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The objective of the study is to compare outcomes from three different strategies for the management of household (HH) contacts of individuals with newly diagnosed microbiologically confirmed active pulmonary TB. The study is a cluster randomized trial with three arms of equal size. The first eligible member of the HH who provides signed informed consent to participate will be randomized to one of the three strategies. The three different study arms are as follows:
The study population includes HIV uninfected persons aged 5-50 years who are HH contacts of individuals with newly diagnosed microbiologically confirmed active pulmonary TB. The planned number of household contacts to recruit is about 1434 in total, or about 455 for each of the three arms. The study will take place in Benin and Brazil.
The primary study outcome is, of those eligible for LTBI therapy, the proportion starting therapy within 3 months of the index TB patient starting active TB treatment. Secondary outcomes measured in each study arm include societal costs, prevalence of microbiologically confirmed and clinically diagnosed active TB, prevalence of TB infection, Incidence of adverse events, proportion who complete LTBI therapy, sensitivity and specificity of Chest Xray reading in each study side, and prevalence of active TB diagnosed using CXR in participants who cannot produce a sputum sample. Details of the statistical analysis plan for each primary and secondary outcome are provided below. Applicable for Brazil only: To evaluate the applicability and performance of material for bacteriological investigation obtained from induced sputum in children under 5 years of age.
Study participants will be recruited over 18 months. Participants will be followed until LTBI treatment is completed.
Full description
Background:
At a recent United Nations high level conference on TB a target was set that more than 30 million individuals should be treated for LTBI over the next 5 years. This ambitious goal will require massive scaling up of LTBI diagnosis and treatment - which will be challenging, if not impossible, with current approaches to diagnosis and treatment of latent TB. Two aspects of management of LTBI - need for CXR and need for TST - are controversial, as both can create important barriers to LTBI initiation, thereby reducing the individual as well as public health benefits of treatment. For TST, difficulties in training and quality assurance of administration and reading, and a global shortage of tuberculin material have reduced uptake. CXR was recommended by WHO in its 2018 guidelines for LTBI management as part of investigations to rule our active TB, however CXR services are not accessible in many settings and even if accessible, the cost for a CXR often falls on patients and is often prohibitively expensive. An alternate strategy is to use GeneXpert equipment, with the Xpert MTB/Rif test (hereafter labelled GX) to replace CXR to exclude prevalent active TB.
Study Objectives:
To compare outcomes from three different strategies for the management of HIV uninfected persons aged 5-50 years who are HH contacts of newly diagnosed microbiologically confirmed active pulmonary TB. (0-5 years only in Brazil)
Design:
This will be a cluster randomized trial with three arms of equal size; clusters will be defined as all the household contacts of patients with newly diagnosed active pulmonary TB. The first eligible member of the HH who provides signed informed consent to participate will be randomized to one of the three strategies. All subsequently enrolled members of the same HH will be assigned to the same study arm.
Study participants will be randomized to one of three different study arms:
Population and Setting:
HIV uninfected persons aged 5-50 years who are household contacts newly diagnosed microbiologically confirmed active pulmonary TB can participate in the study. The planned number of household contacts to recruit is about 1434 in total, or about 455 for each of the three arms. The study will take place in five cities in two countries: Benin (Cotonou and Porto Novo) and Brazil (Rio de Janeiro, Manaus and Porto Alegre). In each city clinics will be selected that are representative of the diagnostic facilities and capacities available in most clinics in the country. For Brazil only they will include under 5 HIV uninfected.
Study duration:
Study participants will be recruited over a period of 18 months. Participants will be followed until LTBI treatment is completed (4-6 months depending on what treatment is given)
Outcomes:
Primary Outcome:
Of those eligible (measured or estimated) for LTBI therapy, the proportion starting therapy within 3 months of the index TB patient starting active TB treatment.
Secondary outcomes:
Statistical analyses:
Primary analysis The primary outcome is the proportion starting LTBI therapy of those eligible (measured or estimated) for latent TB therapy. 'Eligible' will be defined as: aged 5-50 years, HIV uninfected and TST >5mm. For the no TST arm, the expected prevalence for HIV uninfected HH contacts aged 5 years and older will be estimated from age-specific prevalence of positive TST among HH contacts tested in the other two arms. This expected prevalence will be used to estimate the proportion 'eligible' for LTBI therapy in the no TST arm. Treatment initiation will be defined as being given a prescription for LTBI therapy, or dispensed the first month of pills needed for LTBI therapy. Since this is a dichotomous outcome, the primary analysis will be a logistic regression, using an identity link, and estimated via generalized estimating equations (GEE) to account for clustering by household. An exchangeable correlation structure and empirical standard errors will be used. The proportion starting LTBI therapy within 3 months of the index TB patient starting active TB treatment will be compared in each experimental arm against the standard arm.
Secondary analyses.
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Inclusion criteria
Index TB patients:
New diagnosis of pulmonary microbiologically confirmed (smear, GX or culture) active TB within 30 days of treatment initiation.
For Brazil: a new diagnosis of clinically pulmonary active is eligible.
Must have at least one identified household contact, and HHC investigation has not been started already.
Must agree to allow research team to access their medical history and approach their household contacts.
Household contacts:
Exclusion criteria
Index TB patients:
Household contacts:
Primary purpose
Allocation
Interventional model
Masking
1,589 participants in 3 patient groups
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Central trial contact
Chantal Valiquette; Dick Menzies, MD
Data sourced from clinicaltrials.gov
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