Rapid Research in Diagnostics Development for TB Network

Official title

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

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.

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 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.

Interventions

• Diagnostic test Novel mycobacterial culture techniques
  We will evaluate tests intended to make culture more sensitive, faster, and have less contamination.
• Diagnostic test Novel sputum smear microscopy techniques
  We will evaluate new staining techniques or visualization methods to increase the sensitivity of smear microscopy.
• Diagnostic test Sputum-based molecular assays
  We will evaluate semi-automated or automated molecular assays intended for use at near point of care or point of care.
• Diagnostic test Tongue swab-based molecular assays
  We will evaluate semi-automated or automated molecular assays intended for use at near point of care or point of care.
• Diagnostic test Urine LAM assays
  We will evaluate urine LAM assays incorporating techniques such as analyte concentration, higher sensitivity or specificity antibodies, or enhanced visualization to improve LAM detection.
• Diagnostic test Blood-based host immune response assays
  We will evaluate assays measuring host immune response parameters intended for use at near point of care or point of care.
• Diagnostic test Breath-based assays
  We will evaluate assays assessing volatile organic compounds or exhaled breath condensate for near point of care of point of care detection of TB.
• Diagnostic test Artificial intelligence-based digital health tools
  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).
• Diagnostic test Phage-based assays
  We will evaluate assays using phages to lyse mycobacterial cells for detection of DNA or antigens.
• Diagnostic test Cartridge-based molecular assays for detecting drug resistance
  We will evaluate semi-automated or automated molecular assays intended for use at near point of care or point of care.

Primary outcome measures

• Sensitivity [Time frame: 7 months]
• Specificity [Time frame: 7 months]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Diagnostic

Study locations

South Africa · 5 centers

• Brooklyn Chest Hospital — Cape Town
• Khayelitsha District Health Center — Cape Town
• Kraaifontein Community Health Clinic — Cape Town
• Scottsdene primary care clinic — Cape Town
• Wallacedene primary care clinic — Cape Town

India · 3 centers

• Chitoor (Christian Medical College satellite campus) — Vellore
• Christian Medical College CMC Pulmonary Outpatient Department — Vellore
• Primary care clinics (Shalom/LCC, CHAD) — Vellore

Uganda · 2 centers

• Kisenyi Health Center — Kampala
• Mulago Outpatient Department — Kampala

Vietnam · 2 centers

• Hanoi Lung Hospital, Outpatient departments — Hanoi
• National Lung Hospital, Outpatient departments — Hanoi

Georgia · 1 center

• National Center for Tuberculosis and Lung Diseases — Tbilisi

Nigeria · 1 center

• Zankli Research Center — Abuja

Philippines · 1 center

• De La Salle Medical and Health Sciences Institute — Dasmariñas

Zambia · 1 center

• Centre for Infectious Disease Research in Zambia — Lusaka

Publications

• Cho SN, Brennan PJ. Tuberculosis: diagnostics. Tuberculosis (Edinb). 2007 Aug;87 Suppl 1:S14-7. doi: 10.1016/j.tube.2007.05.001. Epub 2007 Jun 20. PMID 17584529
• World Health Organization. Global tuberculosis report Geneva, Switzerland: World Health Organization, 2015.
• Boehme CC, Nabeta P, Hillemann D, Nicol MP, Shenai S, Krapp F, Allen J, Tahirli R, Blakemore R, Rustomjee R, Milovic A, Jones M, O'Brien SM, Persing DH, Ruesch-Gerdes S, Gotuzzo E, Rodrigues C, Alland D, Perkins MD. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med. 2010 Sep 9;363(11):1005-15. doi: 10.1056/NEJMoa0907847. Epub 2010 Sep 1. PMID 20825313
• Walusimbi S, Bwanga F, De Costa A, Haile M, Joloba M, Hoffner S. Meta-analysis to compare the accuracy of GeneXpert, MODS and the WHO 2007 algorithm for diagnosis of smear-negative pulmonary tuberculosis. BMC Infect Dis. 2013 Oct 30;13:507. doi: 10.1186/1471-2334-13-507. PMID 24172543
• World Health Organization. Rapid Implementation of the Xpert MTB / RIF diagnostic test. Technical and operational 'how-to' practical considerations. Geneva, Switzerland, 2011.
• Systematic Screening for Active Tuberculosis: Principles and Recommendations. Geneva: World Health Organization; 2013. Available from http://www.ncbi.nlm.nih.gov/books/NBK294083/ PMID 25996015
• World Health Organization. Drug-resistant TB. https://www.who.int/tb/areas-of-work/drug-resistant-tb/en/.
• Dalton T, Cegielski P, Akksilp S, Asencios L, Campos Caoili J, Cho SN, Erokhin VV, Ershova J, Gler MT, Kazennyy BY, Kim HJ, Kliiman K, Kurbatova E, Kvasnovsky C, Leimane V, van der Walt M, Via LE, Volchenkov GV, Yagui MA, Kang H; Global PETTS Investigators; Akksilp R, Sitti W, Wattanaamornkiet W, Andreevskaya SN, Chernousova LN, Demikhova OV, Larionova EE, Smirnova TG, Vasilieva IA, Vorobyeva AV, PMID 22938757

Identifiers

NCT: NCT04923958 · U01AI152087 · U01AI152087 · R01AI190419

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