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

Early Risk Assessment in TB contactS by New Diagnostic tEsts

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 .

Study Overview

• Status: Active, not recruiting
• Conditions: Tuberculosis
• Intervention / Treatment: Diagnostic test: New test candidates

• Study Type: Observational
• Enrollment (Estimated): 2100

Contacts and Locations

Study Locations

• Mozambique
  • Maputo, Mozambique
    • Instituto Nacional de Saúde (INS) Centro de Investigação e Treino em Saúde da Polana Caniço
• Tanzania
  • Mbeya, Tanzania
    • NIMR - Mbeya Medical Research Centre
• Zimbabwe
  • Harare, Zimbabwe
    • Biomedical Research & Training Institute (BRTI)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

TB index cases will be recruited at the primary health care clinics where the patient is receiving TB treatment. Household contacts have substantial recent exposure to the TB index case in the household (defined as sleeping at least 3/7 nights in the same household in the last 4 weeks).

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Household contacts with co-prevalent/incipient TB; Household contacts diagnosed with active TB at baseline/during the study period	Diagnostic test: New test candidates; 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
Household contacts staying healthy; Household contacts without active TB who remain healthy throughout the study	Diagnostic test: New test candidates; 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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To explore elements shaping adoption of new TB detection technologies among asymptomatic members of community (sub-study I)	In-depth qualitative interviews will be conducted to understand how new technologies could support screening and follow-up of household contacts.	August 2021 to February 2022

Collaborators and Investigators

• Sponsor: Michael Hoelscher
• Collaborators: European and Developing Countries Clinical Trials Partnership (EDCTP)
• Investigators: Principal Investigator: Theodora Mbunda, MD, PhD, National Institute of Medical Research - Mbeya Medical Research Centre; Principal Investigator: Denise F Banze, MD, Instituto Nacional de Saúde (INS); Principal Investigator: Junior Mutsvangwa, MD, Biomedical Research & Training Institute (BRTI)

Publications and helpful links

General Publications

• Drain PK, Bajema KL, Dowdy D, Dheda K, Naidoo K, Schumacher SG, Ma S, Meermeier E, Lewinsohn DM, Sherman DR. Incipient and Subclinical Tuberculosis: a Clinical Review of Early Stages and Progression of Infection. Clin Microbiol Rev. 2018 Jul 18;31(4):e00021-18. doi: 10.1128/CMR.00021-18. Print 2018 Oct.
• Fox GJ, Nhung NV, Sy DN, Hoa NLP, Anh LTN, Anh NT, Hoa NB, Dung NH, Buu TN, Loi NT, Nhung LT, Hung NV, Lieu PT, Cuong NK, Cuong PD, Bestrashniy J, Britton WJ, Marks GB. Household-Contact Investigation for Detection of Tuberculosis in Vietnam. N Engl J Med. 2018 Jan 18;378(3):221-229. doi: 10.1056/NEJMoa1700209.
• Swindells S, Ramchandani R, Gupta A, Benson CA, Leon-Cruz J, Mwelase N, Jean Juste MA, Lama JR, Valencia J, Omoz-Oarhe A, Supparatpinyo K, Masheto G, Mohapi L, da Silva Escada RO, Mawlana S, Banda P, Severe P, Hakim J, Kanyama C, Langat D, Moran L, Andersen J, Fletcher CV, Nuermberger E, Chaisson RE; BRIEF TB/A5279 Study Team. One Month of Rifapentine plus Isoniazid to Prevent HIV-Related Tuberculosis. N Engl J Med. 2019 Mar 14;380(11):1001-1011. doi: 10.1056/NEJMoa1806808.

Helpful Links

• WHO Global Tuberculosis Report 2019
• The Global Plan to End TB 2016 - 2020
• Consensus Meeting Report: Development of a Target Product Profile (TPP) and a framework for evaluation for a test for predicting progression from tuberculosis infection to active disease

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2021
• Primary Completion (Estimated): April 30, 2024
• Study Completion (Estimated): April 30, 2024

Study Registration Dates

• First Submitted: December 21, 2020
• First Submitted That Met QC Criteria: March 1, 2021
• First Posted (Actual): March 4, 2021

Study Record Updates

• Last Update Posted (Actual): November 28, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Tanzania; Tuberculosis; Biomarkers; Artificial Intelligence; Pulmonary Tuberculosis; Latent Tuberculosis; Spirometry; Respiratory Function Tests; Diagnostic Techniques and Procedures; Mozambique; Sputum; Zimbabwe; Housing; Radiography; Africa South of the Sahara; Blood Specimen Collection; Transcriptome; Case-Control Studies; Urine Specimen Collection; Biological Specimen Banks; Family Characteristics; Disease Transmission, Infectious; Interferon-gamma Release Tests; Mass Chest X-ray; Models, Theoretical
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: LMU-IMPH-AIDA-03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Accordance with EU General Data Protection Regulation and local data protection law needs to be worked out.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No