Clinical trial NCT04801602: Commercial Typhoid Tests Validation Trial
Official title: Comparative Study of Commercially Available Typhoid Point of Care Tests to Benchmark Current and Emerging Tools
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Typhoid Fever
Keywords: Typhoid
Enteric Fever
RDTs
Widal test
Lead sponsor: Foundation for Innovative New Diagnostics, Switzerland
Sponsor class: OTHER
Collaborators: name: Department for International Development, United Kingdom
First posted: 2021-03-17
Enrollment: 3091
Sex: ALL
Minimum age (years): 2
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The trial population will be composed of adults and children suspected of typhoid between 2-65 years of age. Participants will be recruited when they present to Aga Khan University or its collection site and 3 different hospitals at Nairobi, Kenya

Brief summary: Typhoid fever (typhoid) is an enteric bacterial infection caused by Salmonella enterica serovar Typhi (Salmonella Typhi; S. Typhi). It is one of the most common bacterial causes of acute febrile illness in the developing world, with an estimated 10.9 million new cases worldwide and 116.8 thousand deaths in 2017. Like many febrile illnesses, typhoid presents with non-specific symptoms and signs, especially in its early stages. In routine healthcare settings in low- and middle-income countries (LMIC), typhoid fever is commonly suspected and treated empirically with antibiotics. This overuse of antibiotics creates a selective pressure for the development of antimicrobial resistance (AMR), that has resulted in the emergence and spread of typhoid strains that are resistant to all first-line antibiotics. Similarly, the low specificity of current rapid diagnostic tests (RDTs) can lead to an over diagnosis of typhoid fever that may result in the overuse of antibiotics and delay the proper treatment for underlying conditions. FIND in collaboration with international typhoid experts developed a target product profile outlining the ideal characteristics of point of care tests. As part of this activity it became apparent that no quality data are available that systematically compare all available commercially point of care tests against the same set of reference standards used in multiple populations (e.g. Africa vs Asia). This lack of benchmarking data significantly impedes health provider's ability to decide on the utility of commercial tests in different settings, ultimately restricting use and access. Further the lack of well characterized samples reduces the ability for targeted innovation in the typhoid space.

The current study aims to benchmark different commercial typhoid tests against a defined reference standard applied in multiple population and simultaneously develop a sample set that can be used in future evaluations of emerging technologies and/or to support innovative test development.

Detailed description: Typhoid is an enteric disease caused by the bacterium Salmonella Typhi; it is estimated that 11 to 20 million people contract typhoid each year and 128 000 to 161 000 die from the disease; children under 5 are at higher risk of contracting the disease.

Typhoid endemic areas are located mainly in South Asia and Sub-Saharan Africa and is transmitted through contaminated water and food. The disease is treatable with a specific antibiotics regimen, however antimicrobial resistance has been reported in several countries, particularly in Pakistan.Several vaccines have been developed but their uptake has been low, partly due to limited information on the exact burden of the disease in endemic countries.

The symptoms of typhoid are similar to other undifferentiated febrile illnesses and typhoid can be mistaken with vector borne febrile illnesses such as scrub typhus.

Blood and bone marrow cultures are considered the gold standard for the diagnosis of typhoid. Those methods require specific infrastructure and skilled staff that are not always available in LMICs and are not adequate for rapid patient management. In addition, although very specific, blood culture sensitivity is impacted by misuse of antibiotics that lower the bacterial load to undetectable levels in patients' blood.

As a consequence, alternatives to blood culture have been used in LMIC. The Widal test is the most used test despite a low performance (sensitivity range: 57-34%; specificity range: 43-83%;reported in several studies. Other options in typhoid diagnosis are rapid diagnostic tests; among them, three tests (Typhidot, Tubex and Test-it™ Typhoid IgM) have been evaluated in several studies. It has been reported a variability of tests performance in different studies and according to the geographical regions. Variability in the test performance reported so far in the literature has hampered WHO to recommend any of these rapid tests in the EDL. FIND in collaboration with international typhoid experts developed a target product profile outlining the ideal characteristics of point of care tests. As part of this activity it became apparent that no quality data are available that systematically compare all available commercially point of care tests against the same set of reference standards used in multiple populations (e.g. Africa vs Asia). These lack of benchmarking data significantly impedes health providers' ability to decide on the utility of commercial tests in different settings, ultimately restricting use and access. Further the lack of well characterized samples reduces the ability for targeted innovation in the typhoid space. A second gap that was identified was the lack of a simple well-performing gold standard suggesting Latent class modelling as a solution used for other pathogens with an imperfect gold standard.

The current study aims to benchmark different commercial typhoid tests against a defined reference standard applied in multiple population and simultaneously develop a sample set that can be used in future evaluations of emerging technologies and/or to support innovative test development.

Eligibility criteria: Inclusion Criteria:

* - Individuals aged 8 years of age to 65 years of age
* Body weight equals to or more than 8kgs
* History of fever or axillary temperature of \>37.50C for at least 3 consecutive days within the last 7 days prior to enrolment
* Clinical suspicion of enteric fever
* One of the following scenarios:

  * Presents to outpatient department or Emergency Department
  * Admitted to hospital within last 12 hours
* Able and willing to provide informed consent (and assent when required)

Exclusion Criteria:

* Unwillingness to participate in the study

  * Inability to provide the required volume of blood
  * Unwillingness to provide blood
  * Known non-infectious / Non typhoid Infectious causes of fever or other alternate diagnosis of fever
  * Taking anticoagulant drugs
  * Unconscious

Primary outcomes:
measure: To evaluate different RDTs that are commercially available internationally for detecting antigens or antibodies to Salmonella Typhi and use blood culture as standard for comparison.
timeFrame: 6-10 months
Secondary outcomes:
measure: Establish a biorepository of well characterized specimen collection that can be used to evaluate emerging tests.
timeFrame: 5 years
measure: Evaluation of operational characteristics of different RDTs including invalid and indeterminate rates
timeFrame: 6-10 months
Other outcomes:
Locations:
city: Nairobi
country: Kenya
facility: KEMRI
city: Karachi
country: Pakistan
facility: Aga Khan University
state: Sindh
Study officials:
affiliation: AKU
name: Rumina Hasan, M.D
role: PRINCIPAL_INVESTIGATOR
affiliation: Kenya Medical Research Institute
name: Robert S Onsare, PhD
role: PRINCIPAL_INVESTIGATOR
References: