Quantifying Infectiousness of Undiagnosed Tuberculosis Cases and the Impact of Enhanced Community-based Active Case Finding Strategy Using Novel Diagnostic Tools: A Randomized Controlled Trial
Trial Snapshot
- Phase
- Not Applicable
- Status
- Completed
- Sponsor
- University of Cape Town
- Enrollment
- 608
- Locations
- 1
- Primary Endpoint
- The time-to-treatment of culture-positive TB cases initiating TB treatment in each study arm.
Study Overview
Brief Summary
TB kills most people with HIV in Africa. TB is out of control. Radically different approaches to deal with the disease is therefor needed. It is known that intensified case finding works in high HIV prevalence environments. However, the poor performance of conventional diagnostics makes the strategy costly and unpalatable for policy makers. If it can be shown that a package of new diagnostic technologies significantly enhances ease and speed of diagnosis, and time to treatment initiation when using intensified case finding, this will usher the way for further studies and policy adjustments to tackle TB. Thus, the work, if found to be useful, could have major policy implications
The purpose of this study will be to determine the diagnostic yield, impact and feasibility of community-based intensified TB case finding using symptom screening, point-of-care TB testing (Xpert Omni), point-of-care HIV testing and CD4 count (Alere PIMA), if HIV-infected, together with a clinic-based diagnostic package (sputum smear microscopy, MGIT sputum culture, and digital chest radiograph). Additionally, the study will assess the infectiousness of previously undiagnosed TB cases in the community using cough aerosol sampling technology (CASS) and will determine the genomic, transcriptomic and lipidomic profile of TB isolates from patients undergoing CASS sampling. The cost-effectiveness of using a novel TB diagnostic platform (Xpert Omni) for intensified case finding compared to conventional methods will also be evaluated.
~6000 people will be screened to enrol 600 participants with suspected TB. It is expected that using the GeneXpert® Omni POC mobile clinic of 2- to 3-person team of healthcare workers in an inexpensive panel van will substantially reduce the time to treatment initiation, and the proportion of individuals initiating and completing TB treatment. Investigators will also review and follow up Household contacts of active TB participants.
As part of the study investigators will also contribute data and specimens to the RePORT consortium (Regional Prospective Observational Research for Tuberculosis), that aims to create a multinational bank with the primary objective of providing specimens and data to RePORT consortia biomarker researchers and their collaborators over the next decade to achieve a better understanding of the prognosis of TB disease; and the pathogenesis of progression from TB exposure to disease.
Detailed Description
Background:
TB kills most people with HIV in Africa. TB is out of control. Healthcare professionals therefore need radically different approaches to deal with the disease. It is known that intensified case finding works in high HIV prevalence environments. However, the poor performance of conventional diagnostics makes the strategy costly and unpalatable for policy makers. If it can be shown that a package of new diagnostic technologies significantly enhances ease and speed of diagnosis, and time to treatment initiation when using intensified case finding, then this will usher the way for further studies and policy adjustments to tackle TB. Thus, the work, if found to be useful, could have major policy implications.
Study hypothesis:
Active community-based case finding using a package of diagnostic tools incorporating the new GeneXpert® Omni will detect untreated highly infectious tuberculosis cases (using cough aerosol sampling) and will reduce time to treatment initiation of confirmed TB cases and will increase the proportion of culture-positive TB cases initiating and completing TB treatment, compared to community based screening using a standard intensive-case finding strategy (smear microscopy).
Study design A randomised controlled trial will be used to compare the two diagnostic packages.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Screening
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •for TB suspects
- •Community participant willing to complete community-based symptom screening, urine testing, blood testing for HIV and/or undergo TB diagnostic tests at the local TB clinic.
- •Provision of informed consent.
- •Has documentation of, or willingness to be tested for HIV infection. HIV testing does not need to be repeated if there is written documentation of a confirmed positive test at any time in the past.
- •HIV-negative adults (older than 18 years) with 1 or more of the following:
- •cough ≥ 2 weeks
- •loss of weight
- •night sweats
- •generalized fatigue
- •haemoptysis
- •chest pain
- •Any HIV+ve adult (older than 18 years).
- •Agrees to the collection and storage of blood, urine, saliva, and sputum specimens for use for future research. (The participant may decline collection of specimens for human genetic research and still be eligible for the study.)
- •To be eligible for the RePORT sample collection aspect of the study, the participant must have either CXR findings consistent with TB, and/or are sputum smear positive by microscopy or by rapid diagnostic test, such as GeneXpert.
- •Confirmatory Inclusion criteria for RePORT sample collection
- •a.) Adults must have pulmonary disease confirmed by culture. i. Mtb identified by culture of expectorated or induced sputum. ii. Mtb identified by culture results from respiratory secretions obtained by broncho-alveolar lavage or bronchial wash may not be used to determine study eligibility.
- •iii. Mtb identified from either liquid or solid culture is acceptable, and may be from either clinical or study-related specimens.
- •iv. Those who have extra-pulmonary manifestations of TB in addition to pulmonary TB may also be enrolled.
- •Participants who fail to meet the confirmatory inclusion criteria noted above will be discontinued from the RePORT aspect of the study. However, specimens that were previously collected from the participant may be retained for use as control specimens, and the participants may still continue participation in the XACT-2 study.
Exclusion Criteria
- •for TB suspects
- •Inability to provide informed consent (e.g. mentally impaired).
- •Patients self-presenting to the TB clinics.
