Clinical trial NCT05845112: Start Taking Action For TB Diagnosis
Official title: Start Taking Action For TB Diagnosis (START4ALL)
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Diagnosis
Tuberculosis
Keywords: TB
Diagnostics
Lead sponsor: Liverpool School of Tropical Medicine
Sponsor class: OTHER
First posted: 2023-05-06
Enrollment: 15300
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Observational model: OTHER
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Individuals suspected of having TB.

Brief summary: Globally, tuberculosis (TB) is one of the main causes of death and the leading cause from a single infectious agent. In 2020, an estimated 9.9 million people developed TB and 1.5 million died. Millions of people remain undiagnosed with TB, hindering efforts to end TB. TB tests have inadequate accuracy or performance characteristics for implementation across all populations and settings. None of the tests meet the WHO-Target-Product Profile for TB screening and most need specialized laboratory staff and infrastructure, making them unsuitable for primary health care (PHC).

The overall aims for this project are to:

1. Accelerate the introduction/adoption of TB diagnostic tools and test combinations at PHC, for the timely detection of TB and improved linkage to treatment
2. Develop conditions for sustainable and equitable access to TB diagnostics tools and test combinations within PHC,
3. Strengthen global alliances and national partnerships to enable scale-up.

   The study is split into two major Phases. This application is focused on Phase 1. Specific Phase 1 objectives are to:
4. Evaluate the performance of selected TB diagnostic tools, and
5. Identify TB test combinations that increase the proportion of people diagnosed with bacteriologically confirmed TB.

Methods in Brief: Activities will be conducted in Bangladesh, Brazil, Kenya, Cameroon, Malawi, Nigeria, and Vietnam.

Each country will study selected priority populations at risk of TB, including adults attending PHC centers and district hospitals; people living with HIV (PLHIV); marginalized populations (internally displaced, refugees and pastoralists), and children. Activities within countries will use standardized protocols for evaluating diagnostic tests and combinations.

Detailed description: Tuberculosis (TB) is second only to the coronavirus infectious disease 2019 (COVID-19) as a single-species cause of adult infectious death worldwide1. Nearly four of the 10.6 million people estimated to develop TB each year are not diagnosed or treated. Moreover, an estimated 1.6 million people died of TB in 2021, with the large gap between TB diagnosis and treatment being a major contributor to mortality1-4. The World Health Organisation (WHO) has identified 30 high TB burden countries (TB burden, HIV-associated TB burden, multi-drug resistant/rifampicin resistant-TB) that are predominately low- or low-to-middle income, and together accounted for 86-90% of the estimated global TB incidence in 20191. Within these countries, and globally, TB disproportionally affects the poor, and most of the 'missed' cases occur among populations with limited access to healthcare (men, people living with HIV, residents of rural and remote settings and informal urban settlements and displaced populations5 and in children6.

The WHO End TB Strategy calls for a 90% reduction in TB deaths by 2030 compared to 2015, an 80% reduction in estimated TB incidence, and elimination of household catastrophic costs due to TB. Unfortunately, the 2021 WHO Global TB Report shows that we are very far from achieving these targets, and they will likely not be met without a step-change in efforts to improve early diagnosis and treatment of TB. Moreover, the COVID-19 pandemic severely disrupted TB diagnosis and treatment programs, hindering efforts to eliminate TB as a public health issue, and the ramifications of the pandemic are likely to be experienced by fragile health systems for many years7. New approaches to facilitate access to same-day, same-setting diagnosis and treatment of TB are urgently required.

TB detection in adults is mainly dependent upon passive case finding (PCF), requiring individuals to visit health facilities, be asked by health workers whether they have symptoms consistent with TB, and subsequently tested for TB. Only some countries use active case finding (ACF) and intensified case funding (ICF) as a complementary measure 8,9. However, this approach has considerable limitations. Exit interviews at clinics and simulated patient studies demonstrate that clinicians rarely ask about TB symptoms10-12, and even when patients volunteer symptoms, sputum testing is infrequently requested, and patients are often unable to produce sputum10. Thus, PCF is insufficient to identify most people with TB and needs to be supplemented with other approaches, such as intensified case finding in health facilities and ACF, which allows detection of people with infectious TB (and potentially asymptomatic TB; an estimated 50% of prevalent community cases14), speeding up diagnosis and linkage to treatment, and potentially reducing transmission. The location where people with presumptive TB are tested and the timeliness of diagnosis are also important. Approaches that rely on sputum transport networks or referral of patients to centralized laboratories often result in diagnostic delays and poor linkage to treatment, while local testing has been associated with increased numbers detected and confirmed and improved linkage to treatment15. TB diagnosis is also particularly challenging for well-defined key and vulnerable populations, including: people living in communities with very high HIV prevalence16; those living in informal urban settlements with poor access to health facilities and marginalized communities, such as refugees and nomadic groups; and in children.

