Evaluation of a Rapid Point-of-Care Serological Triage Test for Active TB
Evaluation of a Rapid Point-of-Care Serological Triage Test for Active TB
The performance of a new triage test for active tuberculosis (TB), SeroSelectTB, will be
 qualified in multi-centre randomised controlled trials at health-posts in South Africa,
 Tanzania and Ethiopia. Cost effectiveness evaluations will be conducted to support a value
 proposition to stakeholders and regulatory authorities, and to support commercialization
 requirements.

 Consenting adults will provide blood and saliva samples for screening by SeroSelectTB, and
 sputum collected for routine TB diagnosis by the health services. Clinical and
 sociodemographic information will be collected.

 A reliable rapid test will make it possible to identify and selectively treat those with
 active TB at the local healthcare level. The expected impact includes accurate same-day
 diagnosis of patients with active TB, reduction of diagnostic delay and TB transmission, and
 diagnostic cost-savings for patients and healthcare systems in high TB-burden countries.
Purpose: Worldwide over 15 million persons live with active TB. While the prevalence of
 latent TB is very high, only disease, and not latent infection, is treated in most high
 burdened countries.

 A rapid triage test for detection of active TB, which can identify symptomatic individuals
 who require confirmatory diagnostic investigation, is a global priority for TB control. A
 rapid triage test can drastically reduce the burden on health systems and patients, and
 reduce diagnostic delay by expediting referral, confirmatory testing and timely commencement
 of adequate treatment. Triage tests, which may utilise point- of-care rapid lateral flow (LF)
 platforms, offer a promising alternative to conventional methods for TB diagnosis (i.e. smear
 microscopy and culture). However, the lack of accurate TB biomarkers has stalled the
 development of serological assays that meet the World Health Organization (WHO)-defined
 criteria for a triage test.

 As an alternative, a rapid molecular diagnostic tool, maned Xpert and Xpert Ultra MTB/RIF,
 which accurately detects active TB, has been introduced in many countries as a replacement
 for smear microscopy and culture. However, Xpert/Ultra is not suited for use at health-posts
 without electricity or laboratory facilities, where the majority of patients present. In
 addition, the affordability of scaling-up Xpert is of concern in high TB-burden countries,
 where it could consume 20-80% of national TB budgets.

 Therefore, to control the emergence and spread of antibiotic resistant TB in a cost-effective
 manner, there is an urgent need for a rapid, inexpensive triage test that can detect active
 TB at health-posts level and expedite referral to facilities supporting molecular
 diagnostics. An ideal cost-effective triage test should be as sensitive as Xpert and cost
 less than US $5 to reduce total diagnostic costs by 30-40%, potentially saving national TB
 programmes US $36 million/year.

 The expected outcome of this project, the implementation of a triage test that will detect
 active TB at a low diagnostic cost, and expedite persons with TB-indicative symptoms to
 centralized healthcare facilities, will be beneficial irrespective of age and gender of
 patients. In addition, SeroSelectTB is sensitive among adults co- infected with TB/HIV.

 Primary objective of field trial is to evaluate the diagnostic delay, measured as the time
 from TB diagnostic to TB treatment initiation between two groups of patients: those who were
 screened with SeroSelectTB triage test compared to patients who received the standard of
 care.

 Persons with reactive SeroSelectTB test results will be referred for same-day confirmatory
 Xpert testing and treatment.

 Secondary objectives are:

 -  To describe SeroSelectTB performance in field conditions, including sensitivity and
 specificity, positive and negative predictive values in the study populations.

 -  Collect blood and saliva samples from all consenting participants and create national
 biobanks, which will facilitate biological samples exchange and sharing with third
 parties for future research.

 -  Assess the added-value of using SeroSelectTB in healthcare systems in South Africa,
 Tanzania and Ethiopia through cost-effectiveness evaluation and inform international and
 national TB prevention programmes stakeholders.

 Study design: This is an interventional, a multi-centre, two parallel-group, randomised,
 controlled field trial conducted in three countries: The South African Republic, United
 Republic of Tanzania, and Republic of Ethiopia.

 In the interventional arm participants will be screened using SeroSelectTB rapid triage test,
 and in the case of positive SeroSelectTB test results, will be referred to TB confirmation
 diagnostics at the referral centre where TB diagnosis will be confirmed by Xpert/Ultra
 molecular diagnostics. In the standard of care arm patients will receive usual TB
 diagnostics: microbiology (culture-confirmed diagnostics) and/or microscopy (sputum
 smear-based diagnostics).

 At inclusion, participants will be blinded to which diagnostic arm they are randomized:
 SeroSelectTB or standard of care arm. Healthcare workers performing the diagnostic test will
 not be blinded since it is unattainable to conceal if they are performing a
 microscopy/culture-based diagnostics or hand-held SeroSelectTB test. Lab technicians at
 Lateral Flow Laboratories, South Africa, and the National Institute of Health and the
 Environment (RIVM), the Netherlands will be blinded to patients' allocation when performing
 quality control analyses.

 Recruitment strategy and retention: An information leaflet and booklet addressing 'Myths and
 Facts' about TB diagnostic testing and the clinical trial, respectively, have been produced
 and translated from English to Kiswahili, Amharic, isiXhosa and Afrikaans. This information
 will be submitted to ethics committees for approval, and be used for public dissemination as
 a community engagement tool and given to every study participant.

 Healthcare facilities and clinical centres involved in this study have access to more than
 7,000 suspected TB cases per year, which ensures a large enough population to identify
 patients with active pulmonary TB disease.

 Loss to follow-up will be minimized by involving the community upfront through our planned
 community engagement plan, performing follow-up interviews with patients on TB treatment
 (DOTs - directly observed therapy - patients will be followed-up by data collection regarding
 their treatment), and/or conducting home visits.

 Recruitment site selection: Healthcare facilities and centres were selected based on reported
 high TB burden and previous experience with clinical and field TB trials. Annually, more than
 the double of confirmed TB cases are reported in the selected sites, which makes recruitment
 of needed number of cases (N=123) over two years' time feasible.

 Study safety: This trial does not contain any experimental intervention that will influence
 patients care. Collection of biological samples will be in accordance with WHO guidelines on
 blood sampling for research purposes.

 Study monitoring and data management: A written contractual agreement ('Consortium
 Agreement') will be signed by the consortium partners, and specific Clinical Trial Agreements
 will be signed by the Norwegian Institute of Public Health (NIPH) and clinical trial centers:
 Stellenbosch University, South African Republic, Kilimanjaro Christian Medical University
 College, United Republic of Tanzania, and Armauer Hansen Research Institute, Republic of
 Ethiopia, before the study start. A primary investigator (PI) at the trial center will be
 responsible for reaching milestones, informing work package (WP) and consortium Steering
 Committee (SC) leaders on progress, and keeping accounts as defined in project guidelines.

 On-site and in-house monitoring of trial data and protocol compliance will be performed
 according to study analysis protocol, written study plans and standard operating procedures
 (SOPs). An independent Data Monitoring Committee (DMC) composed of study site principal
 investigators (PIs), individuals with relevant expertise (e.g. data management and/or
 clinical background), and a statistician from NIPH will report directly to the SC. The role
 of DMC is to monitor data collection, data integrity and project timelines related to data
 collection. In addition, Field Evaluation Trial Committee (FETC), formed by local healthcare
 workers and clinicians, will be responsible for trial sites patients' safety and integrity.
 The FETC will closely work with DMC, and report to the SC.

 A risk-based approach to monitoring will be used. A secured cloud system will be used to
 register screened participants, randomization and assign to a trial arm. Data management,
 including cloud system design and maintenance, data cleaning, creation of listings for
 in-house monitoring, developing randomisation schedule, progress reports, Statistical
 Analysis Plan development, tables, figures, and presentations, and evaluation of primary and
 secondary end points, will be overseen by DMC and FETC.

 The study sponsor will host the database and maintain the oversight over recruitment,
 protocol compliance, study conduct, data correctness and integrity. Monitoring (on-site and
 remotely) and data management will be in the remit of DMC and FETC.

 No data whatsoever will be generated in the European Union (EU) or Norway, or stored on a
 server in the EU or Norway. Data will be stored solely on the institutional servers at our
 partner institutions in South Africa, Tanzania, and Ethiopia as required by institutional and
 national guidelines. To ensure data protection we guarantee that:

 -  Data extracted from the SeroSelectTB case report form entered into and stored on
 national servers in South Africa, Ethiopia, and Tanzania will be anonymized.

 -  A one-way random algorithm will automatically scramble data rows before data is shared
 with the project researchers.

 -  Data cannot be traced back to the source/participant.

 -  Personal identifier information is protected and available only to the national health
 services in South Africa, Ethiopia, and Tanzania as required by national guidelines.

 -  Data made available for analysis (shared with project researchers) will be provided
 f.ex. on Excel spread sheets without the unique participant codes.

 -  The Excel data files will be destroyed after analysis and publication of results.
Inclusion Criteria:

 -  18 years of age or older

 -  Informed Consent Form signed

 -  Unwell, suspected to have TB or pneumonia

 Exclusion Criteria:

 -  Currently receiving TB treatment

 -  On TB treatment past 30 days or more, or last dose less than 1 month before enrolment