Clinical trial NCT04666311: Diagnostic Accuracy of CAD4TB and C-reactive Protein Assay as Triage Tests for Pulmonary Tuberculosis
Official title: Prospective, Multicentre Evaluation of the Accuracy of CAD4TB and C-reactive Protein Assay as Triage Tests for the Diagnosis of Pulmonary Tuberculosis in Presumptive Adult TB Patients (TB TRIAGE+ Accuracy)
Study type: OBSERVATIONAL
Overall status: COMPLETED
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
Lead sponsor: Swiss Tropical & Public Health Institute
Sponsor class: OTHER
Collaborators: name: SolidarMed
name: Human Sciences Research Council
name: Institute of Tropical Medicine, Belgium
name: Radboud University Medical Center
name: Charite University, Berlin, Germany
name: University Hospital, Basel, Switzerland
name: Foundation for Innovative New Diagnostics, Switzerland
name: European and Developing Countries Clinical Trials Partnership (EDCTP)
name: Ministry of Health, Lesotho
First posted: 2020-12-14
Enrollment: 1400
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

Detailed description: This is a prospective, partially blinded, two-centre cross-sectional study in which the diagnostic test accuracy of CAD4TB and an Afinion CRP assay test for TB will be assessed at facility level by evaluating a sample of 1400 adults (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. Participants will be enrolled after giving written informed consent.

Study procedures comprise the following (detailed in the schedule of events): collection of contact, anthropometric, demographic and clinical data, HIV testing and counselling per national guidelines, collection of capillary blood for HIV testing, Afinion CRP assay, differential white blood cell count, VISITECT CD4 Advanced Disease Test (if HIV-positive), CrAg Lateral Flow Assay (if HIV positive and CD4 count \<200 cells/μl as per VISITECT CD4 Advanced Disease Test, and no history of cryptococcal meningitis treatment); collection of urine (if HIV positive) for Alere Determine TB LAM Ag test; chest radiography for CAD4TB and CAD4COVID analysis and remote expert reading; nasopharyngeal swabs for SARS-Cov-2 real-time PCR and SARS-Cov-2 antigen test, collection of two spot sputa samples (S1,S2) for Xpert MTB/RIF, Xpert MTB/RIF Ultra (S1) and for mycobacterial culture \[MGIT\] (S2). At week 12 (±2weeks), we will contact each participant by phone and collect data on their vital status, and any TB treatment since enrolment. For individuals on TB treatment, further information, e.g. on reasons for empirical treatment, will be collected at the health facility the participant started TB treatment.

Eligibility criteria: Inclusion Criteria:

1. Willing and able to provide signed written consent or witnessed oral consent in the case of illiteracy, prior to undertaking any study-related procedure
2. Adults (≥18 years)
3. Any of the cardinal symptoms of TB (cough, weight loss, night sweats, fever) of any duration

Exclusion Criteria:

1. Pregnancy (based on oral information from participant)
2. 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
3. Critically sick patients who need immediate medical care
4. Current anti-TB treatment

Primary outcomes:
measure: Determine CAD4TB cut-off value
timeFrame: 15 months after first patient visit
measure: Determine Afinion CRP assay cut-off value
timeFrame: 15 months after first patient visit
Secondary outcomes:
measure: Evaluate CAD4TB ROC against reference standard
timeFrame: 15 months after first patient visit
measure: Evaluate Afinion CRP assay ROC against reference standard
timeFrame: 15 months after first patient visit
measure: Evaluate CAD4COVID and COVID-19 RDT ROC against reference standard
timeFrame: 15 months after first patient visit
Other outcomes:
Locations:
city: Butha-Buthe
country: Lesotho
facility: Butha-Buthe District Hospital
city: Pietermaritzburg
country: South Africa
facility: Caluza Clinic
state: KwaZulu-Natal
Study officials:
affiliation: Swiss Tropical & Public Health Institute
name: Klaus Reither, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.