Overall, for this study, countries have been selected to provide a broad representation from World Bank country development groups, global regions, covering South-East Asia, Africa, and the Americas, with a combined population of 780 million people. We have included countries with a high TB burden in the general population (Bangladesh, Brazil, Kenya, Nigeria); countries with a high burden of HIV-associated TB (Brazil, Cameroon, Kenya, Malawi, Nigeria); and countries with a high burden of drug resistant TB (Bangladesh, Nigeria, Vietnam)1. Data across partner countries, have shown that TB-affected households experienced health-related costs reaching 50% of their annual household income in Sub Saharan African countries such as Nigeria, Cameroon, Malawi and Kenya17-19. Given these findings, WHO's End TB Strategy included the goal of zero TB-affected families incurring catastrophic costs. These are defined as 20% of annual household income lost due to an episode of TB. Countries that have conducted formal patient cost surveys employing WHO tools and definitions such as Vietnam have measured catastrophic cost incurrence of 63% and 98% among drug susceptible (DS) DS-TB and multidrug resistant (MDR) MDR-TB households, respectively20. Thus, as diagnostics can play a critical role in optimizing the patient pathway, better diagnostic tools and algorithms may also positively impact performance against the End TB Strategy's socioeconomic indicator. In this project we will aim to demonstrate that combinations of current and newer TB tests can facilitate TB diagnostic testing in locations where it is not currently available; that the optimized use of tests at the point of need increases the proportion of people correctly diagnosed, increases access to TB treatment, and potentially reduces TB mortality and transmission.

The project will focus on key and vulnerable populations including in settings where TB diagnostic testing is not normally performed, and people are diagnosed clinically due to limited access to laboratory facilities. In Phase 1 we will identify new combinations of tests to provide same-day, same-setting diagnosis, and assess the feasibility of scaling-up and subsequent linkage to TB care that will be formally assessed in Phase 2 of the research.

Eligibility criteria: Inclusion Criteria for Children (1 - 15 years):

The sampling frame will consist of health-seeking children presenting at participating study site health facilities who:

* Are between 12 months and 15 years of age
* have presumptive TB based on at least one criterion among the following:

  * Persistent cough for more than 2 weeks
  * Persistent fever for more than 2 weeks
  * Recent failure to thrive (documented clear deviation from a previous growth trajectory in the last 3 months or Z score weight/age \< 2)
  * Failure of broad-spectrum antibiotics for treatment of pneumonia to improve symptoms and signs
  * Suggestive CXR features OR
  * History of contact with a person with TB and any of the symptoms listed above with a shorter duration (\< 2 weeks), if the child is HIV infected or presents with Severe Acute Malnutrition
* A parent or guardian present at the time of enrollment to provide signed informed consent and assent signed by children \> 7 years old.

Exclusion Criteria for children:

* - \> 5 days of anti-TB treatment in the last 3 months or individuals receiving TB preventive therapy
* Children \<12 months old
* Exhibiting any danger signs: Danger signs for children \< 5years: unable to eat or drink, vomiting up everything, severe dehydration, severe pallor, stridor, SpO2 \>90%, respiratory distress, seizures, profound lethargy or coma, continuously irritable, neck stiffness or bulging fontanelle, fever \>39C, severe acute malnutrition (weight-for-height in Z-score less than -3 or mid-upper arm circumference less than 115 mm.)
* Danger signs for children \>=5 years: diarrhoea with severe dehydration, severe pallor, shock (cold extremities, capillary refill time \>3 seconds, weak and fast pulse), obstructed or absent breathing, respiratory distress, central cyanosis, coma (or seriously altered level of consciousness), seizures, restless, continuously irritable, fever \>39C, severe acute malnutrition (weight-for-height in Z-score less than -3 or mid-upper arm circumference less than 115 mm.)

