Clinical trial NCT05220163: Evaluating the Impact of Computer-assisted X-ray Diagnosis and Other Triage Tools to Optimise Xpert Orientated Community-based Active Case Finding for TB and COVID-19
Official title: Evaluating the Impact of Computer-assisted X-ray Diagnosis and Other Triage Tools to Optimise Xpert Orientated Community-based Active Case Finding for TB and COVID-19
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Tuberculosis
COVID-19
HIV Infections
Keywords: Tuberculosis
Active case finding
Computer assisted diagnosis
Screening
COVID-19
Lead sponsor: University of Cape Town
Sponsor class: OTHER
Collaborators: name: European and Developing Countries Clinical Trials Partnership (EDCTP)
name: Zambart
name: Biomedical Research and Training Institute
name: Ospedale San Raffaele
name: Radboud University Medical Center
name: Foundation for Innovative New Diagnostics, Switzerland
name: University of Stellenbosch
First posted: 2022-02-02
Enrollment: 26200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SCREENING

Brief summary: Tuberculosis (TB) is now the commonest cause of death in many African countries. Globally, \~35% (almost 1 in 3) of TB cases are 'missed' (remain undiagnosed or undetected). In sub-Saharan Africa, 40-50% of the TB case burden remains undiagnosed within the community. These 'missed' TB cases (at primary care level) serve as a reservoir, which severely undermines TB control. With rapid advances in the development of TB screening tests, the investigators aim to determine the pragmatic utility of computer-assisted x-ray diagnosis (CAD). Recent data suggest that CAD performs on par with experienced radiologists to identify potential TB cases, hereby reducing the frequency at which Xpert tests are requested and helps to focus limited resources on the relevant cases. In addition, the investigators aim to test nascent screening technologies for TB diagnosis such as evaluating urine-based TB screening biosignatures. The COVID-19 pandemic has ravaged African peri-urban communities where TB is also common. With the pressing need to improve screening and diagnosis of COVID-19, the investigators plan to explore the potential for urine- and blood-based COVID-19 screening assays. Symptoms of COVID-19 and TB overlap, and limited affordability, as well as the stigma associated with both diseases, severely limits testing. Data are now urgently needed about the feasibility of co-screening and testing for TB and COVID-19. The utility of such an approach, if any, has not been studied in African communities.

Detailed description: Tuberculosis (TB) is now the commonest cause of death in many African countries. Several factors drive this; however, transmission is the mechanism by which these risk factors translate into active TB. Globally, \~35% (almost 1 in 3) of TB cases are 'missed' (remain undiagnosed or undetected). In sub-Saharan Africa, 40-50% of the TB case burden remains undiagnosed within the community and \~30% of such cases are microscopically smear-positive. These 'missed' TB cases (at primary care level) serve as a reservoir, which severely undermines TB control. Thus, primary care and community-based case finding should be a critical component for TB control.

Detecting cases in the community, however, has been restricted by the lack of sensitive and user-friendly Point-of-Care (POC) diagnostic tools. To address this unmet need, in 2013 the investigators planned a programme of activities (sequential interlinked studies) with the overarching aim of optimising a model for Xpert-related community-based active case finding (ACF) for TB (XACT). By 2017, through the EDCTP-funded XACT-I study, the investigators solved the impasse of rapid POC diagnosis by showing that molecular Xpert-based community-based screening was effective in identifying missing TB cases in the peri-urban 'slums' of Cape Town and Harare using a mini-truck with a generator. However, such an approach was neither broadly affordable nor scalable. The investigators therefore derived a scalable model using portable battery-operated Xpert Edge installed within a low-cost (\< US$) 15 000 Nissan panel van manned by two health care workers (thus making the ACF model affordable and scalable). This completed study, XACT-II, screened over 5 000 participants in the community. The model worked well and was more effective than smear microscopy. Based on these successes, and to translate the XACT concept into policy, the Wellcome Trust and UK MRC has funded the XACT-III study. Currently commenced, XACT-III was initiated as a multi-country demonstration project in four sub-Saharan African countries.

More recently, there have been rapid advances in the development of triage testing for TB, which refers to screening tests that are generally applied in a community-based setting (either at individual community or primary care clinic level). These tests have very high sensitivity (\>95%) but modest specificity (\>70%) as defined by TB-specific target product profiles. A forerunner TB-orientated triage test is computer-assisted x-ray diagnosis (CAD). This entails using artificial intelligence-enabled software to read a digital x-ray and produce a probability of TB within seconds. Recent data suggest that CAD performs on par with experienced radiologists to identify potential TB cases, hereby reducing the frequency at which Xpert tests are requested and helps to focus limited resources on the relevant cases. Although these data appear promising, the feasibility of this strategy in a pragmatic field setting has not been extensively tested. There are several other unanswered questions. Is the strategy of CAD combined with Xpert cost-effective and can it reduce Xpert usage without missing an unacceptable number of TB cases? The investigators will therefore determine the utility of CAD as a triage tool to further optimise the XACT model.

