Prospective Evaluation of Novel Diagnostics for Tuberculosis in KwaZulu-Natal, South Africa (PROVE-TB)

Tuberculosis (TB) infects nearly two billion people and has become the leading infectious cause of mortality worldwide, due in part to inadequate diagnostic and prognostic tests. Older diagnostic tools, such as acid-fast staining, and newer diagnostic tests, such as nucleic acid amplification, are either insensitive, expensive, or not suitable for use at the clinical point-of-care. Therefore, novel diagnostic tests are needed to diagnose active TB disease among adults, people living with HIV (PLHIV), and children in TB-endemic countries. In this project, the investigators will conduct clinical evaluation studies of emerging TB diagnostic tests among (1) hospitalized adults, (2) ambulatory adults in outpatient clinics, and (3) children <12 years suspected of having active TB disease. the investigators will also maintain a biorepository of well-characterized clinical specimens that can be used for either retrospective validation of TB diagnostic tests, establishing a reference LAM test, or to share with partners developing novel TB diagnostics, including new LAM antibodies. The project will be coordinated at the University of Washington, and conducted in partnership with clinical research partners in South Africa, including Umkhuseli Innovation and Research Management (UIRM) and the National Health Laboratory Service (NHLS). The project team is well-equipped to serve as a central clinical research site to evaluate new and emerging point-of-care TB diagnostics, particularly novel urinary LAM assays, at the on-site TB Diagnostics Research Laboratory at Edendale Hospital in KwaZulu-Natal, South Africa.

Study Overview

• Status: Completed
• Conditions: Tuberculosis

• Study Type: Observational
• Enrollment (Actual): 843

Contacts and Locations

Study Locations

• South Africa
  • Pietermaritzburg, South Africa, 3201
    • Edendale Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The study may enroll 3 different types of patient cohorts, including (1) hospitalized adults (≥16 years old), (2) ambulatory adults (≥16 years old) in outpatient clinics, and (3) children <12 years suspected of having active TB disease.

Description

Phase I

1. Eligibility for hospitalized and ambulatory adults:

• ≥16 years old
• Positive Xpert MTB/RIF Ultra test (TB-positive cohort) or no suspicion of clinical TB (TB-negative cohort)
• Have a documented HIV test result or agrees to test for HIV
• Have NOT received IPT within prior 3 months
• Have NOT received anti-TB treatment for more than 24 hours
• Willing/able to provide written informed consent

Phase II:

1. Eligibility for hospitalized adults:

   • ≥16 years old
   • Admitted to inpatient medical ward <72 hours
   • Have a documented positive HIV test
   • Have NOT received IPT within prior 3 months
   • Have NOT received anti-TB treatment for more than 24 hours
   • Willing/able to provide written informed consent

   Study population description:

2. Eligibility for Xpert+ adults (hospitalized and attending outpatient clinics)

   • ≥16 years old
   • Have a documented HIV test result or agrees to test for HIV
   • Positive Xpert MDR/RIF Ultra test documented.
   • Have NOT received anti-TB treatment for more than 24 hours

   • Willing/able to provide written informed consent

     3) Eligibility for children

   • children <12 years of age
   • suspected of having active TB disease by clinical team
   • Have a documented HIV test result or agrees to test for HIV
   • Have not had IPT within 3 months
   • Have not received anti-TB treatment for more than 24 hours within the prior 5 days
   • Parent or guardian is willing/able to provide written informed consent

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
Children
Adults - inpatient
Adults- ambulatory

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Classified with TB Case Definition	TB positive: A person with a positive Xpert MTB/RIF test or TB culture on any bodily fluid specimen that was obtained/tested within 5 days of enrollment. Probable TB: A person with compatible symptoms, signs, histopathological specimens and imaging for TB, but without a positive TB culture or Xpert test on any specimen; empirically initiated on TB treatment. TB negative: A person with a primary hospital diagnosis other than TB, who has no clinical suspicion for TB, and no diagnostic TB testing ordered by the treating team. TB negative (TB excluded): A person with all reference microbiological testing for TB returning negative, including negative Xpert, negative TB culture, other investigations for TB negative (e.g. histopathology, imaging) and either clinical improvement in the absence of anti-TB therapy or alternate diagnosis determined. In addition, no incident TB diagnosis made (including empiric anti-TB treatment initiation) within the 2 months following enrollment.	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants with TB Treatment Outcome	Confirmed TB: Bacteriological confirmation obtained: culture or Xpert MTB/RIF from at least one specimen.; Probable TB: Bacteriological confirmation not obtained AND at least 2 of the following:; Symptoms/signs suggestive of TB (as defined); Chest radiograph or abdominal ultrasound consistent with TB; Close TB exposure or immunologic evidence of M. tuberculosis infection; Positive response to anti-TB treatment (requires documented positive clinical response on TB treatment); TB negative/unlikely: Bacteriological confirmation NOT obtained AND criteria for "unconfirmed tuberculosis" NOT met.	2 Month, 6 Month

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: PATH; University of KwaZulu; Umkhuseli Innovation and Research Management (UIRM); KwaZulu Natal Department of Health; Salus Ltd.
• Investigators: Principal Investigator: Paul K. Drain, MD, MPH, FACP, University of Washington; Principal Investigator: Douglas Wilson, MD, University of KwaZulu

Study record dates

Study Major Dates

• Study Start (Actual): September 18, 2019
• Primary Completion (Actual): August 31, 2022
• Study Completion (Actual): August 31, 2022

Study Registration Dates

• First Submitted: September 29, 2020
• First Submitted That Met QC Criteria: October 6, 2020
• First Posted (Actual): October 12, 2020

Study Record Updates

• Last Update Posted (Actual): August 7, 2024
• Last Update Submitted That Met QC Criteria: August 5, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Diagnostics; Urine-Lam
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: STUDY00009092; OPP1213504 (Other Grant/Funding Number: Bill & Melinda Gates Foundation)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No