- •Patients who have completed TB treatment in the last 2 months or received >1 week (daily or intermittent doses) of any drugs with anti-TB activity within 30 days prior to provisional enrolment, including:
- •Any drug or combination of drugs typically used in a multidrug anti-TB therapy (isoniazid [INH], rifampicin, pyrazinamide, ethambutol); Any fluoroquinolone (e.g., ofloxacin, ciprofloxacin, levofloxacin, moxifloxacin, nalidixic acid, sparfloxacin, and gatifloxacin); Any other drugs with anti-TB activity (e.g., clofazamine, aminoglycosides [amikacin, kanamycin], or capreomycin).
- •Plans to move from his/her current residence, which would interfere with the participant's ability to complete all study visits (through the 6-Month Post-Treatment Visit).
- •Has an active psychiatric condition, or alcohol or drug dependence that, in the opinion of the site investigator or designee, might interfere with the ability to give true informed consent and to adhere to the study requirements.
- •Is currently imprisoned.
- •Inclusion criteria for Household contacts (HHC)
- •Adult (> 18 years old) with significant recent exposure (within the past 6 months) to an adult with untreated or inadequately treated pulmonary TB.
- •No clinical signs or symptoms of active TB that include, but are not limited to: persistent cough, haemoptysis, fever, unintended weight loss or failure to thrive (children), fatigue or lethargy, night sweats, pleuritic chest pain, draining lymph node, or other evidence of extra-pulmonary TB. If clinical signs or symptoms of TB are present, CXR and/or sputum culture results must be included in the overall evaluation to rule out active TB.
- •Has signed a written consent or witnessed oral consent in the case of illiteracy, prior to his/her first sample or other study-specific data being collected.
- •Agrees to the collection and storage of blood, urine, saliva and sputum specimens for use for future research. (The participant may decline collection of specimens for human genetic research and still be eligible for the study.)
- •Exclusion Criteria for Household contacts
- •Plans to move from his/her current residence, which would interfere with the participant's ability to complete all study visits (through the Month 24 Visit).
- •Has an active psychiatric condition, or alcohol or drug dependence that, in the opinion of the site investigator or designee, might interfere with the ability to give true informed consent and to adhere to the study requirements.
- •Is currently imprisoned.
- •Exclusion from the RePORT aspect of the study (patients may still be included in the XACT II study)
- •Participants enrolled as active TB cases will be discontinued from the study for the following reasons:
- •a. More than 1 week of anti-TB therapy was received before the following minimum required baseline laboratory specimens were collected: i. Sputum for culture and Mtb isolate; ii. Sputum for storage; iii. Blood and plasma; and iv. Urine b. The provisional pulmonary TB diagnosis is not confirmed as defined by the protocol (see Confirmatory Inclusion Criteria listed above); c. An HIV test was not completed within the Month 1 Visit window; d. A study outcome occurred: i. Treatment failure (bacteriologic or clinical); ii. TB relapse (bacteriologic or clinical); iii. Emerging resistance; or iv. Completion of the 6-Month Post-Treatment Visit.
- •Household contacts will be discontinued from the study for the following reasons:
- •a. A study outcome occurred: i. Active TB develops before the Month 24 Visit; the participant may enroll as an active TB participant if all eligibility criteria are met; or ii. Completion of the Month 24 Visit.
- •Participants will be discontinued from the study for any of the following reasons:
- •The participant/parent/legal guardian withdraws consent and/or assent;
- •The participant is lost to follow-up or moves out of the area;
- •The participant dies;
- •The participant was inadvertently enrolled;
- •The investigator determines that further participation would be detrimental to the health or well-being of the participant;
- •The study is stopped by a funding organization or other government agency; or
- •The study has to stop for other administrative reasons.
Arms & Interventions
Novel diagnostics arm
The intervention is to screen a sputum specimen collected on a participant with suspected TB in the community at the point-of-contact in a mobile van using an on-site GeneXpert MTB/RIF machine
Intervention: GeneXpert MTB/RIF (Other)
Routine screening arm
The control arm is to send a sputum specimen collected on a participant with suspected TB at the mobile van for routine smear microscopy at a laboratory
Intervention: Smear microscopy (Other)
Outcomes
Primary Outcomes
The time-to-treatment of culture-positive TB cases initiating TB treatment in each study arm.
Time Frame: Within 2 months of enrollment, up to 24 months
Time (in days) as determined by difference between enrolment date and date that treatment is commenced in local TB Clinic attendance register.
Secondary Outcomes
- The proportion of culture-positive TB cases initiating TB treatment in each study arm.(Within 2 months of enrolment, up to 26 months)
- The proportion of culture-positive TB cases completing 6-months of TB treatment in each study arm.(Through study completion, up to 48 months)
- User adherence to methodology of GeneXpert® Omni MTB/RIF at the point-of-care in a mobile unit.(Through study completion, up to 48 months)
- Cost per TB case detected between study arms.(Through study completion, up to 48 months)
- Accuracy of GeneXpert® Omni MTB/RIF at the point-of-care in a mobile unit.(Through study completion, up to 48 months)
- Cost per TB case successfully completing treatment between study arms.(Through study completion, up to 48 months)
- To contribute data and samples as part of the RePORT consortium in order to achieve a better understanding of the prognosis of TB disease and the pathogenesis of progression from TB exposure to disease.(Through study completion, up to 48 months)
- User acceptance to methodology of GeneXpert® Omni MTB/RIF at the point-of-care in a mobile unit.(Through study completion, up to 48 months)
- Feasibility of performing GeneXpert® Omni MTB/RIF at the point-of-care in a mobile unit.(Through study completion, up to 48 months)
Investigators
Keertan Dheda
Principal Investigator
University of Cape Town