Inclusion criteria for adults attending stationary health facilities The sampling frame will consist of health-seeking persons presenting at participating study site health facilities who are

* Age 15+ years,
* PLHIV irrespective of their CD4 count and antiretroviral therapy (ART) status
* At risk of TB disease due to being a close contact of a person with infectious TB as defined by WHO
* People with positive WHO-recommended four-symptom screen (W4SS) or parenchymal abnormalities on chest x-ray regardless of whether they are known to be PLHIV, are known to be HIV-negative, or their HIV status is unknown
* Written informed consent and agreement to follow-up after enrolment (e.g. not planning to relocate)
* A parent or guardian present at the time of enrollment to provide signed informed consent and assent signed for those aged 15 years to age of majority.

Exclusion criteria for adults attending stationary health facilities:

* Current anti-TB treatment (counting from the third dose)
* Any anti-TB treatment within 60 days prior to enrolment
* Any TB preventive therapy within 6 months prior to enrolment.
* Exhibiting any danger signs: respiratory rate \> 30/min and/or fever \> 39°C and/or pulse rate \> 120/min and/or unable to walk.

INCLUSION CRITERIA FOR PARTICIPANTS IN REFUGEE CAMPS OR INTERNALLY DISPLACED The sampling frame will consist of health-seeking persons resident in official refugee camps who have crossed international borders from other countries; or internally displaced individuals (IDPs), defined as persons forced or obliged to flee or to leave their homes to avoid the effects of armed conflict, situations of generalized violence, violations of human rights or natural or human-made disasters, and who have not crossed an internationally recognized state border. IDPs can be recruited from refugee camps or among individuals sharing accommodation with local residents. At the time they are presenting at participating study site health facilities. The same inclusion criteria will be used, as described above for individuals attending health facilities.

EXCLUSION CRITERIA FOR PARTICIPANTS IN REFUGEE CAMPS OR INTERNALLY DISPLACED

* Current anti-TB treatment (counting from the third dose)
* Any anti-TB treatment within 60 days prior to enrolment
* Any TB preventive therapy within 6 months prior to enrolment
* Individuals who intend to leave the local area in the short term and have no means of contact.

INCLUSION CRITERIA FOR NOMADIC POPULATIONS Participants will be selected using active case finding35 consisting primarily of a series of community screening camps targeting the state's nomadic population. Nomadic populations in Nigeria are defined as a member of a groups of people who have no fixed home and move according to the seasons from place to place in search of food, water, and grazing land and are usually herders with traditional hierarchies.

The dates and locations of screening days will usually coincide with community market days, agreed upon after consultation with nomadic community leaders.

EXCLUSION CRITERIA FOR NOMADIC POPULATIONS

* Current anti-TB treatment (counting from the third dose)
* Any anti-TB treatment within 60 days prior to enrolment
* Any TB preventive therapy within 6 months prior to enrolment
* Individuals who intend to leave the local area in the short term and have no means of contact.

INCLUSION CRITERIA FOR INFORMAL SETTLEMENTS, URBAN VULNERABLE GROUPS AND THE RURAL POOR Participants will be selected using active case finding consisting primarily of a series of community screening activities targeting urban vulnerable populations (persons aged \>55 years, urban poor, economic migrants and diabetics) and the rural poor. Screening will be conducted on dates and in locations as agreed with community leaders, depending on the setting.

EXCLUSION CRITERIA FOR INFORMAL SETTLEMENTS, URBAN VULNERABLE GROUPS AND THE RURAL POOR

* Current anti-TB treatment (counting from the third dose)
* Any anti-TB treatment within 60 days prior to enrolment
* Any TB preventive therapy within 6 months prior to enrolment
* Individuals who intend to leave the local area in the short term and have no means of contact.

Primary outcomes:
measure: Primary study endpoint
timeFrame: 12 months
Secondary outcomes:
measure: Secondary study endpoint (1)
timeFrame: 2 years
measure: Secondary study endpoint (2)
timeFrame: 2 years
Other outcomes:
Locations:
Study officials:
References: