Tuberculosis Clinical Trial
Official title:
The Utility of Intensified Case Finding Combined With a Package of Novel TB Diagnostics Using a Mobile Clinic in Africa- a Randomized Controlled Trial (XACT)
The purpose of this study is to compare two different methods of intensified tuberculosis (TB) case finding in the community. These methods all involve the use of a mobile clinic to reach people with TB symptoms who are not able to readily access clinic services. A standard diagnostics package consisting of smear microscopy and culture (with smear result available the next day) will be compared with a novel diagnostics package involving point-of-care sputum GeneXpert MTB/RIF performed at a mobile or conventional clinic (with same day result), sputum culture, and lateral flow urinary lipoarabinomannan (LAM) testing (in HIV +ve subjects only). The primary outcome is a comparison between the number of culture +ve subjects on TB treatment in each group at the end of two months. A secondary aim is an evaluation of the accuracy and feasibility of GeneXpert performed in a mobile clinic. Additional study aims include using chest X-rays obtained during the study to develop and validate of an computer-aided diagnosis (CAD) software package for TB (together with collaborators in the Netherlands), as well as establishing whether LAM is detectable at sub-ELISA concentrations in the urine of those with TB.
Despite recent advances in diagnosis and the availability of effective anti-tuberculous
treatment TB remains one of the world's most devastating infectious disease, with a global
prevalence of more than 14 million in 2006. In high burden communities with the co-localised
HIV epidemic, a major problem hampering control efforts and promulgating the TB epidemic is
the large reservoir of undiagnosed TB disease. This comprises over 50% of the total TB
burden. HIV-infection with its atypical yet infectious presentation where immunity is
attenuated worsens this undetected reservoir. Thus, there is a large case load in the
community that do not access health care or do so late in the course of the disease and
there is thus ongoing disease transmission within the community. If this caseload in not
addressed then the TB epidemic will never be controlled.
Intensified case finding seeks to address this problem. Intensified case finding is a
strategy to identify and treat people with TB who have not sought diagnostic services on
their own initiative. By contrast, passive case finding is only able to identify people with
TB presenting to health care facilities. In 2008 the WHO and Stop TB partnership identified
intensified case-finding as one of four core TB prevention strategies necessary to meet the
sixth Millennium Development Goal of halving the prevalence of TB by 2015. To date, a number
of studies have illustrated the success of intensified case finding to increase
case-detection rates (especially in HIV-infected populations) and to shorten time to
diagnosis thereby limiting attendant morbidity and mortality.
Given both the importance and resource-intensive nature of intensified case finding it is
essential that the optimal, operationally feasible and most cost-effective screening
strategy be used. To date, screening strategies have varied widely across studies but all
have used a combination of symptom screening, radiological (CXR) and microscopy-centre based
laboratory diagnostics (smear microscopy and, if available and cost permitting, TB culture).
This is a major shortcoming as it is now well established that these standard diagnostic
tools perform sub-optimally especially in high HIV prevalent settings. With the recent
development of a number of novel TB diagnostic tools with superior performance compared to
conventional modalities, and the potential for point-of-care (POC) and point-of-treatment
usage, it is imperative that intensified case-finding strategies be reviewed. The 2010
updated WHO "Guidelines for intensified tuberculosis case finding and isoniazid preventive
therapy for people living with HIV in resource constrained settings" recommends the use of a
clinical algorithm for intensified case finding programmes for adults and adolescents living
with HIV and it is important that the incremental diagnostic benefit together with the
feasibility and cost-effectiveness of these novel TB diagnostic tools be assessed for use in
intensified case finding programmes within the context of these updated guidelines.
In 2009, Cepheid released the Xpert® MTB/RIF Assay, which is the only system able to deliver
answers directly from unprocessed samples by combining on-board preparation of the sample
with real-time PCR in less than 2 hours. Additionally, the Xpert® MTB/RIF Assay allows for
simultaneous on-demand molecular testing for the detection of M.tb and RIF resistance. The
GeneXpertâ„¢ system consists of a GeneXpert instrument, personal computer and disposable
fluidic cartridges. The system combines cartridge-based sample preparation with
amplification and detection in a fully integrated and automated nucleic acid analysis
instrument. GeneXpert has been shown to be an accurate tool for the rapid diagnosis of
tuberculosis in both smear-positive and smear-negative samples (with a single Xpert test
having a sensitivity of ~ 70% in smear-negative samples. A large demonstration study of Gene
Xpert based at microscopy-centres is currently underway and preliminary data appear
promising. However, GeneXpert technology has not been used as part of a screening strategy
for intensified case finding and its operational feasible as a point-of-treatment diagnostic
technology based in a mobile clinic has not yet been assessed.
In our recent review we have proposed urinary LAM as a useful "rule in" test for TB in
HIV-infected subjects with advanced immune-suppression. Additionally, the recent development
of a point-of-care urine LAM lateral flow strip test - the Determine TB® - with preliminary
results suggesting equivalent performance to the LAM ELISA make it an appealing diagnostic
for high HIV prevalence areas. A recent study has shown urine LAM to be more sensitive than
smear-microscopy in an ARV clinic-based TB screening study. The use of the Determine TB®
lateral flow strip test has not been studied as part of an intensified case finding strategy
for population-based surveys. The Determine TB® lateral flow test will be used for screening
of HIV-infected patients at point-of-care within the community and subsequent TB clinic
referral for sputum-based diagnostics.
The XACT study has a randomised control study design to evaluate the impact of a package of
novel TB diagnostic tools in the community using a mobile unit compared to standard
intensive-case finding methods. The feasibility of performing new TB diagnostics at the
point-of-care will be examined to determine if the proportion of patients identified,
initiating, and completing TB treatment, is greater compared to the standard diagnostic arm.
Further, the cost-effectiveness of TB cases detected and successfully completing treatment
between study arms can also be investigated.
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Diagnostic
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