Evaluation of Centralised TB Assay Solutions

Study Overview
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Brief Summary
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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.

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

Conditions
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Tuberculosis, Drug-resistant Tuberculosis

Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| TB suspects<br>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?
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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 |