Diagnostic Accuracy of CAD4TB and C-reactive Protein Assay as Triage Tests for Pulmonary Tuberculosis

NCT04666311 | Completed DMC

• 1 other identifier: P1685-20A
• Study Type: observational
• Target: 1,400
• Locations: 2 countries
• Sites: 2

Brief Summary

In the TB TRIAGE+ ACCURACY study, the accuracy of the following products will be determined:

• CAD4TB (Delft Imaging System, NL), a digital chest x-ray analysis software
• Afinion CRP assay (Alere Afinion, USA), which detects a cytokine induced acute phase protein CAD4TB and the C-reactive protein assay are two tests with great potential of becoming a triage test for the diagnosis of tuberculosis (TB). These potential triage tests for TB are intended to serve as rule-out tests with a high sensitivity and negative predictive value. Before impact and cost-effectiveness of new TB triage tests for intensified active case finding can be determined, the diagnostic test accuracy needs to be assessed in comparison to confirmatory reference tests. This accuracy study will define cut-off values for CAD4TB as well as for the Afinion CRP assay to be used in a future cluster-randomised trial on impact and cost-effectiveness of TB triage strategies for intensified active case finding in Lesotho and KwaZulu-Natal, South Africa. A sub-study (detailed in a separate study protocol), hereafter called AHD-FEASIBILITY, explores the feasibility of implementing a series of point-of-care tests, including the new VISITECT CD4 Advanced Disease Test (Omega Diagnostics, UK) as part of the WHO-recommended advanced HIV Disease care package in the context of community-based HIV/TB campaigns. Due to the coinciding pandemics and the overlapping symptoms of TB and COVID-19, it is critical to test for SARS-Cov-2 infections in the study population. In addition, this study will contribute to the evaluation of a novel SARS-Cov-2 antigen rapid diagnostic test (from the diagnostic pipeline of FIND) and CAD4COVID, a digital chest x-ray analysis software (Delft Imaging System, NL) in combination with differential white blood cell count.

Conditions

Pulmonary Tuberculosis; Tuberculosis Diagnosis; Covid-19; HIV

Keywords

Presumptive adult TB; C Reactive Protein assay; CAD4TB; Point of Care Test; TB Triage Test; Diagnostic Accuracy; CAD4COVID; COVID-19 RDT; Advanced HIV Disease (AHD) care package; HIV testing; Community-based triage testing for TB

Outcome Measures

Primary Outcomes (2)

• Determine CAD4TB cut-off value

  Receiver operating characteristic analysis (ROC) of CAD4TB against a composite microbiological reference standard (mycobacterial culture \[MGIT\] or Xpert MTB/RIF) to define an acceptable diagnostic cut-off value.

  15 months after first patient visit

• Determine Afinion CRP assay cut-off value

  Receiver operating characteristic analysis (ROC) of Afinion CRP assay against a composite microbiological reference standard (mycobacterial culture \[MGIT\] or Xpert MTB/RIF) to define an acceptable diagnostic cut-off value.

  15 months after first patient visit

Secondary Outcomes (3)

• Evaluate CAD4TB ROC against reference standard

  15 months after first patient visit

• Evaluate Afinion CRP assay ROC against reference standard

  15 months after first patient visit

• Evaluate CAD4COVID and COVID-19 RDT ROC against reference standard

  15 months after first patient visit

Study Arms (1)

Adult presumptive TB cases

Adult presumptive TB cases (age ≥18years) with one or more TB symptoms (WHO recommended four-symptom screening; cough, weight loss, night sweats, fever) of any duration.

Diagnostic Test: Accuracy of CAD4TB and Afinion CRP assay for pulmonary TB; Diagnostic Test: CAD4COVID+WBC and COVID-19 RDT for SARS-CoV-2 infection

Interventions

Accuracy of CAD4TB and Afinion CRP assay for pulmonary TB DIAGNOSTIC_TEST

CAD4TB version 6 and 7: Software tool for detecting lung abnormalities in computer tomogram images (pulmonary abnormalities) and frontal chest radiograph images (tuberculosis abnormalities) ; availability is guaranteed by Delft Imaging System; EC 0344 Certificate (vs.6); CE mark pending (vs.7). Will be performed by a registered and qualified radiographer in accordance with national regulations. Afinion AS100 Analyzer and Afinion CRP: In vitro diagnostic to determine the amount of CRP in human whole blood, serum or plasma; CE-mark ; Will be performed by qualified, GCP-trained study personnel.

