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

Primary Purpose

Tuberculosis, Tuberculosis, Pulmonary, Tuberculosis, Miliary

Status
Unknown status
Phase
Not Applicable
Locations
Uganda
Study Type
Interventional
Intervention
Alere "Determine" lateral-flow urine lipoarabinomannan assay
Alere "Clearview" ELISA urine LAM assay
Sponsored by
Tuberculosis Clinical Diagnostics Research Consortium
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Tuberculosis focused on measuring Tests, Diagnostic, Mycobacterium tuberculosis, Mycobacterium tuberculosis antigens, TB, Tuberculosis, Tuberculosis, Pulmonary, Tuberculosis, Miliary, Lipoarabinomannan

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

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

Outcomes

Primary Outcome Measures

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
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
Inter-reader variability of the lateral-flow urine LAM assay
Expressed as the percent agreement
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

Secondary Outcome Measures

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
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.
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.
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.
Satisfaction of lateral-flow urine LAM test operators
Based on questionnaire assessment
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

Full Information

First Posted
January 20, 2012
Last Updated
February 1, 2012
Sponsor
Tuberculosis Clinical Diagnostics Research Consortium
Collaborators
Makerere University
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1. Study Identification

Unique Protocol Identification Number
NCT01525134
Brief Title
Feasibility of a Lateral Flow Urine Lipoarabinomannan (LAM) Test for Diagnosis of Tuberculosis
Official Title
Feasibility of Using the Inverness Lateral Flow Urine LAM Test for Diagnosis of Tuberculosis in HIV-Positive TB Suspects
Study Type
Interventional

2. Study Status

Record Verification Date
January 2012
Overall Recruitment Status
Unknown status
Study Start Date
January 2011 (undefined)
Primary Completion Date
February 2012 (Anticipated)
Study Completion Date
April 2012 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Tuberculosis Clinical Diagnostics Research Consortium
Collaborators
Makerere University

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
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.
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.)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Tuberculosis, Tuberculosis, Pulmonary, Tuberculosis, Miliary
Keywords
Tests, Diagnostic, Mycobacterium tuberculosis, Mycobacterium tuberculosis antigens, TB, Tuberculosis, Tuberculosis, Pulmonary, Tuberculosis, Miliary, Lipoarabinomannan

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
504 (Actual)

8. Arms, Groups, and Interventions

Intervention Type
Device
Intervention Name(s)
Alere "Determine" lateral-flow urine lipoarabinomannan assay
Other Intervention Name(s)
Determine lateral-flow urine LAM TB test
Intervention Description
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
Intervention Type
Device
Intervention Name(s)
Alere "Clearview" ELISA urine LAM assay
Other Intervention Name(s)
Clearview ELISA urine LAM TB test
Intervention Description
ELISA-based urine test to detect the lipoarabinomannan component of the M. tuberculosis antigen in the urine of TB suspects, in vitro. Manufacturer: Alere.
Primary Outcome Measure Information:
Title
Sensitivity of the lateral-flow urine LAM assay (LF-LAM)
Description
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
Time Frame
One year
Title
Failure rate of the lateral-flow urine LAM assay
Description
Failure rate expressed as the proportion of lateral flow urine LAM tests that require repeating due to an unevaluable initial result
Time Frame
One year
Title
Inter-reader variability of the lateral-flow urine LAM assay
Description
Expressed as the percent agreement
Time Frame
One year
Title
Specificity of the lateral-flow urine LAM assay (LF-LAM)
Description
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
Time Frame
One year
Secondary Outcome Measure Information:
Title
Sensitivity of the ELISA-based urine LAM test
Description
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
Time Frame
One year
Title
Diagnostic yield (expressed as number of TB cases detected) of various diagnostic strategies (see description)
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.
Time Frame
One year
Title
Time to diagnosis (expressed in days) of various diagnostic strategies (see description)
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.
Time Frame
One year
Title
Accuracy, efficiency, costs, and cost-effectiveness of various combinations of TB diagnostic tests
Description
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.
Time Frame
One year
Title
Satisfaction of lateral-flow urine LAM test operators
Description
Based on questionnaire assessment
Time Frame
One year
Title
Specificity (Sp) of the ELISA-based urine LAM test
Description
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
Time Frame
One year

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Susan Dorman, MD
Organizational Affiliation
Johns Hopkins University
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Yukari Manabe, MD
Organizational Affiliation
Infectious Diseases Institute, Makerere University, Kampala, Uganda
Official's Role
Principal Investigator
Facility Information:
Facility Name
Infectious Diseases Institute, Makerere University
City
Kampala
Country
Uganda
Facility Name
Mulago National Referral Hospital
City
Kampala
Country
Uganda

12. IPD Sharing Statement

Citations:
PubMed Identifier
24675585
Citation
Nakiyingi L, Moodley VM, Manabe YC, Nicol MP, Holshouser M, Armstrong DT, Zemanay W, Sikhondze W, Mbabazi O, Nonyane BA, Shah M, Joloba ML, Alland D, Ellner JJ, Dorman SE. Diagnostic accuracy of a rapid urine lipoarabinomannan test for tuberculosis in HIV-infected adults. J Acquir Immune Defic Syndr. 2014 Jul 1;66(3):270-9. doi: 10.1097/QAI.0000000000000151.
Results Reference
derived

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

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