Rapid Research in Diagnostics Development for TB Network

Overview

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

Full Title of Study: “Rapid Research in Diagnostics Development for TB Network (R2D2 TB Network) Study”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Diagnostic
    • Masking: None (Open Label)
  • Study Primary Completion Date: May 31, 2025

Detailed Description

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/urine Gene 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. The novel TB triage, diagnostic and drug resistance tests that the investigators currently plan to evaluate are shown in Table 1. The countries/study sites in which each novel test will be evaluated are shown in Table 2. This master study protocol will be updated to include additional novel tests as they are identified or to remove novel tests when their evaluation is complete. Additional prototype TB triage, diagnostic and drug resistance tests, including assays that address multiple pathogens in parallel with TB will be evaluated in subsequent project years.

Interventions

  • Diagnostic Test: FLOW-TB Next-generation LAM
    • A next-generation urine lipoarabinomannan (LAM) assay (Salus Discovery, Madison, USA)
  • Diagnostic Test: TAM-TB
    • T-cell Activation Marker (TAM)-TB (Beckman Coulter, Brea, USA), a novel immunodiagnostic test that characterizes expression of an activation marker (CD38) and a maturation marker (CD27) on M. tuberculosis-specific CD4 (cluster of differentiation 4) T cells to discriminate active disease from latent infection or no infection
  • Diagnostic Test: Host Response Cartridge
    • Xpert TB Host-Response (Cepheid, Sunnyvale, USA), a cartridge-based whole blood gene expression assay
  • Diagnostic Test: IChroma POC CRP
    • iChroma POC CRP (Boditech, South Korea), a point-of-care (POC) assay for measuring C-reactive protein (CRP)
  • Diagnostic Test: Breath sensor
    • A breath sensor (Bio-Rad, Hercules, USA)
  • Diagnostic Test: Automated CXR (chest X-ray)
    • CAD for Good (EPCON), an open-source computer-aided diagnosis (CAD) tool for chest x-ray interpretation
  • Diagnostic Test: Next-generation LAM
    • A novel urine LAM assay that seeks to optimize sensitivity without compromising specificity by increasing the affinity of anti-LAM antibodies (Mologic, Thurleigh, UK)
  • Diagnostic Test: Oral swab Xpert Ultra
    • Oral swab analysis (OSA) using Xpert MTB/RIF Ultra (University of Washington, Seattle, USA and Cepheid, Sunnyvale, USA
  • Diagnostic Test: Xpert MTB cfDNA Cartridge
    • Xpert MTB cell-free DNA (Cepheid, Sunnyvale, USA), a cartridge-based assay that detects M. tuberculosis cell-free DNA (cfDNA) in the acellular fraction of plasma or urine, also known as “liquid biopsy”
  • Diagnostic Test: Nanodisk-MS2
    • NanoDisk-MS (mass spectrometer) uses antibody-conjugated nanoparticles to enrich serum peptides derived from M. tuberculosis proteins CFP-10 and ESAT-6. (NanoPin, Phoenix, USA)
  • Diagnostic Test: Deeplex Myc-TB
    • an assay originally developed for NGS (next-generation sequencing) platforms that identifies mutations in 18 main MTB drug resistance-associated gene targets to detect resistance to 13 anti-TB drugs/drug classes including all first- and most second-line drugs (injectables, fluoroquinolones, bedaquiline, clofazimine, linezolid, and ethionamide
  • Diagnostic Test: DeepChek-TB
    • An assay that identifies the established high and medium confidence drug resistance targets for isoniazid, rifampin, ethambutol, injectables, fluoroquinolones, pyrazinamide, and linezolid. (GenoScreen, France)
  • Diagnostic Test: Nanopore-optimized targeted sequencing assay
    • an assay developed specifically for use with the MinION platform. It detects resistance to all first- and most second-line drugs (injectables, fluoroquinolones, ethionamide, bedaquiline, linezolid, and clofazimine). The minimal infrastructure requirements for the MinION platform make it ideally suited to generating rapid and comprehensive drug resistance profiles onsite at district-level and reference laboratories in high burden countries.(Quadram Institute and Oxford Nanopore Technologies [QI/ONT], UK)

Arms, Groups and Cohorts

  • Experimental: Evaluation of various novel TB triage and diagnostic tests.
    • 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 1500 patients, including 300 people living with HIV and 300 people with diabetes, for evaluation of various novel TB triage and diagnostic tests.
  • Experimental: Evaluation of novel rDST assays
    • Clinicians at participating sites will be asked to refer adult patients with rifampin-resistance identified by routine molecular testing. The investigators aim to enroll 200 patients for evaluation of novel rDST assays.

Clinical Trial Outcome Measures

Primary Measures

  • Sensitivity
    • Time Frame: 2 years
    • 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
  • Specificity
    • Time Frame: 2 years
    • 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

Participating in This Clinical Trial

Inclusion Criteria

  • For evaluation of TB triage/diagnostic test: We will include adult outpatients (age ≥18 years) with either a cough ≥2 weeks' duration or a known TB risk factor (HIV or diabetes). – For evaluation of rDST tests: We will include adults (age ≥18 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). – For the usability assessment: 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). Exclusion Criteria:

  • For evaluation of TB triage/diagnostic tests: We will exclude patients 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 – For evaluation of rDST tests: We will exclude patients 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; or are unable or unwilling to provide informed consent. – For the usability assessment: We will exclude staff who are unwilling to provide informed consent.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of California, San Francisco
  • Collaborator
    • University Hospital Heidelberg
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Adithya Cattamanchi, MD, Principal Investigator, University of California, San Francisco
  • Overall Contact(s)
    • Adithya Cattamanchi, MD, +1-415-206-5489, adithya.cattamanchi@ucsf.edu

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