Rapid Research in Diagnostics Development for TB Network

University of California, San Francisco26,436 enrolled

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.

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

Interventions

Novel mycobacterial culture techniquesDIAGNOSTIC_TEST

We will evaluate tests intended to make culture more sensitive, faster, and have less contamination.

Novel sputum smear microscopy techniquesDIAGNOSTIC_TEST

We will evaluate new staining techniques or visualization methods to increase the sensitivity of smear microscopy.

Sputum-based molecular assaysDIAGNOSTIC_TEST

We will evaluate semi-automated or automated molecular assays intended for use at near point of care or point of care.

Tongue swab-based molecular assaysDIAGNOSTIC_TEST

We will evaluate semi-automated or automated molecular assays intended for use at near point of care or point of care.

Urine LAM assaysDIAGNOSTIC_TEST

We will evaluate urine LAM assays incorporating techniques such as analyte concentration, higher sensitivity or specificity antibodies, or enhanced visualization to improve LAM detection.

Blood-based host immune response assaysDIAGNOSTIC_TEST

We will evaluate assays measuring host immune response parameters intended for use at near point of care or point of care.

Breath-based assaysDIAGNOSTIC_TEST

We will evaluate assays assessing volatile organic compounds or exhaled breath condensate for near point of care of point of care detection of TB.

Artificial intelligence-based digital health toolsDIAGNOSTIC_TEST

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).

Phage-based assaysDIAGNOSTIC_TEST

We will evaluate assays using phages to lyse mycobacterial cells for detection of DNA or antigens.

Cartridge-based molecular assays for detecting drug resistanceDIAGNOSTIC_TEST

We will evaluate semi-automated or automated molecular assays intended for use at near point of care or point of care.

Sequencing-based assays for detecting drug resistanceDIAGNOSTIC_TEST

We will evaluate targeted and whole genome sequencing assays.

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

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: 1. PLHIV (Risk Factor), CRP \>5 mg/dL OR abnormal CXR (Positive TB screening definition) 2. Self-reported Close Contact (Risk Factor), abnormal CXR (Positive TB screening definition) 3. History of mining work (Risk Factor), abnormal CXR (Positive TB screening definition) We will exclude people who: 1. completed latent or active TB treatment within the past 12 months (to increase TB prevalence and reduce false-positive results, respectively); 2. have taken any medication with anti-mycobacterial activity (including fluoroquinolones) for any reason, within 2 weeks of study entry (to reduce false-negatives); 3. reside \>20km from the study site or are unwilling to return for follow-up visits; or 4. 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: 1. have negative or contaminated results on all baseline (i.e., enrollment) sputum cultures 2. are unable to provide at least two sputum specimens of 3 mL each within one day of enrollment 3. 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.

Locations (16)

National Center for Tuberculosis and Lung Diseases

Tbilisi, Georgia

RECRUITING

Chitoor (Christian Medical College satellite campus)

Vellore, India

RECRUITING

Christian Medical College CMC Pulmonary Outpatient Department

Vellore, India

RECRUITING

Primary care clinics (Shalom/LCC, CHAD)

Vellore, India

RECRUITING

Zankli Research Center

Abuja, Nigeria

RECRUITING

De La Salle Medical and Health Sciences Institute

Dasmariñas, Philippines

RECRUITING

Brooklyn Chest Hospital

Cape Town, South Africa

RECRUITING

Khayelitsha District Health Center

Cape Town, South Africa

RECRUITING

Kraaifontein Community Health Clinic

Cape Town, South Africa

RECRUITING

Scottsdene primary care clinic

Cape Town, South Africa

RECRUITING

...and 6 more locations

Outcomes

Primary Outcomes

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

Time frame: 7 months

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

Time frame: 7 months

Rapid Research in Diagnostics Development for TB Network

Overview

Conditions

Interventions

Eligibility

Locations (16)

Outcomes

Primary Outcomes

Central Contacts