Early Risk Assessment in Household Contacts (≥10 Years) of TB Patients by New Diagnostic Tests in 3 African Countries

Study Overview
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Brief Summary
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The ERASE - TB study will be conducted in order to fill a critical unmet need for tuberculosis control. Persons who are in contact with an infectious TB case may become infected themselves. Among those who are infected, most will stay healthy but some will develop TB themselves. These people would benefit from preventive treatment, which would also stop TB from being spread to other persons. The problem currently is that it is impossible to determine with certainty who would require preventive treatment, and who will remain healthy. Out of 100 persons exposed to an infectious TB patient, only 2 will go on to have TB according to a study in Vietnam, but there are no good tests available to identify those with a risk for TB disease. Treating 100 persons to prevent 2 cases of TB is not effective, so preventive treatment is not used in adults and adolescents in Tanzania, Mozambique and Zimbabwe, where this study will be conducted, but also in many other settings. The ERASE - TB project will evaluate a number of newly developed diagnostic tests, to see which of those will be able to predict TB in persons at risk, and therefore steer preventive treatment well. For this, the investigators will invite 2,100 household contacts (HHC) of infectious TB patients, who are at least 10 years old, into the study. Everyone will be examined initially, and again in regular intervals, for 1.5 to 2 years; and whenever the participants will present with symptoms that could indicate that they develop TB. At every visit, the investigators will perform an X-ray and take some blood and urine samples to perform new candidate tests. At the first/baseline visit, all household contacts without TB will undergo a spirometry to evaluate their pulmonary function. If someone is unwell, the investigators will also examine sputum for the presence of TB bacilli. In the end, the investigators will then be able to say who of the persons in the study developed TB, and who remained healthy. From all samples taken at different timepoints, the investigators will then determine which test found TB early, and clearly distinguished between persons developing TB, and persons who would remain healthy .

Official Title
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Early Risk Assessment in TB contactS by New Diagnostic tEsts

Conditions
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Tuberculosis

Intervention / Treatment
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* Diagnostic Test: New test candidates


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: TB index case: Aged at least 18 years Having at least one other person living in the household aged ≥10 years Written informed consent to conduct socio-economic and clinical questionnaire, to provide a sputum sample for culture and sequencing, and to approach the household members. Recently diagnosed with active pulmonary TB within the last 4 weeks Has taken less than 7 daily doses of anti-TB treatment since diagnosis; ensuring a positive culture can still be obtained Able to spontaneously produce sputum Sputum microscopy positive in Ziehl-Neelsen or Auramine-O staining of ideally 2+ or higher, but at least 1+ on the IUATLD/WHO scale, OR (in case no sputum microscopy done) GeneXpert positive, at least TB medium A firm home address, maintained unchanged for the last 6 months, that is accessible to visiting Household Contact: Aged at least 10 years Written informed consent for study participation, including HIV testing, and home visits by the study team for follow-up (for minors <18 yr.: consent of the parent/guardian, assent of the participant) Recent (in the last 4 weeks), substantial exposure to an infectious TB case in the household, defined as sleeping at least 3/7 nights in the same household If HIV negative: not on preventive therapy (preventive therapy is not an exclusion criterion for HIV positive persons) Exclusion Criteria: Household Contact Circumstances that raise doubt on free, uncoerced informed consent (e.g. in a mentally handicapped person) Prisoners Recent treatment for active TB, completed within the last 30 days OR on current TB treatment for active TB.

Ages Eligible for Study
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Minimum Age: 10 Years

Sexes Eligible for Study
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All

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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Household contacts with co-prevalent/incipient TB<br>Household contacts diagnosed with active TB at baseline/during the study period | Diagnostic Test: New test candidates<br>* The following new diagnostic tests will be done after the completion of the study with the samples (blood, sputum, urine) and data (digital X-ray) obtained during the study period: CAD4TB / qXR Xpert Ultra® FLOW-TB TAM-TB 4RISK and COR Cepheid 3-gene signature cartridge BioMérieux ISIT TB blood transcription signature assay Multiplex LSHTM in-house host biomarker assay TB Screen biosignature SeroSelect Retrospective testing of participants' samples and data acquired during the study period, differentiated between participants with co-prevalent/incipient TB and participants staying health throughout the trial<br>|
| Household contacts staying healthy<br>Household contacts without active TB who remain healthy throughout the study | Diagnostic Test: New test candidates<br>* The following new diagnostic tests will be done after the completion of the study with the samples (blood, sputum, urine) and data (digital X-ray) obtained during the study period: CAD4TB / qXR Xpert Ultra® FLOW-TB TAM-TB 4RISK and COR Cepheid 3-gene signature cartridge BioMérieux ISIT TB blood transcription signature assay Multiplex LSHTM in-house host biomarker assay TB Screen biosignature SeroSelect Retrospective testing of participants' samples and data acquired during the study period, differentiated between participants with co-prevalent/incipient TB and participants staying health throughout the trial<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitivity and specificity of new diagnostics to diagnose co-prevalent TB against a clinica/microbiological reference standard case definition | to determine sensitivity and specificity of new diagnostics for diagnosing TB earlier with a special focus on subclinical disease. New diagnostics will be evaluated against a reference standard for classification of presence of, or development of TB disease in a person exposed to a source case; with the following possibilities: Co--prevalent symptomatic TB Co--prevalent subclinical TB Minimal TB, with incident TB during follow-up Remained healthy | Co-prevalent TB disease can be diagnosed at Baseline (Month 0) | 
| Evaluation of novel diagnostics for detection of developing, minimal TB against a clinica/microbiological reference standard case definition | to evaluate novel diagnostics for detection of developing, minimal TB that would cause infectious disease in the future. For reference standard case classification, see 1. | TB disease can be diagnosed through study completion, up to Month 24 | 
| Enhancement of diagnostic performance by simulating testing algorithms coupled with a risk estimate from a mathematical model | to enhance diagnostic performance by simulating testing algorithms coupled with a risk estimate from a mathematical model For reference standard case classification, see 1. | TB disease can be diagnosed through study completion, up to Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| M.tb infection status as measured by an immunological assay | M.tb infection status as measured by an immunological assay: M.tb infected at baseline M.tb uninfected at baseline through to end of study Change of M.tb infection status from negative (baseline) to positive during follow-up | through study completion, up to Month 24 | 
| Classification of cases of co-prevalent or incident TB; through M.tb isolate sequencing and comparison with the source case isolate | Classification of cases of co-prevalent or incident TB; through M.tb isolate sequencing and comparison with the source case isolate: Secondary, infected by source case - defined timepoint of infection Other, unknown source of infection - unknown timepoint of infection | through study completion, up to Month 24 | 
| Assessment of the proportion of HHC (without co-prevalent TB) with abnormal pulmonary function at baseline | to assess the proportion of HHC (without co-prevalent TB) with abnormal pulmonary function at baseline, the type and severity of impairments, the relationship between pre-existing abnormal pulmonary function and incident TB (and the changes in pulmonary function measured by spirometry after incident TB and TB treatment completion). | Spirometry will be done only at baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Biomarkers, Tuberculosis, Latent Tuberculosis, Pulmonary Tuberculosis, Case-Control Studies, Disease Transmission, Infectious, Blood Specimen Collection, Urine Specimen Collection, Sputum, Diagnostic Techniques and Procedures, Interferon-gamma Release Tests, Mass Chest X-ray, Radiography, Respiratory Function Tests, Spirometry, Artificial Intelligence, Transcriptome, Biological Specimen Banks, Models, Theoretical, Housing, Family Characteristics, Africa South of the Sahara, Zimbabwe, Mozambique, Tanzania