Commercial Typhoid Tests Validation Trial

Typhoid Fever Clinical Trial

Official title:

Comparative Study of Commercially Available Typhoid Point of Care Tests to Benchmark Current and Emerging Tools

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04801602
• Other study ID #: FE006
• Status: Completed
• Start date: October 25, 2020
• Est. completion date: December 31, 2021

Study information

• Verified date: May 2022
• Source: Foundation for Innovative New Diagnostics, Switzerland
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3091
• Est. completion date: December 31, 2021
• Est. primary completion date: September 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Typhoid Fever

Intervention

Diagnostic Test:
• Rapid diagnostic tests
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.

Locations

Country	Name	City	State
Kenya	KEMRI	Nairobi
Pakistan	Aga Khan University	Karachi	Sindh

Sponsors (2)

Lead Sponsor	Collaborator
Foundation for Innovative New Diagnostics, Switzerland	Department for International Development, United Kingdom

Countries where clinical trial is conducted

Kenya,  Pakistan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	Estimates of sensitivity and specificity will be calculated based on the definitions; 95% confidence intervals will be calculated using Wilson's score method.	6-10 months
Secondary	Establish a biorepository of well characterized specimen collection that can be used to evaluate emerging tests.	does not require any statistical analysis	5 years
Secondary	Evaluation of operational characteristics of different RDTs including invalid and indeterminate rates	The number of indeterminate and invalid test results will be reported for each RDT, together with the relative percentage over the total number of tests performed.	6-10 months