The trial will be conducted by the implementing partners in the three countries using staff already involved in TB contact tracing activities. Routine contact tracing activities will be augmented by research staff to obtain written informed consent, administer study questionnaires, and collect samples. We will use existing laboratory systems and patients requiring treatment will be referred to routine health services. This intervention will be tested pragmatically, under real-life settings to better inform adoption if successful.
Work Package 1 will include two phases. Phase I: Prior to delivery of the pragmatic CRT, 100 TB source cases will be enrolled and requested to identify contacts that can provide sputum for testing with Ultra and will have LTBI tested. If the proportion of contacts eligible for LTBI treatment (i.e. HIV positivity on history, <5 years or LTBI positivity), in each country is lower than 80%, we will consider LTBI testing in the main trial. We are not planning follow up except to report positive TB cases and those with LTBI if guidelines warrant treatment for LTBI and ensure linkage to care for those individuals.
In Phase II, we will conduct a CRT with randomisation at household level of TB source case (index patient). At enrolment, TB source cases and their households will be randomized into either ‘standard TB screening’ or ‘universal testing’ arms. The primary outcome of the trial is TB yield among household contacts.
The Aurum Institute will WP1 overall with the project manager overseeing progress the three countries.
To measure effectiveness of universal testing compared to standard TB screening for detection of TB among household and community contacts
Aurum, as coordinator, will be responsible for designing the protocol, contract management, data management, and quality management. External quality control will be provided to ensure adherence to international trial standards. Investigator meetings will be held once a month. Operational meetings will be held with all sites represented and Aurum and UCL for management of the CRT weekly. We envisage three Consortium meetings where we will review progress and provide a platform for junior researchers to interact with the site PIs and co-ordinators.
A stakeholder engagement plan will be drawn up where all the potential stakeholders will be listed with a strategy to engage them. These will include national and local health officials, patient interest groups, communities and non-governmental organisations working in the areas. A dissemination plan including open access peer-reviewed publications and presentations will be drawn up to ensure dissemination of results.
We aim to describe factors that inform stigma and practices that may interfere with TB screening and adherence to treatment. Using an adapted stigma and discrimination framework, TB source cases, caregivers (parents and legal guardians) of children on TPT, household contacts and community contacts will provide valuable insights on fear, lack of awareness, social judgement, culture and gender norms and socio-economic influences when screening for TB or taking TB treatment. We will further explore stigmas that intersect with TB, such as HIV co-infection, symptoms of TB, race, gender, and poverty. We will interview at least 30 people source cases, 10 caregivers of children on TPT, 30 household contacts and 30 community contacts from each country.
We will perform a full economic costing from a societal perspective including both provider and patient costs. Provider costs include all resources utilized in the two contact tracing strategies. To the extent possible, patient costs of TB treatment will be based on published literature and complemented with data from local surveys as required. We will build a Markov model with activation to active TB as the main outcome. Preventive treatment uptake and completion will be based on empirical data generated within the project. Assumptions about treatment efficacy and safety as well as base case activation rate in contacts will be based on published data from recent meta-analyses. ICERs will be calculated both as incremental cost per averted active case and incremental cost per quality-adjusted life-year (QALY) gained.
Whole genome sequencing of specimens for all TB sources cases and all contacts identified with TB. We will aim to understand transmission dynamics using NG-WGS between source cases and their household and community contacts. This would ultimately help refine programmatic efforts for household contact tracing and scale-up of preventive therapy. Cultures from TB source cases and contacts would be used to identify transmission patterns using NG-WGS and to identify mixed infections.
We will implement TB screening specific to child contacts <10 years and refer all symptomatic participants for sputum collection. In a sub-group of children with symptoms, additional stool and urine samples will be collected and tested using Ultra or the FujiLAM assay.The paediatric component will focus on increasing the capacity of study and clinic staff to manage and prevent paediatric TB, by providing clinical training on-site in each country, support visits to clinics and ensuring formal training of at least one clinician per site.We will also conduct training courses on paediatrics and provide additional equipment to support paediatric testing.
CUT-TB will develop TB research capacity and paediatric TB clinical capacity in all three African sites, but particularly in Lesotho. Other activities will include mentorship and site leadership for Drs Velen, Sabi and Chakare; training of two socio-economic and one micro-epidemiology PhD.In addition, we will ensure that at each site a clinician is identified for formal training in paediatric TB. In addition, Prof Lönnroth and Dr Copas will provide mentorship to Aurum based researchers in health economics and statistics.
Database development, capturing of data, cleaning of data and analysis of data.