Adult presumptive TB cases

CAD4COVID+WBC and COVID-19 RDT for SARS-CoV-2 infection DIAGNOSTIC_TEST

CAD4COVID: Non-commercial product. Software tool for detecting pneumonia-related features to be expected in COVID-19 patients; availability is guaranteed by Delft Imaging System; CE certified. Will be performed by a registered and qualified radiographer/health professional in accordance with national regulations. Analysis in combination with differential white blood cell count. SD Biosensor, STANDARDTM Q COVID-19 Ag Test (rapid chromatographic immunoassay for the qualitative detection of specific antigens to SARS-CoV-2)

Adult presumptive TB cases

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Adult presumptive TB cases (age ≥18years) with one or more TB symptoms (WHO recommended four-symptom screening; cough, weight loss, night sweats, fever) of any duration. Presumptive TB patients will be recruited (i) at the outpatient departments of the Butha-Buthe District Hospital (Butha-Buthe, Lesotho) and the Caluza Clinic (Pietermaritzburg, KwaZulu-Natal, South Africa) and (ii) during community-based health campaigns by SolidarMed in Lesotho and HSRC in South Africa.

You may qualify if:

• 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)
• Any of the cardinal symptoms of TB (cough, weight loss, night sweats, fever) of any duration

You may not qualify if:

• Pregnancy (based on oral information from participant)
• Any condition for which participation in the study, as judged by the investigator, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments
• Critically sick patients who need immediate medical care
• Current anti-TB treatment

Sponsors & Collaborators

• Klaus Reither: lead
• SolidarMed: collaborator
• Human Sciences Research Council: collaborator
• Institute of Tropical Medicine, Belgium: collaborator
• Radboud University Medical Center: collaborator
• Charite University, Berlin, Germany: collaborator
• University Hospital, Basel, Switzerland: collaborator
• Foundation for Innovative New Diagnostics, Switzerland: collaborator
• European and Developing Countries Clinical Trials Partnership (EDCTP): collaborator
• Ministry of Health, Lesotho: collaborator

Study Sites (2)

Butha-Buthe District Hospital

Butha-Buthe, Lesotho

Location

Caluza Clinic

Pietermaritzburg, KwaZulu-Natal, South Africa

Location

Related Publications (3)

• Glaser N, Bosman S, Madonsela T, van Heerden A, Mashaete K, Katende B, Ayakaka I, Murphy K, Signorell A, Lynen L, Bremerich J, Reither K. Incidental radiological findings during clinical tuberculosis screening in Lesotho and South Africa: a case series. J Med Case Rep. 2023 Aug 25;17(1):365. doi: 10.1186/s13256-023-04097-4.

  PMID: 37620921 RESULT

• Bosman S, Ayakaka I, Muhairwe J, Kamele M, van Heerden A, Madonsela T, Labhardt ND, Sommer G, Bremerich J, Zoller T, Murphy K, van Ginneken B, Keter AK, Jacobs BKM, Bresser M, Signorell A, Glass TR, Lynen L, Reither K. Evaluation of C-Reactive Protein and Computer-Aided Analysis of Chest X-rays as Tuberculosis Triage Tests at Health Facilities in Lesotho and South Africa. Clin Infect Dis. 2024 Nov 22;79(5):1293-1302. doi: 10.1093/cid/ciae378.

  PMID: 39190813 RESULT

• Gils T, Lynen L, Muhairwe J, Mashaete K, Lejone TI, Joseph P, Ngubane T, Keter AK, Reither K, van Heerden A. Feasibility of implementing the advanced HIV disease care package as part of community-based HIV/TB activities: a mixed-methods study protocol. BMJ Open. 2022 Feb 7;12(2):e057291. doi: 10.1136/bmjopen-2021-057291.

  PMID: 35131835 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary; COVID-19; Alagille Syndrome

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Cholestasis, Intrahepatic; Cholestasis; Bile Duct Diseases; Biliary Tract Diseases; Digestive System Diseases; Liver Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Genetic Diseases, Inborn

Study Officials

• Klaus Reither, MD, PhD

  Swiss Tropical & Public Health Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Head of Clinical Research Unit

Study Record Dates

• First Submitted: December 7, 2020
• First Posted: December 14, 2020
• Study Start: February 15, 2021
• Primary Completion: April 5, 2022
• Study Completion: August 11, 2022
• Last Updated: September 22, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will share
• Time Frame: 12 months after completion of the EDCTP-funded TB TRIAGE+ project
• Access Criteria: The Executive Group of the TB TRIAGE+ project will establish a Data Access Committee (DAC). The DAC will review all requests for data sharing. After approval by the DAC, the final verified and anonymised datasets and support for analysis will be made available to all relevant stakeholders, both at local level (health facility, region and country) as well as international decision makers (e.g. WHO) and interested research groups in order to advance research in TB.

Locations

LE (1); ZA (1)