limited number of specific mutations included in the initial design-locked assay and prevents them from integrating new mutations and new drug resistance prediction without going back to complete product development and validation Next generation sequencing NGS technology has the potential to revolutionize global comprehensive DST Targeted NGS tNGS can be used to interrogate more than numerous genome-wide targets in the Mycobacterium tuberculosis MTB that contain mutations associated with resistance and differentiate them from mutations that do not confer resistance providing better performance than probe or array-based molecular diagnostics
For DR-TB diagnosis tNGS offers huge potential gains over culture-based methods and other molecular diagnostics in terms of speed ease of use and comprehensive coverage However the uptake of sequencing for DR-TB patient care in LMICs has been limited due to i the absence of a standardized and complete solution directly from clinical samples to data analysis and interpretation ie an end-to-end solution ii lack of verification and validation of such commercial end-to-end sequencing solutions to drive policy and guidelines for use of sequencing as an in vitro diagnostic and iii perceived technical and cost barriers The WHO and FIND developed a technical guide on requirements and utilization of sequencing for clinical diagnosis of DR-TB and a consensus-based Target Product Profile TPP for sequencing The standard components of an End-to-end solution include DNA extraction from sputum sample library preparation sequencing and data analysisinterpretation for clinical result reporting Based on the published TPP guidelines a number of manufacturers have developed end-to-end solutions for DR-TB diagnosis These sequencing solutions require rigorous analytical testing laboratory validation and clinical evaluation in order to ensure that they meet technical as well as operational target product profile criteria
The current study is part of a two-phase project to assess performance of culture-free tNGS end-to-end solutions for drug resistant TB diagnosis and to recommend their use in diverse clinical settings
Phase 1 is an analytical study performed at the manufacturer site It is a blinded laboratory analytical validation of tNGS end-to-end solutions using a well-characterized panel of MTB strains
Phase 2 the current study is a multi-centre clinical trial to evaluate the diagnostic accuracy and performance of up to 3 tNGS end-to-end sequencing solutions in settings of intended use
The two study phases will provide complementary bodies of evidence to address the study objectives and determine whether tNGS solutions meet the diagnostic performance criteria outlined in the NGS Target Product Profile TPP for clinical diagnosis of drug resistant TB The purpose of this clinical trial is to confirm accuracy estimates observed in the laboratory validation study and ensure that tNGS diagnostic performance characteristics are consistent at sites of intended use
The focus of this protocol is the multi-centre clinical evaluation of the diagnostic accuracy and technical performance of End-to-end tNGS solutions for DR-TB diagnosis
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None