GXT - GeneXpert or Chest-X-ray or Tuberculin Skin Testing for Household Contact Assessment
Condition: Latent Tuberculosis
MeSH terms: Tuberculosis; Latent Tuberculosis
Study type: Interventional

Summary: 
      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:

        1. Standard care (control arm): Participants will receive symptom screening and tuberculin
           skin testing (TST). If symptom screen positive and/or TST positive, they undergo chest
           x-rays (CXR). If CXR abnormal, they undergo microbiological investigation. If CXR normal
           or if microbiological investigation negative, TST positive receive latent TB infection
           (LTBI) treatment. If microbiological investigation is positive, they will be offered
           treatment for active TB. For children under 5 years of age in Brazil, sputum induction
           will be performed for bacteriological investigation

        2. GeneXpert (GX): Participants follow an algorithm similar to the standard care, however
           participants with positive symptom screen and/or positive TST will receive GX (i.e., GX
           replaces CXR in standard care algorithm). GX positive are considered to have active TB.
           TST positive and GX negative receive LTBI treatment. If an individual is not able to
           provide sputum, they will undergo a CXR.

        3. CXR for all/NoTST: Participants will receive symptom screening and CXR. No TST will be
           performed. If CXR abnormal or symptom positive, they undergo microbiological
           investigation. If the CXR is normal, and/or microbiological investigations negative -
           they receive LTBI treatment as per national guidelines. If microbiological investigation
           is positive they will be offered treatment for active TB.

      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.
    

Detailed 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:

        1. Standard care (control arm): Participants will receive symptom screening and tuberculin
           skin testing (TST). If symptom screen positive and/or TST positive, they undergo chest
           x-rays (CXR). If CXR abnormal, they undergo microbiological investigation. If CXR normal
           or if microbiological investigation negative, TST positive receive latent TB infection
           (LTBI) treatment. If microbiological investigation is positive, they will be offered
           treatment for active TB. For children under 5 years of age in Brazil, sputum induction
           will be performed for bacteriological investigation.

        2. GeneXpert (GX): Participants follow an algorithm similar to the standard care, however
           participants with positive symptom screen and/or positive TST will receive GX (i.e., GX
           replaces CXR in standard care algorithm). GX positive are considered to have active TB.
           TST positive and GX negative receive LTBI treatment. If an individual is not able to
           provide sputum, they will undergo a CXR.

        3. CXR for all/NoTST: Participants will receive symptom screening and CXR. No TST will be
           performed. If CXR abnormal or symptom positive, they undergo microbiological
           investigation. If the CXR is normal, and/or microbiological investigations negative -
           they receive LTBI treatment as per national guidelines. If microbiological investigation
           is positive they will be offered treatment for active TB.

      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:

        1. Societal costs (health system and patient costs) of the full cascade of care - from
           initial identification to LTBI therapy completion.

        2. Prevalence of microbiologically confirmed and clinically diagnosed active TB - detected
           as part of the initial contact investigation, who initiate LTBI treatment within 3
           months of the index TB patient starting active TB treatment.

        3. Prevalence of positive TST (>5 mm or >10 mm) - overall, and by age group.

        4. Incidence of grade 1-4 adverse events related to LTBI therapy.

        5. Proportion who complete LTBI therapy - defined as having taken at least 80% of doses in
           120% of allowed time.

        6. Sensitivity and specificity of CXR reading by usual providers in each study site
           (reference standard will be readings by external reviewers).

        7. Prevalence of active TB diagnosed using CXR in participants who cannot produce a sputum
           sample.

        8. 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.

      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.

        1. Societal costs (health system and patient costs) of the full cascade of care - from
           initial identification to LTBI therapy completion will be considered. Using all relevant
           cost components and an ingredients approach, differences in health system costs will be
           assessed for each of the strategies. Patient time will be valuated based on an
           assumption of income equivalent to the average per capita income in the country. Health
           care personnel time will be valuated based on average salaries from information provided
           by facility management in each setting.

        2. Prevalence of microbiologically confirmed and clinically diagnosed active TB - detected
           as part of the initial contact investigation, who initiate LTBI treatment within 3
           months of the index TB patient starting active TB treatment, will be compared between
           all three arms.

        3. Prevalence of positive TST (5 mm or 10 mm cut-points) by age group - 0-4 (for Brazil
           only), 5-10, 11-17, 18-24, 25-34 years, and older in Standard and GX Strategies. This is
           simple descriptive analysis - and will be presented as overall prevalence in the
           specified age groups, plus stratified by country.

        4. Incidence of serious adverse events related to LTBI therapy. Adverse events are
           relatively rare dichotomous outcomes. As such, Poisson regression will be used to
           compare the occurrence of the adverse events between each of the two experimental arms
           and the conventional arm. To account for clustering by household, GEE, with an
           exchangeable correlation structure and empirical standard errors will be used.
           Investigators will compare in the same way - the occurrence of grade 1-2 adverse events
           reported by study investigators.

        5. Completion of LTBI therapy - defined as taking at least 80% of doses in 120% of allowed
           time. (For 6H this means taking at least 144 doses within 216 days; for 4R this means 96
           doses within 144 days, and for 3HR - 72 doses within 108 days.) Since this is a
           dichotomous outcome, the primary analysis will use logistic regression, with an identity
           link, and estimated via GEE to account for clustering by household. An exchangeable
           correlation structure and empirical standard errors will be used. The proportion
           completing treatment in each experimental arm against the standard arm will be compared.

        6. Sensitivity and specificity of CXR reading by usual providers in each study site. For
           this analysis, the reference standard will be the readings by the external CXR review.

        7. Active TB - defined as treatment initiated for active TB - detected only as a result of
           the CXR done in persons who could not produce a sputum sample.
    

Intervention name(s): Strategy 2: Symptom screen, Genexpert and TST; Strategy 3:Symptom screen, CXR but NO TST
Intervention type(s): Other; Other
Intervention description(s): Participants follow an algorithm similar to the standard care, however participants with positive symptom screen and/or positive TST will receive GX (i.e., GX replaces CXR in standard care algorithm). GX positive are considered to have active TB. TST positive and GX negative receive LTBI treatment. If an individual is not able to provide sputum, they will undergo a CXR.; Participants will receive symptom screening and CXR. No TST will be performed. If CXR abnormal or symptom positive, they undergo microbiological investigation. If the CXR is normal, and/or microbiological investigations negative - they receive LTBI treatment as per national guidelines. If microbiological investigation is positive they will be offered treatment for active TB.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Latent Tuberculosis; GeneXpert; Chest X-Ray; Tuberculin Skin Testing