Feasibility of a Lateral Flow Urine Lipoarabinomannan (LAM) Test for Diagnosis of Tuberculosis

Feasibility of Using the Inverness Lateral Flow Urine LAM Test for Diagnosis of Tuberculosis in HIV-Positive TB Suspects

The purpose of this study is to evaluate the accuracy, diagnostic yield, operational performance, and time to diagnosis of a novel lateral-flow urine lipoarabinomannan (LAM) test in detecting tuberculosis in HIV-infected adults.

A secondary study objective is to determine the accuracy, efficiency, costs, and cost-effectiveness of various combinations of Tuberculosis (TB) diagnostic tests, including the novel Xpert MTB/Rif test.

Study Overview

Detailed Description

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, efficiency, costs, and cost-effectiveness of various combinations of TB diagnostic tests, including the novel Xpert MTB/Rif test. The Xpert MTB/Rif test will be performed on a subset of participants (approximately 200 participants out of the total of 500 participants we expect to enroll for the LAM component of the study.)

Study Type

Interventional

Enrollment (Actual)

504

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Kampala, Uganda
        • Infectious Diseases Institute, Makerere University
      • Kampala, Uganda
        • Mulago National Referral Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Sensitivity of the lateral-flow urine LAM assay (LF-LAM)
Time Frame: One year
  • 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
Time Frame: One year
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
Time Frame: One year
Expressed as the percent agreement
One year
Specificity of the lateral-flow urine LAM assay (LF-LAM)
Time Frame: One year
  • 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
Time Frame: One year
  • 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)
Time Frame: One year
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 Frame: One year
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
Time Frame: One year
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
Time Frame: One year
Based on questionnaire assessment
One year
Specificity (Sp) of the ELISA-based urine LAM test
Time Frame: One year
  • 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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Collaborators

Investigators

  • Principal Investigator: Yukari Manabe, MD, Infectious Diseases Institute, Makerere University, Kampala, Uganda

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

January 1, 2011

Primary Completion (Anticipated)

February 1, 2012

Study Completion (Anticipated)

April 1, 2012

Study Registration Dates

First Submitted

January 20, 2012

First Submitted That Met QC Criteria

February 1, 2012

First Posted (Estimate)

February 2, 2012

Study Record Updates

Last Update Posted (Estimate)

February 2, 2012

Last Update Submitted That Met QC Criteria

February 1, 2012

Last Verified

January 1, 2012

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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