Community-based active case finding (ACF) using Gene Xpert OMNI (in a low cost scalable mini-mobile clinic) performed at point-of-care (POC) is feasible and more effective (proportion of TB cases failing to initiate treatment especially if they are ‘super-spreaders’ i.e. highly infectious) than Xpert performed in a centralised laboratory.

Primary Outcome Measure
The proportion of participants with pre-treatment loss to follow-up and/or the proportion of infectious TB patients not initiating treatment within 14 days of diagnosis
Secondary Outcome Measure
Multiple outcome measures including time to TB treatment initiation, the time-specific proportion of patients initiated on TB treatment up to 60 days, transmission impact using modelling analysis based on exposure scores, imaging and CASS, etc.
Health Economic Outcomes
Cost-effectiveness of an ACF strategy using Xpert Ultra when placed at POC versus distant from point-of-care in terms of cost per person diagnosed with TB, cost per averted case based on transmission modelling, and death and disability-associated life years averted.
Work Packages


Project Management
Lead: UCT LI

The PI at UCTLI (Keertan Dheda) will undertake overall coordination and management of the project. This will be facilitated through a comprehensive project management plan (outlined in detail in WP1 and in the management governance figure.


Clinical activity, recruitment, and infectiousness studies
Lead: UCT LI

This work package uses the ACF to find undiagnosed TB cases in the community using a mobile clinic, consisting of a small panel van housing a portable Xpert platform and HIV/CD4 testing facilities in South Africa, Zimbabwe, Mozambique, and Zambia. Cough aerosol sampling (CASS) quantifies the infectiousness of TB cases diagnosed using an ACF strategy to determine the transmission risk of these undiagnosed individuals residing in the community. CASS will give us the ability to sequence individual mycobacteria to provide insights into strain variability and genotypic markers influencing transmission (part of WP 4). The Zimbabwe trial site will be funded by EDCTP.


Imaging studies
Lead: RUMC

The WP entails the use of serial chest x-rays (baseline in all and end of treatment in those with TB) and PET-CTs (at baseline) in all Xpert positive patients (Cape Town sites only) to feed into the TB computer aided diagnostic (TB CAD) software developed and pre-validated by Bram Van Ginneken at Radboud University. This will be used to determine the extent of disease in these undiagnosed cases in the community. Additionally, this will help to develop a phenotypic signature of TB cases with minimal symptoms in the community. The PET-CT component will be funded by EDCTP.


M. tuberculosis genomic and host transcriptomic studies
Lead: OSR and LSHTM

OSR will undertake whole genome sequencing of mycobacterial DNA taken directly from the sputum or from isolates grown from sputum cultures and CASS plates (WP2). Strain type and genomic mutations (SNPs) will be correlated with clinical parameters, phenotypic drug resistance markers and patient outcomes. We will also sequence isolates from CASS positive patients to gain insights into genetic factors influencing transmission dynamics among different strain types. Blood based host transcriptomics using RNAseq will be performed by LSHTM (Taane Clark). In parallel, bioinformatics capacity will be built at UCT. This process has already been initiated in other ongoing studies including collaborations with Prof Taane Clark.


Cost-effectiveness and modelling studies

This work package, led by LSHTM, will outline the health economics and modelling studies to determine the economic impact of an active case fining strategy taking into account TB transmission in the community. Total economic costs will be estimated, using data from a healthcare and patient perspective, for both arms of the trial. Cost-effectiveness of these strategies will be estimated and compared within the trial setting including transmission effects. Infectiousness data (CASS, microbiological and radiological) will be collected and used to inform model assumptions of the impact of ACF on transmission. Sensitivity analyses will be performed to determine the main cost drivers for each strategy. Prof Vassall has extensive experience in health economic analyses and will oversee this aspect of the work package. Prof White will oversee the development of the transmission model to incorporate into the economic analysis.


Data management
Lead: UCT LI

A data management plan has been created and shared with all partners. An electronic CRF will be used to capture data at each recruitment site, and will be upload and transferred via the internet to the UCT server. Similar data management schemes have worked well in previous clinical trials, including the XACTII study.


Capacity development and Networking

The capacity building activities will include site infrastructure upgrades to facilitate sustainable clinical trials capacity in Africa, training of postgraduate students and scientists, and short courses. The capacity-development activities will be synchronised and amplified through the capacity-development activities of the existing NExT study, the EDCTP-funded TESA NOE, the NIH-funded CASS and XACT II studies, The UK MRC funded TB-CHIM and EDCTP funded career development fellowships. These interactions will support sharing of bio-banks and a mentorship scheme to train scientists and health care workers (HCWs) who will drive a poverty-related disease agenda, and provide a platform for exchange of people and ideas.