Feasibility of a Lateral Flow Urine LAM Test for Diagnosis of Tuberculosis in South Africa

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the accuracy, diagnostic yield, operational performance, and time to diagnosis of a novel lateral-flow urine LAM test in detecting tuberculosis in HIV-infected adults. A secondary study objective is to evaluate the accuracy and diagnostic yield of the Cepheid Xpert MTB/Rif test in detecting tuberculosis in the blood of HIV-infected adults.

Detailed Description
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Background: Tuberculosis (TB) incidence and mortality have increased dramatically as a result of the HIV epidemic. In parts of sub-Saharan Africa, TB is the leading cause of death among HIV-infected patients and approximately 50% of TB patients are HIV co-infected. Early treatment of TB is hindered by the lack of rapid, accurate diagnostic modalities that can be applied in resource-constrained settings. Mycobacterial culture is the laboratory standard for diagnosis of active TB, but it is costly, requires access to specialized laboratories, and takes weeks to provide results. Sputum smear microscopy detects less than half of HIV-infected TB cases in many settings. The Global Plan to Stop TB has prioritized the development of simple, accurate, inexpensive tests for TB case detection in HIV-positive individuals. LAM: As a strategy for rapid TB diagnosis, the detection of Mycobacterium tuberculosis antigens has been explored over several decades. Lipoarabinomannan (LAM), a glycolipid component of the outer cell wall of mycobacteria, is an attractive diagnostic target for several reasons: it is heat-stable; cleared by the kidney; detectable in urine; and as a bacterial product, has the theoretical potential to discriminate active TB from latent TB infection independent of human immune responses. A urine test could facilitate TB diagnosis in patients in whom sputum is uninformative or not obtainable, and lacks the infection-control risks associated with sputum production or blood collection. Urine LAM detection may be amenable to simple, rapid, inexpensive point-of-care platforms. This is a prospective study to evaluate the accuracy, diagnostic yield, operational performance, and time to diagnosis of a novel lateral-flow urine LAM test in detecting tuberculosis in HIV-infected adults. HIV-positive adults suspected to have TB will be enrolled after providing informed consent. Urine will be obtained for testing using the novel lateral flow urine LAM assay and an existing ELISA-based urine LAM assay. Conventional microbiological tests for TB and chest x-rays will also be performed. These tests will be performed on all participants enrolled (target sample size = 500). A secondary study objective is to determine the accuracy and diagnostic yield of the Cepheid Xpert MTB/Rif test in detecting tuberculosis in the blood of HIV-infected adults (the same set of participants on whom the LAM testing is done; approximate sample size = 500).

Official Title
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Feasibility of Using the Inverness Lateral Flow Urine LAM Test for Diagnosis of Tuberculosis in HIV-Positive TB Suspects in Cape Town, South Africa

Conditions
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Tuberculosis, Tuberculosis, Pulmonary, Tuberculosis, Miliary

Intervention / Treatment
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* Device: Alere Determine lateral-flow urine lipoarabinomannan assay
* Device: Alere Clearview ELISA urine LAM assay
* Device: Cepheid Xpert MTB/Rif assay


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (Individuals must meet all of the following inclusion criteria in order to be eligible to participate): Informed consent Suspected active tuberculosis Willingness and ability to comply with study procedures Any one or more of the following: Current cough Fever at any time within the preceding 4 weeks Night sweats at any time within the preceding 4 weeks Weight loss within the preceding 4 weeks HIV-positive based on any one or more of the following: written results of a positive HIV antibody test, and/or written results of a positive HIV viral load, and/or documentation in the medical record of positive HIV status by a treating clinician. Exclusion Criteria (Any subjects meeting any of the following exclusion criteria at baseline will be excluded from study participation): Multidrug tuberculosis treatment for greater than two days within the previous 60 days Unwillingness or inability to provide a urine sample Known chronic pulmonary condition, e.g. asthma, chronic obstructive pulmonary disease, emphysema Respiratory distress, defined as respiratory rate of >30 or oxygen saturation <90% Any specific condition that in the judgment of the investigator precludes participation because it could affect a subject's safety.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Device: Alere Determine lateral-flow urine lipoarabinomannan assay|lateral-flow (point-of-care) urine test to detect the lipoarabinomannan (LAM) component of the M. tuberculosis antigen in the urine of TB suspects, in vitro. Manufacturer: Alere|
|Device: Alere Clearview ELISA urine LAM assay|ELISA-based urine test to detect the lipoarabinomannan component of the M. tuberculosis antigen in the urine of TB suspects, in vitro. Manufacturer: Alere.|
|Device: Cepheid Xpert MTB/Rif assay|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitivity of the lateral-flow urine LAM assay (LF-LAM) | Conventional TB tests (mycobacterial blood & sputum culture) will be the reference standard used to calculate sensitivity of the LF-LAM test Sensitivity is defined as TP/(TP+FN), or the number of true positives over (the number of true positives + the number of false negatives) true positive = a positive LF-LAM result in a patient also having ≥1 culture positive for M. tuberculosis false negative = a negative LF-LAM result in a patient also having ≥1 culture positive for M. tuberculosis | One year | 
| Failure rate of the lateral-flow urine LAM assay | Failure rate expressed as the proportion of lateral flow urine LAM tests that require repeating due to an unevaluable initial result | One year | 
| Inter-reader variability of the lateral-flow urine LAM assay | Expressed as the percent agreement | One year | 
| Specificity of the lateral-flow urine LAM assay (LF-LAM) | Conventional TB tests (blood & sputum culture) will be the reference standard used to calculate specificity (Sp) of the LF-LAM Sp=TN/(TN+FP), or #true negatives / (#true negatives + #false positives) true negative = negative LF-LAM in Not TB patient false positive = positive LF-LAM in Not TB patient Not TB = meets all criteria below no sputum/blood culture positive for MTB no smear microscopy positive for acid-fast bacilli no granulomas/caseous necrosis on histopathology no clinical response to TB treatment a plausible alternative diagnosis | One year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitivity of the ELISA-based urine LAM test | Conventional TB tests (mycobacterial blood & sputum culture) will be the reference standard used to calculate sensitivity of the ELISA LAM test Sensitivity is defined as TP/(TP+FN), or the number of true positives over (the number of true positives + the number of false negatives) true positive = a positive ELISA LAM result in a patient also having ≥1 culture positive for M. tuberculosis false negative = a negative ELISA LAM result in a patient also having ≥1 culture positive for M. tuberculosis | One year | 
| Diagnostic yield (expressed as number of TB cases detected) of various diagnostic strategies (see description) | Diagnostic yield will be measured for strategies including a) lateral flow urine LAM testing plus sputum smear microscopy; b) ELISA urine LAM testing plus sputum smear microscopy; c) sputum smear microscopy plus sputum culture; d) sputum culture plus mycobacterial blood culture. | One year | 
| Time to diagnosis (expressed in days) of various diagnostic strategies (see description) | Time to diagnosis will be measured for strategies including a) lateral flow urine LAM testing plus sputum smear microscopy; b) ELISA urine LAM testing plus sputum smear microscopy; c) sputum smear microscopy plus sputum culture; d) sputum culture plus mycobacterial blood culture. | One year | 
| Accuracy, efficiency, costs, and cost-effectiveness of various combinations of TB diagnostic tests | TB diagnostic tests to be included in this analysis: sputum smear microscopy, sputum culture, mycobacterial blood culture, chest X-ray, lateral-flow urine LAM testing, ELISA urine LAM testing, and Xpert MTB/Rif. | One year | 
| Satisfaction of lateral-flow urine LAM test operators | Based on questionnaire assessment | One year | 
| Specificity (Sp) of the ELISA-based urine LAM test | Conventional TB tests (blood & sputum culture) will be the reference standard used to calculate Sp of ELISA LAM Sp=TN/(TN+FP), or #true negatives / (#true negatives + #false positives) true negative = negative ELISA LAM in Not TB patient false positive = positive ELISA LAM in Not TB patient Not TB = meets all criteria below no sputum/blood culture positive for MTB no smear microscopy positive for acid-fast bacilli no granulomas/caseous necrosis on histopathology no clinical response to TB treatment a plausible alternative diagnosis | One year | 
| Sensitivity of the Xpert MTB/Rif test to detect MTB in blood | Conventional mycobacterial blood culture will be the reference standard used to calculate sensitivity of Xpert MTB/Rif in blood Sensitivity is defined as TP/(TP+FN), or the number of true positives over (the number of true positives + the number of false negatives) true positive = a positive Xpert MTB/Rif result in a patient also having ≥1 mycobacterial blood culture positive for M. tuberculosis false negative = a negative Xpert MTB/Rif result in a patient also having ≥1 mycobacterial blood culture positive for M. tuberculosis | One year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TB, Tests, Diagnostic, Mycobacterium tuberculosis, Mycobacterium tuberculosis antigens, Tuberculosis, Tuberculosis, Pulmonary, Tuberculosis, Miliary, Lipoarabinomannan