Clinical trial NCT04781257: Early Risk Assessment in Household Contacts (≥10 Years) of TB Patients by New Diagnostic Tests in 3 African Countries
Official title: Early Risk Assessment in TB contactS by New Diagnostic tEsts
Study type: OBSERVATIONAL
Overall status: ACTIVE_NOT_RECRUITING
Conditions: Tuberculosis
Keywords: Tuberculosis
Latent Tuberculosis
Pulmonary Tuberculosis
Case-Control Studies
Disease Transmission, Infectious
Blood Specimen Collection
Urine Specimen Collection
Sputum
Diagnostic Techniques and Procedures
Biomarkers
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
Lead sponsor: Ludwig-Maximilians - University of Munich
Sponsor class: OTHER
Collaborators: name: European and Developing Countries Clinical Trials Partnership (EDCTP)
First posted: 2021-03-04
Enrollment: 2100
Sex: ALL
Minimum age (years): 10
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
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).

Brief summary: 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 .


Eligibility criteria: 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.

Primary outcomes:
measure: Sensitivity and specificity of new diagnostics to diagnose co-prevalent TB against a clinica/microbiological reference standard case definition
timeFrame: Co-prevalent TB disease can be diagnosed at Baseline (Month 0)
measure: Evaluation of novel diagnostics for detection of developing, minimal TB against a clinica/microbiological reference standard case definition
timeFrame: TB disease can be diagnosed through study completion, up to Month 24
measure: Enhancement of diagnostic performance by simulating testing algorithms coupled with a risk estimate from a mathematical model
timeFrame: TB disease can be diagnosed through study completion, up to Month 24
Secondary outcomes:
measure: M.tb infection status as measured by an immunological assay
timeFrame: through study completion, up to Month 24
measure: Classification of cases of co-prevalent or incident TB; through M.tb isolate sequencing and comparison with the source case isolate
timeFrame: through study completion, up to Month 24
measure: Assessment of the proportion of HHC (without co-prevalent TB) with abnormal pulmonary function at baseline
timeFrame: Spirometry will be done only at baseline
Other outcomes:
measure: To explore elements shaping adoption of new TB detection technologies among asymptomatic members of community (sub-study I)
timeFrame: August 2021 to February 2022
Locations:
city: Maputo
country: Mozambique
facility: Instituto Nacional de Saúde (INS) Centro de Investigação e Treino em Saúde da Polana Caniço
city: Mbeya
country: Tanzania
facility: NIMR - Mbeya Medical Research Centre
city: Harare
country: Zimbabwe
facility: Biomedical Research & Training Institute (BRTI)
Study officials:
affiliation: National Institute of Medical Research - Mbeya Medical Research Centre
name: Theodora Mbunda, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Nacional de Saúde (INS)
name: Denise F Banze, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Biomedical Research & Training Institute (BRTI)
name: Junior Mutsvangwa, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.