The COVID-19 pandemic, due to SARS-CoV-2, has ravaged African peri-urban communities where TB is also common. Symptoms of COVID-19 and TB overlap, and limited affordability, as well as the stigma associated with both diseases, severely limits testing. Data are now urgently needed about the feasibility of co-screening and testing for TB and COVID-19. The utility of such an approach, if any, has not been studied in African communities. As Xpert POC TB testing and x-rays for CAD will be performed in the proposed study, it affords a unique and easy opportunity to seamlessly screen for both diseases when appropriate.

Other nascent screening technologies are rapidly emerging for TB and COVID-19, including urine- and blood-based triage tests. XACT-19 provides a unique opportunity to collect the relevant samples and test new technologies in a pragmatic community-based setting.

In summary, the XACT-19 study results will have substantial implications for public health policy and practice and will likely define a new standard for community-based ACF for TB, and potentially COVID-19 in tandem.

Eligibility criteria: Inclusion Criteria:

* Participants willing to complete community-based symptom screening, finger-prick and venepuncture blood sampling, urine testing, and/or undergo TB and/or COVID-19 diagnostic testing.
* Provision of informed consent.
* Participant 18 years or above.
* HIV-positive or negative participants will be included.

Exclusion Criteria:

* Inability to provide informed consent (e.g., mentally impaired).
* Participants who have completed TB treatment in the last two months, or who have self-presented to their local TB clinic and are currently being worked up for suspected TB.
* Participants already diagnosed with active TB on treatment.
* Participants unable to commit to at least a two-month follow-up.
* Female participants who are pregnant or who refuse a urine pregnancy test.
* Participants in the community who cannot access healthcare due to severe ill health or lack of access to the local clinic.

Primary outcomes:
measure: Time to detection of microbiologically proven TB
timeFrame: Through study completion, up to 48 months
Secondary outcomes:
measure: Feasibility of CAD + POC Xpert performed by minimally trained healthcare workers
timeFrame: Through study completion, up to 48 months
measure: Number of infectious TB cases detected (defined by cough aerosol sampling system [CASS] and/or smear and/or cavitatory disease positive)
timeFrame: Through study completion, up to 48 months
measure: Time-specific proportion of participants initiated on TB treatment up to 60 days post-sample donation in each arm (7-, 14-, 30- and 60-days)
timeFrame: Through study completion, up to 48 months
measure: Time to TB treatment initiation (both the median time to treatment in each group and time to event [treatment] analyses will be conducted)
timeFrame: Through study completion, up to 48 months
measure: Yield of culture positive TB in household contacts of index participants
timeFrame: Through study completion, up to 48 months
measure: NPV and false negative rate (TB cases missed per 1 000 persons screened) of CAD and other screening tests for TB
timeFrame: Through study completion, up to 48 months
measure: Reduction in number of sputum induction procedures and/or Xpert tests performed
timeFrame: Through study completion, up to 48 months
measure: Global and country-specific cost-effectiveness analysis for each strategy
timeFrame: Through study completion, up to 48 months
measure: Transmission and disease burden impact using modelling based on exposure scores, imaging, and CASS
timeFrame: Through study completion, up to 48 months
measure: Rates or prevalence of microbiological versus probable (clinical TB)
timeFrame: Through study completion, up to 48 months
measure: Proportion of culture-positive TB cases completing three- and six-months of TB treatment in each study arm
timeFrame: Through study completion, up to 48 months
measure: Middleware/dashboard design requirements and deployment models for each strategy
timeFrame: Through study completion, up to 48 months
measure: Feasibility and yield of POC Xpert (Xpress cartridge) for COVID-19 detection
timeFrame: Through study completion, up to 48 months
measure: Feasibility and performance of CAD4COVID for PCR-positive COVID-19 detection
timeFrame: Through study completion, up to 48 months
measure: Feasibility of a novel mass screening strategy for COVID-19 that uses pooling of specimen from a group of COVID-19 suspects
timeFrame: Through study completion, up to 48 months
Other outcomes:
measure: Economic outcome: Cost effectiveness of CAD + POC Xpert (cost per TB case diagnosed and/or averted, and cost per death and disability-adjusted life year [DALY] averted)
timeFrame: Through study completion, up to 48 months
measure: Economic outcome: Direct comparison of the cost effectiveness of ACF compared to passive case finding (the current public health practice)
timeFrame: Through study completion, up to 48 months
measure: Economic outcome: Cost effectiveness considering drug resistant TB (DR-TB) and HIV prevention
timeFrame: Through study completion, up to 48 months
Locations:
city: Cape Town
country: South Africa
facility: University of Cape Town
state: Western Cape
city: Lusaka
country: Zambia
facility: Helen Ayles
city: Harare
country: Zimbabwe
facility: Junior Mutsvangwa
Study officials:
affiliation: University of Cape Town
name: Keertan Dheda, PhD
role: PRINCIPAL_INVESTIGATOR
References: