Tuberculosis Diagnostic Trial of CAD4TB Screening Alone Compared to CAD4TB Screening Combined With a CRP Triage Test, Both Followed by Confirmatory Xpert MTB/RIF Ultra in Communities of Lesotho and South Africa

Study Overview
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Brief Summary
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According to WHO, about 40% of the incident TB cases in 2020 are either under-reported or under-diagnosed causing on one hand major health risks and on the other hand catastrophic financial consequences. In particular, indigent people in hard-to-reach communities with high TB/HIV burden are at high risk of missed or delayed diagnoses. Hence, active case finding for TB remains an integral part of tuberculosis control in high-risk groups, such as people living with HIV (PLHIV) or diabetes mellitus, people living in specific geographical locations associated with a high burden of TB and poor access to health care, miners, or prisoners. CAD4TB (Delft Imaging, NL), a digital chest X-ray analysis software, and point-of care C-reactive protein assay (POC-CRP; e.g. LumiraDx, UK), which detects a cytokine induced acute phase protein, are two tests which have great potential of becoming a screening and triage test for TB as outlined in the WHO target product profiles. Data on CAD4TB and CRP suggest that accuracy can be improved if thresholds are stratified by patient characteristics, such as HIV status, history of TB and TB symptoms. TB TRIAGE+ Trial takes place in the communities of Lesotho and South Africa, which present high prevalence of subclinical TB, where a symptom-based screening would miss almost half of all infectious TB cases. TB TRIAGE+ Trials conducts a direct (in the same individual) comparison of the two screening/triaging approaches which are not based on symptoms: CAD4TB screening alone (approach 1) versus CAD4TB screening with POC-CRP triage testing (approach 2), and followed by confirmatory Xpert MTB/RIF Ultra testing in both approaches. TB TRIAGE TRIAL is investigates the hypothesis that a community-based active case finding strategy with CAD4TB screening with POC-CRP triage testing (approach 2) will be non-inferior compared to CAD4TB screening alone (approach 1) with regard to yield of detected TB cases and superior with regard to cost effectiveness.

Official Title
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Tuberculosis Diagnostic Trial of CAD4TB Screening Alone Compared to CAD4TB Screening Combined With a CRP Triage Test, Both Followed by Confirmatory Xpert MTB/RIF Ultra in Communities of Lesotho and South Africa

Conditions
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Tuberculosis

Intervention / Treatment
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* Diagnostic Test: CAD4TB
* Diagnostic Test: POC-CRP
* Diagnostic Test: Xpert MTB/RIF Ultra


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide signed written consent or witnessed oral consent in the case of illiteracy, prior to undertaking any study-related procedure Adults (≥18 years) Exclusion Criteria: Any condition for which participation in the study, as judged by the investigator or a designated staff member, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments Seriously ill person who needs immediate medical care Current anti-TB treatment Lesotho only: Pregnancy (self-reported)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: In this study a paired screen-positive design is used to directly compare two screening/triage approaches in the same individual based on a paired analysis: CAD4TB screening only (approach 1) versus CAD4TB screening with POC-CRP triage algorithm (approach 2).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Approach 1 - CAD4TB screening<br>Participants with a CAD4TB version 7 (Delft Imaging, NL) score above the overall threshold (as defined for study approach 1) are eligible for Xpert MTB/RIF Ultra testing. | Diagnostic Test: CAD4TB<br>* A posterior anterior digital chest X-ray incoporated in a mobile diagnostic unit is analysed by CAD4TB version 7 (Delft Imaging, NL). A trained and qualified person in compliance with national regulations will operate the digital chest X-ray.<br>Diagnostic Test: Xpert MTB/RIF Ultra<br>* Depending on CAD4TB (approach 1 & 2) or POC-CRP score (approach 2) a confirmatory Xpert MTB/RIF Ultra(Cepheid, USA) rapid sputum molecular testing follows for both Mycobacterium tuberculosis complex and rifampicin resistance;<br>|
| Experimental: Approach 2 - CAD4TB screening with POC-CRP triage testing<br>Participants with a CAD4TB version 7 (Delft Imaging, NL) score within the threshold window (between lower and upper limit threshold as defined for study approach 2), a POC-CRP LumiraDx (LumiraDx Limited, UK) test will follow as a triage test. If CRP is above the determined threshold as defined for approach 2, Xpert MTB/RIF Ultra will be performed. If the CAD4TB score is above the upper limit threshold as defined for approach 2, Xpert MTB/RIF Ultra will be performed (without further CRP testing). | Diagnostic Test: CAD4TB<br>* A posterior anterior digital chest X-ray incoporated in a mobile diagnostic unit is analysed by CAD4TB version 7 (Delft Imaging, NL). A trained and qualified person in compliance with national regulations will operate the digital chest X-ray.<br>Diagnostic Test: POC-CRP<br>* A quantitative POC-CRP LumiraDx (LumiraDx Limited, UK) triage test will be performed by finger-prick if CAD4TB scores is within the defined threshold window of study approach 2 triage testing<br>Diagnostic Test: Xpert MTB/RIF Ultra<br>* Depending on CAD4TB (approach 1 & 2) or POC-CRP score (approach 2) a confirmatory Xpert MTB/RIF Ultra(Cepheid, USA) rapid sputum molecular testing follows for both Mycobacterium tuberculosis complex and rifampicin resistance;<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Yield of detected TB cases per study approach: number of positive Xpert MTB/RIF Ultra results per hypothetical study approach. |  | 24 Months | 
| Cost-effectiveness of approach 2 using approach 1 as a comparator: the incremental (differential) costs per for each additional positive Xpert MTB/RIF Ultra case detected in approach 2 compared to approach 1. |  | 24 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Yield of detected TB cases per study approach in defined subgroups (HIV infected vs. uninfected participants, participants with and without TB history and with and without TB symptoms) |  | 24 Months | 
| Economic costs of approach 1 versus approach 2 of the TB active-case finding campaign |  | 24 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lesotho, South Africa, community-based, tuberculosis, active case findings, cost-effectiveness, CAD4TB, POC-CRP, Xpert MTB/RIF Ultra, triage, screening