Evaluation of Centralised TB Assay Solutions

Multicentre Trial to Assess the Performance of Centralized Assay Solutions for Detection of MTB and Resistance to Rifampin and Isoniazid

Tuberculosis (TB) remains a life-threatening disease partly due to increasing incidence of multidrug and extensively drug-resistant TB. Diagnostic based on culture and conventional drug susceptibility testing using media take several weeks leading to prolonged periods of ineffective therapy and ongoing transmission. Development of rapid molecular diagnostic tests for the identification of Mycobacterium tuberculosis (MTB) and drug resistance has become a high priority.

The Xpert® MTB/RIF Assay does not provide information on INH-resistance and the LPA is only recommended for use in smear-positive samples, complex to perform and requires manual interpretation. Several novel assays have been recently developed/CE-marked offering high sample throughput and higher sensitivity for detection of MTB, RIF- and INH-resistance in centralized laboratories. However, published data on their performance and operational characteristics is extremely limited.

This is a prospective, multicentre, diagnostic accuracy trial in which the performance of centralised TB assay solutions will be assessed at the intended setting of use with culture, phenotypic DST and sequencing as reference standard.

Potential trial participants will be identified at participating TB clinics or hospitals (enrolment sites). Sputum samples will be collected and transported to the associated TB reference laboratories (testing sites).

In order for the results of this trial to be generalizable, adults with symptoms compatible with pulmonary TB undergoing evaluation will be screened for inclusion at geographically diverse participating centres in high burden TB countries. Additionally, to supplement the drug-resistant cases to timely achieve accurate performance estimates, well-characterized frozen sputum samples from the FIND specimen bank will be used.

Study Overview

• Status: Completed
• Conditions: Tuberculosis; Drug-resistant Tuberculosis

• Study Type: Observational
• Enrollment (Actual): 1050

Contacts and Locations

• Study Contact: Name: Margaretha de Vos, PhD; Phone Number: +41 (0) 22 749 29 31; Email: margaretha.devos@finddx.org
• Study Contact Backup: Name: Pamela Nabeta, MD; Phone Number: +41 (0) 22 710 27 87; Email: pamela.nabeta@finddx.org

Study Locations

• Georgia
  • Tbilisi, Georgia
    • National Center for Tuberculosis and Lung Diseases
• Germany
  • Borstel, Germany, 23845
    • Forschungszentrum Borstel. Leibniz Lungenzentrum (Borstel)
• India
  • Bhubaneswar, India, 751023
    • Indian Council of Medical Research (ICMR) Regional Medical Research Centre
  • Chennai, India, 600031
    • National Institute for Research in Tuberculosis
• Moldova, Republic of
  • Chisinau, Moldova, Republic of, 2025
    • Institute of Phthisiopneumology "Ch. Draganiuc" (PPI NRL), Moldova
• South Africa
  • Johannesburg, South Africa, 2193
    • Division of Wits Health Consortium (DMMH)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Patients in whom pulmonary TB is suspected. Additionally, well-characterized RIF-resistant and INH-resistant samples will be used to supplement drug-resistant cases.

Description

Inclusion Criteria:

Patients are eligible to be included as trial participants only if all of the following inclusion criteria apply:

• Aged ≥18 years

• Clinical suspicion of pulmonary TB including cough ≥2 weeks (or any duration if HIV positive ) and ≥1 other symptom typical of pulmonary TB listed below:

  • Fever
  • Malaise
  • Recent weight loss
  • Night sweats
  • Contact with active case
  • Haemoptysis
  • Chest pain
  • Loss of appetite

Exclusion Criteria:

Participants are excluded from the trial if any of the following exclusion criteria apply:

• Unwilling or unable to provide informed consent
• Unwilling to provide four sputum specimens at enrolment i.e. 2x sputa on day 1 and 2x sputa on day 2 (up to 1 week from enrolment)
• Patients with only extra-pulmonary TB signs & symptoms
• Receipt of any dose of TB treatment within 6 months prior to enrolment

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

TB suspects; Sputum specimens will be collected from TB suspects enrolled in the study. The specimens will be tested with; Roche cobas MTB - for the detection of Mycobacterium tuberculosis complex; Roche cobas MTB-RIF/INH - all specimens that are Mycobacterium tuberculosis complex positive will be reflexed to the Roche cobas MTB-RIF/INH test for the detection of resistance to rifampicin and isoniazid; Hain FluoroType MTBDR - for the detection of Mycobacterium tuberculosis complex and the detection of resistance to rifampicin and isoniazid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic accuracy for MTB detection	clinical sensitivity and specificity by smear-status measured against mycobacterial culture as the reference standard.	four to six months
Diagnostic accuracy for RIF/INH detection	clinical point estimates of sensitivity and specificity measured against a composite reference standard of phenotypic DST and targeted sequencing.	four to six months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Operational characteristics:	description of operator experience with the assays through daily observed usage and user appraisal questionnaires.	four to six months

Collaborators and Investigators

• Sponsor: Foundation for Innovative New Diagnostics, Switzerland

Study record dates

Study Major Dates

• Study Start (Actual): May 20, 2019
• Primary Completion (Actual): April 17, 2023
• Study Completion (Actual): September 1, 2023

Study Registration Dates

• First Submitted: October 30, 2019
• First Submitted That Met QC Criteria: October 30, 2019
• First Posted (Actual): November 1, 2019

Study Record Updates

• Last Update Posted (Estimated): November 17, 2023
• Last Update Submitted That Met QC Criteria: November 16, 2023
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Multidrug-Resistant
• Other Study ID Numbers: 7213-2/1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No