Rapid Research in Diagnostics Development for TB Network

Study Overview
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Brief Summary
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To reduce the burden of TB worldwide through more accurate, faster, simpler, and less expensive diagnosis of TB Every year, more than 3 million people with TB remain undiagnosed and 1 million die. Better diagnostics are essential to reducing the enormous burden of TB worldwide. The Rapid Research in Diagnostics Development for TB Network (R2D2 TB Network) brings together experts in TB care, technology assessment, diagnostics development, laboratory medicine, epidemiology, health economics and mathematical modeling with highly experienced clinical study sites in 10 countries

Detailed Description
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The Rapid Research in Diagnostics Development for TB Network (R2D2 TB Network) study seeks to identify and rigorously assess promising early stage tuberculosis (TB) triage, diagnostic and drug resistance tests (hereafter referred to as novel tests) in clinical studies conducted in settings of intended use. Rapid diagnosis, identification of drug resistance and effective treatment are critical for improving patient outcomes and reducing TB transmission. However, analysis of care cascades and prevalence surveys indicate that 40-60% of patients with TB are not initiated on effective treatment.1,2 The different types of tests required to reduce this diagnostic gap have been described in the form of target product profiles (TPPs). The highest- priority TPPs are for: 1) a point-of-care, non-sputum biomarker-based test to facilitate rapid TB diagnosis using easily accessible samples (a biomarker-based diagnostic test) and 2) a simple, low-cost test that can be used by front-line health workers to rule-out TB (a triage test). The R2D2 TB Network study will evaluate the sensitivity and specificity of novel triage and diagnostic tests against a reference standard including sputum Xpert® MTB/RIF (Mycobacterium tuberculosis/Rifampin) Ultra and sputum mycobacterial culture. The sensitivity and specificity of rapid drug susceptibility tests (rDST) will be compared against a reference standard including culture-based phenotypic DST and whole genome sequencing (WGS) of mycobacterial DNA. In addition, the usability of novel tests will be assessed through direct observations and surveys of routine health workers.

Official Title
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Rapid Research in Diagnostics Development for TB Network (R2D2 TB Network) Study

Conditions
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Tuberculosis

Intervention / Treatment
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* Diagnostic Test: Novel mycobacterial culture techniques
* Diagnostic Test: Novel sputum smear microscopy techniques
* Diagnostic Test: Sputum-based molecular assays
* Diagnostic Test: Tongue swab-based molecular assays
* Diagnostic Test: Urine LAM assays
* Diagnostic Test: Blood-based host immune response assays
* Diagnostic Test: Breath-based assays
* Diagnostic Test: Artificial intelligence-based digital health tools
* Diagnostic Test: Phage-based assays
* Diagnostic Test: Cartridge-based molecular assays for detecting drug resistance
* Diagnostic Test: Sequencing-based assays for detecting drug resistance


Participation Criteria
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Eligibility Criteria
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Novel TB triage and diagnostic tests: We will include non-hospitalized adults (age ≥ 12 years) with either 1) cough ≥2 weeks' duration, a commonly accepted criterion for identifying people with presumed pulmonary TB (to facilitate standardization across sites and comparison of test performance across sub-groups or 2) risk factors for which TB screening is recommended (HIV infection, self-reported close contact, history of mining work). People with risk factors will be included if they screen positive for TB based on WHO-recommended screening tools as specified below: Positive TB screening definitions by risk factor: PLHIV (Risk Factor), CRP >5 mg/dL OR abnormal CXR (Positive TB screening definition) Self-reported Close Contact (Risk Factor), abnormal CXR (Positive TB screening definition) History of mining work (Risk Factor), abnormal CXR (Positive TB screening definition) We will exclude people who: completed latent or active TB treatment within the past 12 months (to increase TB prevalence and reduce false-positive results, respectively); have taken any medication with anti-mycobacterial activity (including fluoroquinolones) for any reason, within 2 weeks of study entry (to reduce false-negatives); reside >20km from the study site or are unwilling to return for follow-up visits; or are unwilling to provide informed consent Novel TB rDST assays: We will include adults (age ≥12 years) who are positive for TB and RIF resistance according to routine diagnostic testing (based typically on Xpert MTB/RIF, Xpert MTB/RIF Ultra, or Hain MTBDRplus). We will exclude people who: have negative or contaminated results on all baseline (i.e., enrollment) sputum cultures are unable to provide at least two sputum specimens of 3 mL each within one day of enrollment are unable or unwilling to provide informed consent Assessment of the usability of novel TB tests: We will include health workers at each clinical site who are 1) aged ≥18 years and 2) involved in routine TB testing (collecting specimens for or performing TB tests). We will exclude staff who are unwilling to provide informed consent.

Ages Eligible for Study
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Minimum Age: 12 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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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Evaluation of various novel TB triage and diagnostic tests.<br>For the novel TB triage and diagnostic tests, the investigators will conduct large-scale evaluation of design-locked tests in a cohort of adults with presumed TB, with nested feasibility/pilot studies of early and late prototype tests. The investigators aim to enroll 300-450 participants per year at each of five enrollment sites for evaluation of various novel TB triage and diagnostic tests and 50 health workers to assess test usability. | Diagnostic Test: Novel mycobacterial culture techniques<br>* We will evaluate tests intended to make culture more sensitive, faster, and have less contamination.<br>Diagnostic Test: Novel sputum smear microscopy techniques<br>* We will evaluate new staining techniques or visualization methods to increase the sensitivity of smear microscopy.<br>Diagnostic Test: Sputum-based molecular assays<br>* We will evaluate semi-automated or automated molecular assays intended for use at near point of care or point of care.<br>Diagnostic Test: Tongue swab-based molecular assays<br>* We will evaluate semi-automated or automated molecular assays intended for use at near point of care or point of care.<br>Diagnostic Test: Urine LAM assays<br>* We will evaluate urine LAM assays incorporating techniques such as analyte concentration, higher sensitivity or specificity antibodies, or enhanced visualization to improve LAM detection.<br>Diagnostic Test: Blood-based host immune response assays<br>* We will evaluate assays measuring host immune response parameters intended for use at near point of care or point of care.<br>Diagnostic Test: Breath-based assays<br>* We will evaluate assays assessing volatile organic compounds or exhaled breath condensate for near point of care of point of care detection of TB.<br>Diagnostic Test: Artificial intelligence-based digital health tools<br>* We will evaluate AI-based algorithms evaluating images (chest x-ray, ultrasound) or sounds (cough sounds, lung sounds) including an Infrasound-to-ultrasound e-stethoscope (Level 42 AI, USA).<br>Diagnostic Test: Phage-based assays<br>* We will evaluate assays using phages to lyse mycobacterial cells for detection of DNA or antigens.<br>|
| Experimental: Evaluation of novel rDST assays<br>Clinicians at participating sites will be asked to refer adult patients with rifampin-resistance identified by routine molecular testing. The investigators aim to enroll 100-200 patients per year at each of three enrollment sites for evaluation of novel rDST assays. | Diagnostic Test: Cartridge-based molecular assays for detecting drug resistance<br>* We will evaluate semi-automated or automated molecular assays intended for use at near point of care or point of care.<br>Diagnostic Test: Sequencing-based assays for detecting drug resistance<br>* We will evaluate targeted and whole genome sequencing assays.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitivity | Number of positive results for a given index test/(Total positive + negative results for a given index test) among patients with TB using the microbiological reference standard | 2 years | 
| Specificity | Number of negative results for a given index test/(Total positive + negative results for a given index test) among patients without TB using the microbiological reference standard | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis, Diagnostics, Global Health