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Tuberculosis (TB) is the leading cause of death caused by infectious agent globally. Estimated 10 million people get ill with TB every year and in 2022 globally there was an increase in Tuberculosis cases, first time since 2010. While in previous years, the decrease in TB numbers was reflecting the impact of disruptions to essential TB services during the COVID-19 pandemic, the increase in numbers in following years have highlighted how severe this disruptions impacted essential TB services.
Access to early diagnosis, including drug resistance testing, is essential in the cascade of care. Early diagnosis enables a timely and adequate start of treatment, reducing TB transmission and increasing the likelihood of favorable outcomes of treatment. Most of the tests that are used today to diagnose TB are slow and difficult to use. A few years ago, a new simple and sensitive test for detection of TB was introduced, the Xpert MTB/RIF. A new version of this, Xpert Ultra (Ultra) has been developed.
National Center for Tuberculosis and Lung Diseases in collaboration with Swiss Tropical and Public Health Institute is investigating whether new test Xpert / Ultra, when carried out at the Primary Health Care facilities, would help patients in getting a fast and reliable TB diagnosis in the country of Georgia.
The study will involve approximately 1600 participants. The study was approved by the local Ethics Committee of the National Center for Tuberculosis and Lung Diseases.
Full description
BACKGROUND INFORMATION The use of the rapid diagnostic test Xpert MTB/RIF (Xpert) for simultaneous detection of Mycobacterium tuberculosis and Rifampicin resistance has been scaled up in recent years globally, but real-life effectiveness studies could not demonstrate the expected beneficial impact on patient important clinical outcomes such as: time to diagnosis, time to treatment initiation and mortality among others.
The ideal rapid diagnostic tool should demonstrate better sensitivity and most importantly contribute to the detection of more TB cases and decreased time to diagnosis at decentralized Health Care facilities closest to the homes of the patients.
The new highly sensitive Xpert® MTB/RIF Ultra (Ultra) assay on GeneXpert® platform have the potential to overcome the limitations of Xpert by providing molecular TB testing with an improved sensitivity operating at peripheral facilities.
The presented study will assess the clinical impact and operational characteristics of Ultra at decentralized Primary Health Care (PHC) level, compared to existing routine diagnostic algorithm based on Xpert at specialized central TB service points (TB Cabinets).
OBJECTIVES AND PURPOSE In 2010, the World Health Organization (WHO) endorsed Xpert MTB/RIF, a rapid molecular diagnostic test with good performance characteristics[2,3]. In smear-positive patients, the test has a pooled sensitivity of 89%, whereas the pooled sensitivity in smear-negative, culture-positive patients is only 67%. Specificity is excellent in both groups at 99%[4].Xpert has been successfully rolled out in most high TB burden countries. However, efficacy trials showing excellent results were not further supported by real world effectiveness studies done after implementation of test by National TB Programs. In addition, tests in most cases have not been brought to the point of care level and thus could not pose a significant change.
In 2014, the WHO convened a meeting of stakeholders to establish consensus on identifying high-priority target product profiles (TPPs) for new tuberculosis diagnostics[5]. The identified high priority TPPs included; 1) a point-of-care non-sputum-based test capable of detecting all forms of TB by identifying characteristic biomarkers or bio signatures (the biomarker test), 2) a point-of-care triage test, which should be a simple, low-cost test that can be used by first-contact health-care providers to identify those who need further testing (the triage test), 3) a point-of-care sputum-based test to replace smear microscopy for detecting pulmonary TB (the smear-replacement test) and 4) a rapid drug-susceptibility test that can be used at the microscopy-centre level of the health-care system to select first-line regimen-based therapy (the rapid DST test).
The newly developed Ultra cartridge along with GeneXpert system, both products of Cepheid, Inc. - have the potential to become the smear-replacement test as outlined in the TPPs by overcoming operational challenges and the suboptimal sensitivity of the present Xpert. The new Ultra cartridge can detect TB with sensitivity similar to standard liquid culture [6]. As shown by Dorman et al for tuberculosis case detection, sensitivity of Xpert Ultra is superior to that of Xpert in patients with paucibacillary disease and in patients with HIV. The Ultra has also enhanced ability for detection of rifampicin resistance[7]. As a downside, the higher sensitivity of Ultra leads to the detection of non-viable mycobacteria, mainly in individuals with recent history of TB. The false positive results are seen predominately in samples with small amount of bacilli ("trace call" positive) which need to be interpreted according to recommendations by the WHO and in the light of the local epidemiology[8]. Furthermore, introducing a new diagnostic technology might lead to better patient care by shorter time to diagnosis, rather than through specific improved performance characteristics[9].
The proposed project will investigate the next generation molecular test Ultra with improved sensitivity onGeneXpert platform adjusted to environmental and clinical needs at point-of-care level.
HYPOTHESES
MAIN OBJECTIVES OF THE TB DIAGNOSIS STUDY AT PHC LEVEL:
Trial subject population
Presumptive pulmonary TB patients attending selected PHC facilities will be invited to participate in the study.
TRIAL DESIGN
1.1 Primary and secondary endpoint
Primary endpoints:
Secondary endpoints:
3 Proportion of patients with unfavourable outcomes after enrolment and loss to follow up measured at 6 months Unfavourable outcome is defined as lost to follow-up, death, treatment failure, and patient transfer 4 Proportion of patients with bacteriologically confirmed TB after 6 months Numerator: Participants with positive smear, culture, Xpert or Ultra result 30 days after enrolment Denominator: All participants of the study arm. 5 Proportion of patients diagnosed with TB from PHC sites Numerator: Number of all confirmed TB cases from all PHC site Denominator: Number of all confirmed TB cases diagnosed during trial period in RCT catchment area (self-referred, referred from specialized secondary, tertiary level clinics) 6 Operational characteristics of Ultra:
1.2 Trial design
This is a pragmatic, prospective, parallel cluster randomized trial in PHC facilities, routine diagnostic settings of the Georgian health system.
1.3 Measure to minimize bias
The objective of the study is to assess Ultra in routine use. The study-related procedures will be embedded into the routine practice at the PHC facilities to avoid any influence by the study. Enrolment criteria will be defined identically for both intervention and non-intervention arms to avoid selection bias.
Selection of study sites will not consider factors such as urban representation. PHC facilities with rationale amount of registered beneficiaries (population attributed to receive health care at selected HCF) and number of TB suspects are located only at city levels. The capital city Tbilisi will not be considered for the study due to a different set-up of patient/sample flow in comparison to the rest of the country.
1.4 Study duration and duration of subject participation
Study duration will be 24 months:
1.5 Recruitment
The most common symptom of Pulmonary TB "cough more than two weeks" will be a sign for "presumptive TB case". This symptom will be added to standard registration log at the entrance of every PHC facility in both intervention and control arms. Cough information along with standard registration details will be filled by registration desk.
In the intervention PHC facilities, patients with cough for more than two weeks on initial presentation will immediately be referred to the study nurse. The study nurse will obtain informed consent. All consenting patients will obtain one on spot sputum sample for further investigation with Xpert/Ultra on the site. After testing, cases with positive Ultra results will be referred to TB cabinets. Notification of positive cases will also be sent to TB cabinets and regional coordinators. In non-intervention PHC facilities, patients with "cough more than two weeks" will be added to the standard registration log at the entrance and will continue with the standard approach for examinations and referral without having Xpert Ultra testing.
All study participants from intervention and control arm will receive the same standard of care for tuberculosis diagnostics and consecutive treatment at TB cabinet level. TB diagnosis will further be confirmed with standard examinations according to National Guidelines approved by the MoH, which includes additional clinical examination, chest x-ray and laboratory examinations (culture and DST), TB treatment based on molecular or phenotypic DST and further follow up. The only difference will be: treatment will be initiated based on Ultra results in the interventional arm and on MTB/RIF results or clinical decision in control arm.
Enrolment will continue for a total of 12 months. Clinical and contact data (address, phone numbers) will be collected from participants on day 0.
1.6 Inclusion criteria
1.7 Exclusion criteria
1.8 Criteria for discontinuation of trial site
Reasons for the early closure of a study site by investigator may include but are not limited to:
Enrollment
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Volunteers
Inclusion criteria
Exclusion criteria
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778 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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